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Department of Pharmacology, Shiga University of Medical Science, Seta, Otsu, Japan (N.T., K.A., T.O.); and Toyama Institute for Cardiovascular Pharmacology Research, Azuchi-machi, Chuo-ku, Osaka, Japan (N.T.)
Abstract I. Introduction II. Endothelium-Derived Relaxing Factor and Angiotensin: Synthesis and Mechanisms of Action on Blood Vessels A. Nitric Oxide B. Prostaglandin I2 (Prostacyclin) C. Endothelium-Derived Hyperpolarizing Factor D. Angiotensin III. Angiotensin-Induced, Endothelium-Derived Relaxing Factor-Mediated Vasodilatation A. Angiotensin II-Induced Vasodilatation 1. In Vitro Studies. 2. Studies on Gene-Targeted Mice. 3. In Vivo Studies. 4. Involvement of Angiotensin II Receptors Other Than Angiotensin Receptor Type 2. B. Angiotensin III [Angiotensin-(2-8)]-Induced Vasodilatation C. Angiotensin-(1-7)-Induced Vasodilatation D. Angiotensin IV [Angiotensin-(3-8)]-Induced Vasodilatation IV. Radical Oxygen Species Production Stimulated by Angiotensin II V. Vasodilatation Induced by Angiotensin I-Converting Enzyme (Kininase II) Inhibitors Associated with Endothelial Nitric Oxide via Bradykinin A. Human Studies VI. Mechanisms Underlying Vasodilatation Induced by Angiotensin Receptor Type 1 Blockade VII. Interaction between Endothelial Nitric Oxide and Angiotensin II in Patients and Healthy Subjects A. Coronary Blood Flow Response B. Renovascular Response C. Forearm and Other Regional Blood Flow Responses D. Blood Pressure Response E. Other Responses VIII. Interaction between Endothelial Nitric Oxide and Angiotensin II in Experimental Animals A. Systemic Blood Pressure B. Regional Blood Flow C. Renal Vasculature 1. In Vivo Study in Rats. 2. In Vivo Study in Mice. 3. In Vivo Study in Dogs, Sheep, Pigs, and Rabbits. 4. In Vitro Study. D. Coronary Vasculature and the Heart 1. Coronary Vasculature. 2. Myocardium. E. Cerebral Vasculature F. Pulmonary Vasculature G. Mesenteric Vasculature H. Placental and Uterine Vasculatures I. Other Vasculatures J. Kidney 1. Renal Function a. Studies in rats. b. Studies in dogs and rabbits. 2. Renin. K. Other Organs and Tissues
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I. Introduction |
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), was identified to be nitric oxide (NO) by three different groups, Furchgott (1988), Ignarro et al. (1987), and Palmer et al., (1987). Introduction of NO synthesis inhibitors (Palmer et al., 1988) greatly contributed to clarifying the physiological roles of NO not only in the vasculature but also in the central and peripheral nervous systems, immune system, and other miscellaneous biological reactions. NO is now regarded as an intercellular messenger or transmitter that plays a pivotal role in circulatory regulations, including vasodilatation, increased blood flow, lowered systemic blood pressure, and inhibitions of platelet aggregation and adhesion, leukocyte adhesion and transmigration, smooth muscle proliferation, and low-density lipoprotein oxidation.
Angiotensin (ANG) II has long been known to be an intense vasoconstrictor peptide that is responsible for hypertension, decreased regional blood flow, impaired renal function, atherosclerosis, and cardiac hypertrophy. Therefore, suppression of the renin-ANG system is quite an important strategy for preventing and treating cardiovascular dysfunction, particularly essential hypertension. From the early period of NO discovery, counteracting the effects of endogenous NO on ANG II has been a major concern of cardiovascular researchers and clinicians. Recent studies have revealed that members of the ANG family have different hemodynamic actions and that the various ANG II receptor subtypes contribute to heterogeneous actions on blood vessels. ANG II acts directly on its type 1 (AT1) receptors to cause vascular smooth muscle contraction and also elicits vasoconstriction indirectly by forming reactive oxygen species (ROS) that scavenge NO. Imbalanced functioning of NO and ANG II in vasculatures is considered to be one of the important pathogenic factors in cardiovascular disease. Therefore, in addition to simply reducing the synthesis of ANG II by ANG I-converting enzyme (ACE) inhibition or inhibiting the action of ANG II on AT1 receptors responsible for vasoconstriction, important pharmacological strategies for treatment of essential hypertension include increased availability of counteracting vasodilators. Besides NO, prostaglandin (PG) I2 formed in endothelial cells (Weksler et al., 1977) and endothelium-derived hyperpolarizing factors (EDHF) (Chen et al., 1988) also play roles in cardiovascular physiology and pathophysiology.
This review article covers areas of research about the interactions between EDRF, mainly endothelial NO, and ANG in the circulation in reference to the mechanisms underlying actions of the ANG family on EDRF release and superoxide generation and those of ACE inhibitors and ANG receptor blockers in various vascular beds of humans in health and disease as well as in those of experimental animals.
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II. Endothelium-Derived Relaxing Factor and Angiotensin: Synthesis and Mechanisms of Action on Blood Vessels |
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NO is produced when L-arginine is transformed to L-citrulline by catalysis of nitric-oxide synthase (NOS) in the presence of O2 and the cofactors NADPH, tetrahydrobiopterin, calmodulin, heme, FAD, and FMN. Ca2+ is required for the activation of neuronal NOS (nNOS, NOS I) and endothelial NOS (eNOS, NOS III) but not inducible or immunological NOS (iNOS, NOS II). nNOS, mostly a soluble enzyme, is constitutively expressed in the brain, peripheral nerves, including parasympathetic postganglionic nerves innervating blood vessels (nitrergic nerve), and kidneys (Bredt et al., 1990). eNOS is also constitutively expressed mostly in particulate fractions of the endothelial cell (Förstermann et al., 1991). iNOS is not constitutively expressed but is induced mainly in macrophages with bacterial lipopolysaccharide and cytokines.
eNOS binds to caveolin-1 in the caveolae, microdomains of the plasma membrane. Caveolin-1 inhibits eNOS activity, and this interaction is regulated by Ca2+/calmodulin (Michel et al., 1997). eNOS intracellularly migrates in response to increased cytosolic Ca2+ in the presence of calmodulin (Fig. 1) and becomes activated for NO synthesis. The transmembrane influx of Ca2+ and its mobilization from intracellular storage sites are caused by stimulation of drug receptors, such as muscarinic, bradykinin, and ANG receptors, located on the endothelial cell membrane or by mechanical stimuli, such as shear stress and vascular smooth muscle stretch. Recent studies have provided a novel hypothesis that shear stress, bradykinin, or insulin induce the phosphorylation of Ser1177/1179 of eNOS through phosphatidylinositol-3 kinase and the downstream serine/threonine protein kinase Akt (protein kinase B), resulting in enhanced NO formation (Dimmeler et al., 1999; Fulton et al., 1999). This mechanism does not require the increase in intracellular Ca2+ for NO production (Fig. 1).
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The synthesis of NO by NOS isoforms is inhibited by L-arginine analogs, including NG-monomethyl-L-arginine (L-NMMA), NG-nitro-L-arginine (L-NA), NG-nitro-L-arginine methyl ester (L-NAME), and asymmetric dimethylarginine (ADMA) (Vallance et al., 1992). 7-Nitroindazol is one of the most promising nNOS inhibitors so far introduced (Moore et al., 1993).
NO or nitrovasodilators activate soluble guanylyl cyclase and produce cyclic GMP from GTP in smooth muscle cells. Methylene blue, hemoglobin, and 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (Garthwaite et al., 1995) inhibit the guanylyl cyclase activity. Accumulation of cyclic GMP causes activation of cyclic GMP-dependent protein kinase that is involved in the reduction of intracellular Ca2+ and a decrease in the sensitivity of contractile elements to Ca2+. Cyclic GMP is degraded by phosphodiesterase type-5 to 5'-GMP.
B. Prostaglandin I2 (Prostacyclin)
The PG family, including PGI2, is synthesized from arachidonic acid formed from phospholipids through phospholipase A2. Cyclooxygenase synthesizes PG endoperoxides from arachidonic acid, and its activity is inhibited by aspirin, indomethacin, ibuprofen, and other nonsteroidal anti-inflammatory drugs. An enzyme that transforms PG endoperoxides to PGI2 was found in microsomes prepared from the aorta (Moncada et al., 1976) and in cultured endothelial cells (Weksler et al., 1977). Activation of receptors by agonists or mechanical stress applied to the endothelial cell membrane leads to transmembrane Ca2+ influx; the cations activate phospholipase A2 to form arachidonic acid, thus increasing the PGI2 synthesis (Fig. 1). PGI2 liberated from endothelial cells binds to prostacyclin receptors located in muscle cell membranes, activates adenylyl cyclase, and stimulates cyclic AMP production, resulting in vascular smooth muscle relaxation.
C. Endothelium-Derived Hyperpolarizing Factor
Endothelium-dependent vasodilatation is not always blocked by inhibitors of NOS and cyclooxygenase. Chen et al. (1998) found that acetylcholine (ACh) elicited relaxation and hyperpolarization of muscle cell membranes in the rat aorta and pulmonary artery with intact endothelium. The mechanical response was abolished by hemoglobin and methylene blue without any effect on hyperpolarization, suggesting that ACh releases two different substances, NO and EDHF, from endothelial cells. The electrical and mechanical responses mediated by EDHF are blocked by treatment with K+ channel inhibitors or exposure to high K+ media. Ca2+-activated K+ channels seem to play a major role in hyperpolarization that is responsible for muscle relaxation (Fig. 1). Although different mechanisms of action of EDHF are reported in a variety of blood vessels, there is still considerable debate regarding the nature of EDHF (Busse et al., 2002; Triggle et al., 2002).
ANG II, the most active ANG peptide, is derived from angiotensinogen in two enzymatic steps. First, renin cleaves the decapeptide ANG I from the amino terminus of angiotensinogen (renin substrate). Then ACE removes the carboxy-terminal dipeptide of ANG I to produce the octapeptide ANG II. ANG II is degraded subsequently by peptidases to yield ANG III, ANG IV, and ANG-(1-7) (Haulica et al., 2005). These enzymatic steps are summarized in Fig. 2. ANG II binds to G protein-coupled receptors in cell membranes, resulting in biological actions.
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III. Angiotensin-Induced, Endothelium-Derived Relaxing Factor-Mediated Vasodilatation |
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1. In Vitro Studies.
It was demonstrated that ANG II elicited an intracellular cyclic GMP production possibly mediated by NO in murine neuroblastoma NIE-115 cells (Zarahn et al., 1992) and neuroblastoma neuro-2A cells (Chaki and Inagami, 1993). The former authors suggested that AT1 receptor-mediated mobilization of intracellular Ca2+ is involved in this response, whereas the latter authors concluded that the newly found ANG II receptor may be responsible for activation of guanylyl cyclase that is mediated by NO formed through Ca2+ influx. Porsti et al. (1993) noted ANG II-induced biphasic changes of coronary perfusion pressure in isolated perfused rabbit hearts: an initial increase was followed by a decrease, an effect that was independent of NO and PGI2. Their conclusion was that the ANG II-induced vasodilatation may reflect rapid desensitization of the arterial muscle to the vasoconstrictor effect.
Hannan et al. (2003) provided evidence that AT2 receptor-mediated inhibition of ANG II-induced contraction of rat uterine artery segments may involve NO production. Batenburg et al. (2004) concluded that AT2 receptor-mediated vasodilatation in human coronary microarteries seems to be mediated by bradykinin B2 receptors and NO. ANG II stimulates dilatation of bovine adrenal cortical arteries, possibly through endothelial cell AT2 receptor activation and NO release (Gauthier et al., 2005). Cosentino et al. (2005) suggested that the losartan-unmasked AT2 receptor-mediated vasodilatation seen in the aorta isolated from SHR may contribute to the beneficial hemodynamic effects of AT1 receptor blockade. Arun et al. (2004) noted that ANG II-induced relaxation, evident only in the presence of the AT1 blocker, was enhanced in aortic rings isolated from diabetic rats but not control rats, the response being attenuated by L-NAME or ATP-sensitive K+ channel blockers and abolished by treatment with both inhibitors. [3H]ANG II saturation binding at the AT2 receptor was enhanced in aortic membranes from diabetic rats compared with control rats. They concluded that AT2 receptor density and AT2-induced relaxations mediated by NO and ATP-sensitive K+ channels are enhanced in the diabetic rat aorta. There was evidence that ANG II evoked AT1 receptor-mediated vasoconstriction and AT2 receptor-mediated vasodilatation in isolated porcine coronary arterioles and that ANG II at a subvasomotor level impaired endothelium-dependent NO-mediated dilatation attributable to elevated superoxide production via AT1 receptor activation of NADPH oxidase (Zhang et al., 2003). In aortic rings from mice subjected to abdominal aortic banding that increased blood pressure, plasma renin levels, and AT2 receptor mRNA, the contractile response to ANG II was depressed and was restored by the AT2 receptor antagonist PD123319 or the bradykinin B2 receptor antagonist; the cyclic GMP content in aortas of banding mice was greater than that of sham-operated mice, and ANG II increased the nucleotide content only in the aorta of banding mice (Hiyoshi et al., 2004). Aortic banding seems to induce up-regulation of the AT2 receptor through increased circulating ANG II via the AT1 receptor, thereby activating a vasodilatory pathway in vessels through the AT2 receptor via the kinin/NO/cyclic GMP system. Olson et al. (2004) found that ANG II stimulated an increase in NOS mRNA, protein expression, and NO production via AT2 receptors, whereas signaling via the AT1 receptor negatively regulated NO production in pulmonary endothelial cells. According to Zhao et al. (2005), ANG II stimulates an increase in NOS mRNA levels, eNOS protein expression, and NO production via the AT2 receptor, whereas ANG II seems to down-regulate eNOS protein expression via an AT1 receptor-linked pathway involving the G
q protein/phosphatidylinositol phospholipase C/Ca2+/protein kinase C- signaling pathway in bovine pulmonary artery endothelial cells. Andresen et al. (2005) provided evidence supporting the hypothesis that AT2 receptors in rat preglomerular smooth muscle cells inhibit AT1-mediated phospholipase D activation through a NO/cyclic GMP-dependent mechanism most likely mediated by phosphorylation of RhoA at Ser188. Hiyoshi et al. (2005) noted that the mRNA levels of AT2 receptor, but not those of AT1 and bradykinin B2 receptors, and cyclic GMP levels increased in aortas from mice with two-kidney, one-clip hypertension; the aortic levels of eNOS, phosphorylated eNOS at Ser1177, total Akt, and phosphorylated Akt at Ser473 (Fig. 1) also increased. The administration of PD123319 to the hypertensive mice decreased phosphorylated eNOS and cyclic GMP to sham levels without affecting blood pressure and the levels of eNOS, Akt, and phosphorylated Akt. Therefore, it was suggested that NO production is enhanced by increased eNOS phosphorylation via the activation of AT2 receptors in the course of two-kidney, one-clip hypertension. Hill-Kapturczak et al. (1999) provided evidence that ANG II-stimulated NO release from porcine pulmonary endothelial cells is mediated, at least in part, through ANG IV and AT4 receptors.
In isolated microperfused rabbit afferent arterioles, activation of the AT2 receptor seemed to cause endothelium-dependent vasodilatation via a cytochrome P-450 pathway, possibly by epoxyeicosatrienoic acids, rather than the NO pathway (Arima et al., 1997; Kohagura et al., 2000). According to de Godoy et al. (2004), the ANG II-induced relaxation of rat anococcygeus smooth muscle seems to be mediated by stimulation of AT2 receptors and activation of the nNOS/soluble guanylyl cyclase pathway. Fukuda et al. (2005) suggested that AT2 receptors located in smooth muscle of rat aortic rings may mediate vasorelaxation via stimulation of the NO-cyclic GMP pathway, vasodilator cyclooxygenase products, and voltage-dependent and Ca2+-activated large-conductance K+ channels.
In isolated canine coronary and mesenteric arteries and monkey mesenteric arteries, ANG II-induced contractions, susceptible to the nonselective ANG II receptor antagonist saralasin, were potentiated by treatment with aspirin and indomethacin, whereas monkey and canine cerebral arterial contractions evoked by the peptide were suppressed by the cyclooxygenase inhibitors, suggesting that ANG II releases vasodilator PGs, possibly PGI2, in the peripheral arteries and vasoconstrictor PGs in cerebral arteries (Minami and Toda, 1988; Toda et al., 1990). It was not determined whether NO was also released by ANG II from these isolated arteries. Evidence for interactions between PGI2 and NO has been reported in endothelial cells. According to Hardy et al. (1998), NO-induced vasorelaxation of piglet retinal and choroidal arteries seems to be mediated by stimulating PGI2 formation of endothelial origin via a mechanism independent of guanylyl cyclase, which involves the opening of Ca2+-activated K+ channels. Niwano et al. (2003) suggested that the stable analog of PGI2 beraprost increases eNOS expression through a cyclic AMP-responsive element in human and bovine aortic endothelial cells.
2. Studies on Gene-Targeted Mice.
Siragy et al. (1999) noted that mice lacking the AT2 receptor had low basal levels of renal interstitial fluid bradykinin and cyclic GMP, an index of NO production, compared with wild type mice; in wild type, but not AT2-null mice, dietary sodium restriction or ANG II infusion increased renal interstitial fluid bradykinin and cyclic GMP. Therefore, the authors suggested that the AT2 receptor plays a counterregulatory protective role mediated by bradykinin and NO against the antinatriuretic and pressor actions of ANG II. According to Brede et al. (2003), experimental myocardial cryoinjury led to an increased heart weight/body weight ratio in AT2-deficient mice compared with control mice; expression of eNOS was lower in hearts from AT2-deficient mice, with eNOS down-regulation being accompanied by a decrease in cardiac cyclic GMP. The authors concluded that AT2 receptors seem to exert an antihypertrophic effect in cardiac remodeling after myocardial cryoinjury and link the expression of cardiac eNOS to AT2 receptor activation. In perfused carotid arteries from wild-type mice, inhibition of AT2 receptors reduced NO-mediated, flow-induced dilatation but had no effect in tissue kallikrein-deficient mice; the B2 receptor antagonist reduced the response to flow in the wild-type mice, but not in AT2-deficient mice, suggesting that the presence of functional AT2 receptors is necessary to observe the contribution of the vascular kinin-kallikrein system to flow-dependent dilatation (Bergaya et al., 2004).
Chronic infusion of ANG II into AT2-overexpression mice abolished the AT1-mediated pressor effect, which was blocked by icatibant, a B2 receptor antagonist, and L-NAME. Aortic explants from transgenic mice showed increased cyclic GMP production and diminished ANG II-induced vascular constriction, these AT2-mediated effects being abolished by removal of the endothelium or treatment with icatibant and L-NAME, suggesting that AT2 receptors in aortic smooth muscle cells stimulate the production of bradykinin, which stimulates the NO/cyclic GMP system in a paracrine manner to promote vasodilatation (Tsutsumi et al., 1999). Kurisu et al. (2003) obtained evidence from studies on AT2 receptor transgenic and wild-type mice that stimulation of AT2 receptors present in cardiomyocytes may attenuate perivascular fibrosis by a kinin/NO-dependent mechanism.
3. In Vivo Studies.
In anesthetized rats, intravenous infusion of subpressor doses of ANG II increased tissue NO concentrations in the renal medulla to a greater extent than in the renal cortex, and renal medullary interstitial infusion of L-NAME blocked ANG II-induced NO increases in the renal medulla but not in the renal cortex (Zou et al., 1998). They concluded that small elevations of circulating ANG II levels increase medullary NO production and concentration, which seem to play an important role in buffering against the vasoconstrictor effects of this peptide and in maintaining a constancy of medullary blood flow. Hennington et al. (1998) noted that in rats treated with captopril, acute suprarenal infusion of ANG II increased renal eNOS mRNA but had no effect on renal eNOS protein concentration; in contrast, chronic infusion of ANG II for 10 days had no effect on renal eNOS mRNA levels but increased eNOS protein, suggesting that ANG II can stimulate eNOS synthesis and thus may enhance NO production. Losartan prevented increased vasopressor response to ANG II in hypertensive rats, and this effect was associated with restoration of NOS mRNA expression and NOS activity; in addition, ANG II-dependent NO release in hypertensive rats was potentiated by treatment with losartan (Martinez et al., 2002).
In rat choroidal plexus, phentolamine attenuated the blood flow-lowering effect of a moderate ANG II dose and unmasked the vasodilator actions of the peptide at high concentrations; in L-NAME-treated rats, high ANG II lowered blood flow and increased vascular resistance, indicating that choroidal vasodilator actions of ANG II may be mediated by NO derived from the endothelium and nitrergic nerves (Chodobski et al., 1999). In newborn pigs equipped with a closed cranial window, the AT2 receptor agonist CGP 42112A induced vasodilatation associated with elevated cyclic GMP in artificial cerebrospinal fluids, both of which were blocked by L-NA, indicating that stimulated NO release may contribute to AT2-induced vasodilatation (Baramov and Armstead, 2005). Lambers et al. (2000) found that in nonpregnant sheep treated with an AT1 receptor antagonist, vasodilatation was induced by intra-arterial infusion of ANG II in the uterine artery, which was reversed by administration of the AT2 receptor antagonist or by L-NAME, suggesting that the AT2 receptor subtype may modulate uterine vascular responses to ANG II potentially by release of NO. In anesthetized pigs, the baseline output of jejunal luminal NO correlated to baseline mucosal iNOS protein content, and treatment with the AT2 agonist CGP 42112A increased luminal NO output, with the agonistic action being reversed by the AT2 receptor antagonist, suggesting an involvement of AT2 receptors in increasing the luminal NO output (Ewert at al., 2003).
4. Involvement of Angiotensin II Receptors Other Than Angiotensin Receptor Type 2.
A number of reports in the literature so far have suggested the involvement of AT2 receptors in the ANG II-induced release of NO from the endothelium. However, evidence against this hypothesis has also been reported. McLay et al. (1995) indicated that the ANG II-induced increase in NO production in primary cultures of human proximal tubular cells may not be mediated by AT1 and AT2 receptors but are instead mediated by a novel, as yet unidentified, ANG receptor. Saito et al. (1996) provided evidence that ANG II stimulates NO release by activation of Ca2+/calmodulin-dependent constitutive NOS via AT1 receptors in cultured bovine endothelial cells. Patzak et al. (2004) also suggested an ANG II-induced NO release in afferent arterioles isolated from mice, which is mediated by AT1 receptor subtypes. Sarkis et al. (2003) demonstrated that in anesthetized Lyon rats, after i.v. ANG II, the initial renal medullary vasoconstriction was followed by a long-lasting vasodilatation and that blockade of AT1 receptors abolished all the effects of ANG II, whereas AT2 receptor blockade did not change these effects. Furthermore, indomethacin decreased the medullary vasodilatation induced by low doses of ANG II, and, in contrast, L-NAME and the bradykinin B2 receptor antagonist lowered the medullary vasodilatation at the high doses of ANG II. It seems that AT1 receptor-mediated medullary vasodilator response to low doses of ANG II is mainly due to the release of PGs, whereas the dilator response to high doses has additional NO- and kinin-dependent components. Losartan had no effect on basal ovarian blood flow in rats but blocked the ANG II-induced flow reduction, and, in contrast, the AT2 receptor antagonist PD123319 increased ovarian basal blood flow and failed to reverse the effect of exogenous ANG II, indicating that under physiological conditions, ovarian blood flow of the rat is negatively regulated by ANG II through AT2 receptors (Mitsube et al., 2003). Bayraktutan and Ulker (2003) suggested that ANG II stimulates NO production in rat coronary microvascular endothelial cells in both an AT1- and AT2-receptor-regulated manner.
Heinemann et al. (1997) noted that intravenous injections of ANG II increased blood pressure, which was accompanied by a decrease in blood flow through the superior mesenteric artery and an increase in femoral blood flow, possibly due to vasodilatation; telmisartan prevented all of the hemodynamic responses, and the ANG II-evoked femoral vasodilatation was suppressed by L-NAME. The femoral vasodilator response to ANG II depended on the increase in vascular perfusion pressure, because vasodilatation was reversed to vasoconstriction when blood pressure remained constant. These results demonstrate that the effects of ANG II to increase systemic blood pressure and the resulting rise of perfusion pressure in the femoral artery stimulate the formation of NO and thereby dilate the femoral arterial beds.
B. Angiotensin III [Angiotensin-(2-8)]-Induced Vasodilatation
ANG III as well as ANG I, II, IV, and ANG-(1-7) increased nitrite release from microvessels or large coronary arteries isolated from the canine heart, the effect being blocked by L-NAME, HOE-140, and protease inhibitors, suggesting that formation of NO from coronary arteries and microvessels in response to ANG peptides is due to the activation of local kinin production in the coronary vascular wall (Seyedi et al., 1995). These results indicated the involvement of AT1 and AT2 receptors in the ANG III-induced NO release. Li et al. (1995) found that in rat aortic rings, concentration-contractile response curves of ANG II, III, and IV were shifted to the right by losartan; however, PD123177 shifted left-ward only the curve of ANG III and destruction of the endothelium or incubation with L-NMMA enhanced the contractile response to all three peptides. ANG III seems to release NO from the aortic endothelium through activation of AT2 receptor subtypes.
In the conscious rabbit, intravenous boluses of ANG III produced a pressor followed by a depressor response; losartan blocked both responses, whereas PD123319 had no effect on either element of the response, leading to a conclusion that the depressor effect is mediated by AT1 receptors and there is no indication that AT2 receptors could be involved (Rowe and Dixon, 2000).
C. Angiotensin-(1-7)-Induced Vasodilatation
This peptide is a bioactive component of the renin-angiotensin system that is endogenously formed by several endopeptidases and carboxypeptidases from either ANG I or ANG II (Benter et al., 1993; Erdos et al., 2002; Ferrario and Chappell, 2004). Ferrario et al. (2005) found a role for ACE2 in ANG-(1-7) formation from ANG II in the kidney of normotensive rats and found that renal cortex ACE2 activity was augmented in rats medicated with lisinopril or losartan. Because plasma levels of ANG-(1-7) are elevated during ACE inhibition or AT1 blockade (Fig. 2), part of the effects of therapeutics that inhibit ACE activity and block AT1 receptors may be mediated through ANG-(1-7) (Iyer et al., 2000; Ferrario and Chappell, 2004; Igase et al., 2005). ANG-(1-7) is expected to act as a counteracting factor for the vasoconstrictor effects of ANG II (Haulica et al., 2005).
ANG-(1-7) may oppose the actions of ANG II directly or as a result of increasing NO or PGs (Chappell et al., 1998). In feline hindquarters and mesenteric vascular beds, injections of ANG-(1-7) caused vasodilatation or modest vasoconstriction, depending on the dose; the vasoconstriction was blocked by an AT1 receptor antagonist but not by a cyclooxygenase inhibitor, and the vasodilatation was partially attenuated by L-NAME (Osei et al., 1993). ANG-(1-7)-induced relaxation of porcine coronary artery rings was endothelium-dependent and suppressed by L-NA but was not affected by AT1 or AT2 receptor blockade or cyclooxygenase inhibition, suggesting that the relaxation to this peptide is mediated by the release of NO from the endothelium through activation of an, as yet unidentified, ANG receptor (Porsti et al., 1996). Similar results were also obtained in canine coronary arteries (Brosnihan et al., 1996). There was evidence supporting the hypothesis that ANG-(1-7) acts as a local synergistic modulator of kinin-induced vasodilatation by inhibiting ACE and releasing NO (Li et al., 1997). There was evidence suggesting that the AT2 receptor mediates ANG-(1-7)-induced relaxation of porcine coronary arteries associated with NO and kinins (Gorelik et al., 1998). It was suggested that the antiangiogenic effect of ANG-(1-7) in the mouse sponge model of angiogenesis is associated with NO release by activation of an ANG receptor distinct from AT1 and AT2 (Machado et al., 2001). In preexisting (skin) and newly formed vasculature (14-day-old polyurethane sponge implants) in mice, ANG-(1-7)-induced vasodilator effects was prevented by the specific receptor antagonist (D-Ala7)-ANG-(1-7) and abolished by NOS inhibitors, suggesting that this peptide contributes to the vasodilatation via NO also in newly formed vascular beds (Machado et al., 2002). ANG-(1-7) and AVE 0991 released NO and superoxide anions from bovine aortic endothelial cells, the effect being inhibited by a selective ANG-(1-7) antagonist, and an AT2 antagonist inhibited AVE 0991-stimulated NO production but had no inhibitory effect on superoxide production (Wiemer et al., 2002).
Santos et al. (2003) demonstrated that genetic deletion of the G-protein-coupled receptor encoded by the Mas protooncogene abolished the binding of ANG-(1-7) to mouse kidneys and that Mas-deficient aortas lost the ANG-(1-7)-induced relaxant response, thus identifying Mas as a functional receptor for ANG-(1-7). Lemos et al. (2005) obtained results showing that ANG-(1-7) and AVE 0991, a nonpeptide mimetic of the effects of ANG-(1-7), produced an NO-dependent vasodilator effect in the mouse aorta that is mediated by the G protein-coupled receptor Mas. In the presence of losartan, ANG-(1-7) induced a decrease in perfusion pressure of isolated, perfused mouse hearts, which was blocked by the Mas antagonist A-779, indomethacin, and L-NAME; in contrast, in the presence of PD123319, ANG-(1-7) increased the perfusion pressure, suggesting that ANG-(1-7) produces complex vascular effects in isolated mouse hearts involving interaction of its receptor with AT1- and AT2-related mechanisms, leading to the release of NO and PGs (Castro et al., 2005). From studies on ANG-(1-7) receptor Mas-knockout mice and on Mas-transfected mice, Pinheiro et al. (2004) provided evidence that AVE 0991 is a Mas receptor agonist and that the antidiuretic effect of AVE 0991 is mediated by AT2 and AT1 receptors, and NO release from Mas-transfected Chinese hamster ovary cells is mediated by ANG-(1-7) receptors.
On the other hand, Sasaki et al. (2001) provided evidence that ANG-(1-7)-evoked vasodilatation was independent of NO synthesis in forearm circulation of normotensive subjects and patients with essential hypertension. It was suggested that in rat aortic rings, ANG-(1-7) elicits an endothelium-dependent antagonism of ANG II, which involves AT2 and ANG-(1-7) receptors but is independent of NO production (Roks et al., 2004). There is evidence for the involvement of PGs in the vascular actions of ANG-(1-7). In SHR treated with either lisinopril or losartan or a combination of both drugs, neutralization of circulating ANG-(1-7) by monoclonal antibody and CGS 24592, a blocker of ANG-(1-7) formation, resulted in an increase in blood pressure, and indomethacin increased blood pressure to an extent similar to that of CGS 24592, suggesting that vasodilatory PGs mediate the antihypertensive effects of endogenous ANG-(1-7) in lisinopril/losartan therapy (Iyer et al., 2000). Tallant and Clark (2003) also suggested that ANG-(1-7) inhibits vascular growth through the release of PGI2, through the PGI2-mediated production of cyclic AMP, and activation of cyclic AMP-dependent protein kinase. In SHR treated with L-NAME, ANG-(1-7) attenuated development of severe hypertension and endorgan damage; PGs seemed to participate in the hypotensive and cardioprotective effects of this peptide (Benter et al., 2006).
Gironacci et al. (2004a,b) noted that in hypothalami isolated from aortic coarcted hypertensive rats or SHR, ANG-(1-7) diminished the K+-evoked norepinephrine release and blocked the ANG II-enhanced amine release induced by K+, the responses being prevented by an ANG-(1-7) specific antagonist, AT2 receptor antagonist, B2 receptor antagonist, L-NAME, and soluble guanylyl cyclase inhibitor as well as by a cyclic GMP-dependent protein kinase inhibitor. They concluded that ANG-(1-7) decreases norepinephrine release from the hypothalamus via the ANG-(1-7) or AT2 receptors, acting through a bradykinin/NO-mediated mechanism that stimulates cyclic GMP/protein kinase signaling; thus, this peptide may decrease sympathetic nervous system activity and exert an antihypertensive effect.
D. Angiotensin IV [Angiotensin-(3-8)]-Induced Vasodilatation
The hexapeptide ANG IV is an active metabolite of ANG II. In the rat subjected to experimental subarachnoid hemorrhage, ANG IV increased cerebral blood flow, and this effect was not influenced by pretreatment with saralasin or an NOS inhibitor (Naveri et al., 1994). Naveri (1995) suggested that ANG IV increased cerebral blood flow after subarachnoid hemorrhage, possibly by dilating cerebral vessels through stimulation of the AT4 receptor but not the release of NO. In contrast, Kramar et al. (1998) noted that in anesthetized rats, the ANG IV-induced increase in cerebral blood flow was blocked by pretreatment with L-NAME and thus suggested that cerebral vasodilatation is dependent upon the synthesis and release of NO from the endothelium. There are many reports in the literature supporting the involvement of NO in ANG IV-induced vasodilatation. From incubated canine large coronary arteries and coronary microvessels, ANG I, II, III, IV, and ANG-(1-7) increased the release of nitrite, and this effect was blocked by L-NAME and HOE-140; only AT2 receptors mediated nitrite release after ANG IV, whereas AT1 and AT2 receptors were involved in the release of nitrite in response to other ANGs (Seyeki et al., 1995). In the isolated perfused rat lung, ANG IV showed vasoconstrictor activity that was decreased by an AT1 receptor antagonist and enhanced by L-NAME and meclofenamate, suggesting that responses to ANG IV are modulated by the release of NO and vasodilator PGs (Nossaman et al., 1995). A similar conclusion was also obtained in the renal vascular response, since in anesthetized SHR and normotensive rats, intrarenal infusion of ANG IV produced biphasic vasoconstrictor responses: a rapid, transient response followed by a sustained lesser level of vasoconstriction; the initial response was enhanced by L-NAME but not affected by indomethacin, and the simultaneous administration of these inhibitors resulted in a greater sustained level of vasoconstriction, which was inhibited by losartan (Yoshida et al., 1996). Coleman et al. (1998) noted that intrarenal infusions of ANG IV produced an increase in renal cortical blood flow without altering systemic blood pressure, and divalinal ANG IV, an AT4 receptor antagonist, or L-NMMA completely blocked the effect of ANG IV, suggesting that ANG IV exerts a unique influence upon renal hemodynamics via the AT4 receptor subtype that is responsible for the release of NO. In porcine pulmonary arterial endothelial cells, ANG IV increased eNOS activity as well as cellular cyclic GMP content, and divalinal ANG IV, but not saralasin, losartan, or PD12377, inhibited the effects of ANG IV (Patel et al., 1998). L-NAME or methylene blue but not indomethacin diminished ANG IV-stimulated levels of cyclic GMP. Collectively, ANG IV seems to bind to AT4 receptors, activates eNOS, stimulates cyclic GMP accumulation in endothelial cells, and causes pulmonary arterial vasodilatation. It is likely that ANG IV-mediated activation of eNOS is regulated by intracellular Ca2+ mobilization and by increased expression of the Ca2+ binding protein calreticulin (Patel et al., 1999) and that intracellular Ca2+ is mobilized through receptor-coupled G-protein/phospholipase C/PI3/kinase signaling mechanisms (Chen et al., 2000).
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IV. Radical Oxygen Species Production Stimulated by Angiotensin II |
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) noted that the free radical scavengers superoxide dismutase (SOD), catalase, SOD-catalase, and dimethyl sulfoxide inhibited vascular hyperpermeability and endothelial and smooth muscle cellular damage in intestinal small arteries from rats made acutely hypertensive with ANG II infusions and suggested that free radicals play a role in the pathogenesis of hypertensive vascular disease. NADPH oxidase was found to be a major source of superoxide anions detected by lucigenin-elicited chemiluminescence in bovine coronary artery endothelium (Mohazzab et al., 1994). Infusion of ANG II increased systemic blood pressure and doubled vascular superoxide anion production predominantly from the vascular media in rats; the predominant source of superoxide was thus suggested to be an NADH/NADPH-dependent, membrane-bound oxidase (Rajagopalan et al., 1996). ANG- but not norepinephrine-induced hypertension was associated with impaired relaxations to ACh and nitroglycerin; these relaxations were corrected by SOD, and losartan normalized the superoxide production and the relaxations, suggesting that AT1 receptor stimulation increases superoxide production via NADH/NADPH oxidase activation (Fig. 1). The acute superoxide-producing effect is likely to be specific to ANG II in the rat mesenteric microcirculation (Kawazoe et al., 1999). Infusion of ANG II into rats for 7 days increased ROS in tubular cells of the kidney and stimulated protein expression of p27 (Kip1), an inhibitor of cyclin-dependent kinases, and the radical scavenger dimethylthiourea abolished this protein expression, indicating that ANG II seems to induce p27 expression in vivo that is mediated by ROS (Wolf et al., 2001). Superoxide anions depressed the modulatory influence of endogenous NO on ANG II-induced afferent arteriolar constriction in rats with insulin-dependent diabetes mellitus (Schoonmaker et al., 2000).
In early renovascular hypertension in pigs, increases in plasma renin activity and arterial pressure were associated with increased systemic oxidative stress (Lerman et al., 2001). There was evidence that ANG II at a subpressor level impaired endothelium-dependent NO-mediated dilatation in isolated porcine coronary arterioles, and this action was attributable to elevated superoxide production via AT1 receptor activation by NADPH oxidase (Zhang et al., 2003). In the anesthetized SHR, tempol, a membrane-permeable mimetic of SOD, given in the drinking water decreased arterial pressure and increased renal medullary blood flow without altering total renal blood flow and attenuated the ANG II-induced decrease in medullary blood flow but not that in renal blood flow, suggesting that tempol enhances vasodilator mechanisms of the medullary circulation, possibly by interacting with the NO system (Feng et al., 2001). Shinozaki et al. (2004a,b) noted that losartan normalized blood pressure, NADPH oxidase activity, endothelial function, and ANG II-induced vasoconstriction in fructose-fed mice that were made insulin resistant. In addition, expression of AT1a receptor mRNA was enhanced in fructose-fed mice and NADPH oxidase protein expression was increased in these animals, whereas the expression was decreased in fructose-fed, AT1a knockout mice.
In anesthetized rabbits, topical application of ANG II inhibited vasodilatation of cerebral arterioles to the endothelium-dependent agonist bradykinin, and a superoxide scavenger and an inhibitor of NADPH oxidase (diphenylene iodonium) prevented the inhibitory effect, implicating the superoxide-mediated vascular dysfunction by ANG II (Didion and Faraci, 2003). Rugale et al. (2005) found that enalapril and the NADPH oxidase inhibitor apocynin reduced the overproduction of superoxide anions by rat left ventricle and reduced the rise in advanced oxidation protein products induced by ANG II and thereby suggested that the antioxidant effect of enalapril may participate in the preventive and therapeutic effects on the ANG II-induced cardiovascular and renal alterations. In anesthetized mice, intravenous ANG II attenuated the cerebral blood flow increase produced by mechanical stimulation of the vibrissae; the effect was blocked by losartan and SOD and was not observed in mice lacking the gp91 phox subunit of NADPH oxidase (Kazama et al., 2004). ANG II increased ROS production in cerebral microvessels, an effect blocked by the ROS scavenger and by apocynin. Therefore, these authors suggest that ANG II impairs functional hyperemia by activating AT1 receptors and inducing ROS production via a gp91 phox containing NADPH oxidase. Kinugawa et al. (2003) provided evidence that endothelial stunning is caused by oxidant processes inhibited by ascorbate in conscious dogs, and the activation of NADPH oxidase by increased ANG II plays an important role in this process. There were higher baseline renal blood flow and lower renal vascular resistance in gp91 (an NADPH oxidase subunit) gene knockout mice compared with wild-type mice without a difference in arterial pressure; intravenous infusion of ANG II caused a lesser degree of renal blood flow decrease and urinary excretion of nitrate/nitrite was higher in the knockout mice, indicating an increase in NO bioavailability that could be the cause of high renal blood flow in gp91 gene knockout mice (Haque and Majid, 2004). The mechanism of ANG II-mediated renal vascular action seems to involve concomitant generation of superoxide anions. In SHR, urinary isoprostane excretion, as a measure of ROS activity, and nNOS immunoreactivity of juxtaglomerular apparatus were higher than those in Wistar-Kyoto rats; apocynin, a specific NADPH oxidase inhibitor, reduced isoprostane excretion, whereas renin mRNA, plasma renin activity, glomerular filtration rate (GFR), and systolic blood pressure remained unchanged, suggesting that NADPH oxidase is an important contributor to elevated levels of ROS in hypertension (Paliege et al., 2006).
Mori et al. (2006) concluded in their review article that ANG II-induced oxidative stress within the renal medulla can induce hypertension and can also make the kidney functionally more vulnerable to the effects of ANG II. Sulfhydryl-containing ACE inhibitors (captopril, epicaptopril, zofenopril, and fentiapril) were shown to be effective scavengers of nonsuperoxide free radicals; captopril also scavenged the other toxic ROS hydrogen peroxide and singlet oxygen and inhibited microsomal lipid peroxidation (Chopra et al., 1992). Takai et al. (2005) showed that a lipophilic ARB, telmisartan, which was superior to losartan, prevented NADPH oxidase activity in the aorta from stroke-prone SHR (SHRSP) and thereby conferred vascular protection from remodeling.
Both superoxide anion and hydrogen peroxide production by leukocytes and the plasma levels of lipid peroxides were higher and plasma nitrite levels were lower in patients with uncontrolled essential hypertension compared with normal control subjects; ANG II stimulated free radical generation in normal leukocytes, suggesting that an increase in free radical generation and a simultaneous decrease in the production of NO and antioxidants occurs in essential hypertension (Kumar and Das, 1993). In healthy humans, the in vivo forearm vasoconstrictor actions of ANG II were enhanced during clamping of NO concentrations by using the combination of L-NMMA and sodium nitroprusside and attenuated during administration of vitamin C, suggesting direct ANG II-associated stimulation of endothelial NO and of oxygen radicals, respectively (Dijkhorst-Oei et al., 1999). In internal mammalian artery rings sampled during bypass surgery from patients with stable coronary artery disease, physical exercise training before the surgery resulted in improved ACh-mediated vasodilatation and reduced vascular expression of NADPH oxidase and AT1 receptor subtypes, resulting in decreased local ROS generation (Adams et al., 2005). Wolf (2000) suggested that drugs interfering with ANG II effects may serve as antioxidants, preventing vascular and renal changes, but the clinical studies are not so straightforward.
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V. Vasodilatation Induced by Angiotensin I-Converting Enzyme (Kininase II) Inhibitors Associated with Endothelial Nitric Oxide via Bradykinin |
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). L-Arginine increased the effect of captopril, whereas the NOS inhibitor L-NMMA antagonized the effect of captopril. These authors also revealed that in patients with stable, exercise-induced angina pectoris, captopril given 1 h before exercise improved the ST-segment depression, maximal workload, and time to angina compared with placebo, suggesting that the sulfhydryl group of certain ACE inhibitors can potentiate their effect on the endogenous nitrovasodilator EDRF and that this may lead to improved performance in patients with angina. De Graeff and van Gilst (1992) hypothesized that ACE inhibitors may cause coronary vasodilatation by a bradykinin-mediated release of EDRF. Similar results suggesting the involvement of reduced bradykinin degradation and increased endothelium-derived NO formation in the vasodilator effect of ACE inhibitors were also obtained in renal blood flow of conscious rabbits (Evans et al., 1994), coronary blood flow of chronically instrumented, conscious dogs (Zanzinger et al., 1994), and isolated, perfused porcine ciliary vasculature (Meyer et al., 1995). Hajj-ali and Zimmerman (1992) noted that L-NA reversed partially the increase in renal blood flow of anesthetized rabbits caused by Dup 753, an AII receptor blocker, and almost completely reversed the effect of lisinopril, an ACE inhibitor, suggesting that NO plays an important role in the renal hemodynamic effect of the ACE inhibitor, more so than its contribution to the effect of the ARB. The different efficacy of these inhibitors may be explained by the hypothesis that ACE inhibitors induce the vasodilator effect in association with NO released via inhibition of bradykinin degradation and with other mechanisms derived from decreased AII actions. Kitakaze et al. (1995) demonstrated that in open-chest dogs, in which the left anterior descending coronary artery was perfused through a bypass tube from the carotid artery, the increased coronary blood flow by cilazaprilat was attenuated by HOE-140, an inhibitor of B2 bradykinin receptors, and by L-NAME, and intracoronary administration of bradykinin mimicked the effects of the ACE inhibitor; CV11974, an ARB, increased coronary blood flow to a lesser extent than cilazaprilat. Therefore, the authors concluded that the ACE inhibition can increase coronary blood flow primarily due to accumulation of bradykinin and production of NO by the myocardium. Kitakaze et al. (1998) also reported that ACE inhibitors increased cardiac NO levels via the accumulation of bradykinin in the ischemic myocardium. E4177, an ARB, dilated afferent and efferent arterioles in superficial nephrons of the canine kidney, and cilazaprilat caused further arteriolar dilatation and a further increase in sodium excretion; effects of this ACE inhibitor were abolished by a bradykinin antagonist, suggesting an extra action of ACE inhibition in addition to ANG II receptor blockade (Matsuda et al., 1999). There is evidence supporting the idea that ACE inhibition increases the coronary blood flow by a bradykinin-mediated, NO-dependent mechanism in dogs with myocardial ischemia (Kitakaze et al., 2002) and those with pacing-induced dilated cardiomyopathy (Nikolaidis et al., 2002).
In contrast, Sudhir et al. (1993) provided evidence suggesting that inhibition of AT1 receptors in the dog coronary circulation in vivo results in vasodilator responses greater in magnitude than those with ACE inhibition. The reason for the opposite results from those by others was not determined.
In bradykinin B2 receptor knockout mice with ANG II infusion (Ang II/B2R-/- mice), mean arterial pressure was higher than in ANG II-infused wild-type (Ang II/B2R+/+) mice under anesthesia; short-term NOS inhibition by L-NAME caused a greater increase in arterial pressure in Ang II/B2R+/+ mice than in Ang II/B2R-/- mice, so that the mean arterial pressure after NOS inhibition in Ang II/B2R+/+ approached that of Ang II/B2R-/- mice (Cervenka et al., 2001). Therefore, they postulated that the kallikrein-kinin system selectively buffers the vasoconstrictor activity of ANG II via the release of NO. From studies with conductance and resistance coronary vessels in conscious dogs, Su et al. (2000) drew a conclusion that stimulation of B1 receptors produces vasodilatation, which is mediated by NO but not modulated by ACE, whereas the vasodilator response to B1 receptor stimulation is not as great as that produced by B2 receptor stimulation. In contrast to the literature so far reported for involvement of NO in ACE inhibitor-induced vasodilatation, Ehring et al. (1994) obtained evidence that the attenuation of myocardial stunning by ramiprilat in anesthetized open-chest dogs involved a signal cascade of bradykinin and PGs but not NO. In chronically instrumented dogs, S-nitrosocaptopril, a hybrid compound of NO and captopril, and nitroglycerin increased epicardial coronary diameter and coronary blood flow, whereas captopril had no effect on coronary diameter and blood flow, suggesting that S-nitrosocaptopril may dilate coronary arteries by virtue of its NO moiety rather than by its ACE inhibitory properties (Nakae et al., 1995).
In isolated canine coronary microvessels with intact endothelium, ramiprilat, bradykinin, kallikrein, and kininogen increased nitrite production, and the stimulating effect was blocked by L-NA, HOE-140, or the kinin antibody, suggesting that either increasing kininogen to promote endogenous kinin formation or inhibiting ACE to decrease kinin breakdown increases NO production (Zhang et al., 1997a). According to Wiemer et al. (1994), cultured porcine brain capillary endothelial cells are capable of producing and releasing kinins in amounts that lead via stimulation of B2-kinin receptors to an enhanced intracellular Ca2+ concentration as well as NO and PGI2 synthesis and release, provided that degradation of kinins is prevented by inhibition of endothelial ACE.
Rosenkranz et al. (2002) noted that in isolated rat hearts, the acute antihypertrophc action of bradykinin was accompanied by increased left ventricular cyclic GMP, and the inhibitory effect of ramiprilat on ANG II-induced increase in phenylalanine incorporation was attenuated by HOE-140 or 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a selective guanylyl cyclase inhibitor (Garthwaite et al., 1995), suggesting that elevation of cardiomyocyte cyclic GMP, possibly via endothelial NO (Yayama et al., 1998), may be an important antihypertrophic mechanism used by bradykinin and remipril in the heart. Gryglewski et al. (2003) provided evidence supporting the idea that in anesthetized rats ACE inhibitors induce thrombolysis via accumulation of endogenous kinins in the endothelium and subsequent activation of B2 receptors followed by the release of NO and PGI2.
Brosnihan et al. (1998) summarized mechanisms of ANG-(1-7) underlying the coronary vasodilatation in their review. The ANG-(1-7)-induced vasodilatation mediated by endothelium-dependent release of NO is attenuated by the B2 receptor antagonist HOE-140 (icatibant); AT1 and AT2 receptors are not involved in the effect of ANG-(1-7). This peptide potentiates bradykinin-induced vasodilatation but not the response to ACh or sodium nitroprusside and retards the degradation of bradykinin, like ACE inhibitors. Thus, they postulated novel actions of ANG-(1-7) as a vasodilator and a local synergistic modulator of kinin-induced vasodilation in coronary arteries.
In the skin of human volunteers and rabbits, captopril injected intradermally increased skin blood flow, and this response was abolished by coinjecting either an NOS inhibitor or a cyclooxygenase inhibitor. Intradermal bradykinin increased rabbit skin blood flow; the responses to bradykinin and captopril were abolished by coinjecting a B2 receptor antagonist or inhibitors of NOS or cyclooxygenase (Warren and Loi, 1995). Captopril seems to increase skin microvascular blood flow in humans and rabbits secondary to an increase in endogenous bradykinin; this stimulates B2 receptors with subsequent release of NO or PGs. In coronary microvessels from the heart obtained from patients with end-stage heart failure, bradykinin, kininogen, and ACE inhibitors (ramiprilat, enalaprilat, and captopril) increased nitrite in the incubation media; nitrite production in response to ACE inhibition was blocked by L-NAME and icatibant, indicating that ACE/kininase II inhibitors may increase NO production by the coronary microvasculature in the failing human heart through an increase in available kinins (Kichuk et al., 1997).
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VI. Mechanisms Underlying Vasodilatation Induced by Angiotensin Receptor Type 1 Blockade |
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). The greater effectiveness of the AT1 antagonist may be explained by blockade of actions of ANG II that is formed not only through ACE but also alternative pathways such as that with chymase (Fig. 2). A coronary blood flow increase by the AT1-receptor antagonist was also observed in open-chest dogs with ischemic myocardium (Kitakaze et al., 1995). In hearts isolated from SHR, minimum coronary vascular resistance was greater than in those from the Wistar-Kyoto rat, and treatment for 2 weeks with the AT1-antagonist reduced the vascular resistance in SHR; although L-NAME failed to increase the coronary vascular resistance in SHR, treatment with ARB restored the response to L-NAME (Takeda et al., 1994). ARB seems to improve the NO availability in SHR coronary blood vessels. Involvement of NO in the vasodilatation induced by losartan was found in anesthetized and conscious rats (Sigmon and Beierwaltes, 1993a; Sigmon et al., 1994).
ACh relaxed the isolated aorta from renal hypertensive rats less than that from normotensive rats, and losartan enhanced the ACh-induced, NO-mediated relaxation (Lee and Shin, 1997). Moreover, ACh lowered the mean arterial pressure less effectively in hypertensive rats than in normotensive ones, the depressor response being potentiated by losartan. The authors suggested that NO may interact with the renin-ANG system in controlling the vascular tension and systemic arterial circulation in renal hypertensive rats. In anesthetized rats, candesartan reduced arterial pressure and renal vascular resistance; pretreatment with L-NAME did not affect the depressor effect but blunted the renal response to the ARB, suggesting that AT1-receptor blockade is associated with an increase in NO-dependent renal vasodilatation (Demeilliers et al., 1999). Bennai et al. (1999) noted that in the SHRSP, cerebral intraparenchymal vessels showed lesions of the vascular wall and its periphery, and renal lesions were more pronounced. Beneficial effects of candesartan were more evident in the brain than in the kidney. In untreated SHRSP, eNOS immunoreactivity was decreased, but iNOS increased, and these changes were prevented in the ARB-treated group. A "role switch" of vascular eNOS in hypertension from physiological eNOS t
, superoxide anion; AC, adenylyl cyclase; GC, soluble guanylyl cyclase; PDEV, phosphodiesterase type 5; MB, methylene blue.