Comparative effects of a selective adenosine A2 receptor agonist, CGS 21680, and nitroprusside in vascular smooth muscle

doi:10.1016/0014-2999(91)90416-N

European Journal of Pharmacology

Volume 196, Issue 2, 17 April 1991, Pages 117-123

https://doi.org/10.1016/0014-2999(91)90416-N Get rights and content

Abstract

CGS 21680 (2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine) is an adenosine agonist that has been reported recently to bind selectively to adenosine A₂ receptors in rat brain. This adenosine agonist, and the parent compound NECA (5'-N-ethylcarboxamidoadenosine), were found to be potent vasorelaxants of prostaglandin F_2α (PGF_2α) precontracted porcine coronary smooth muscle with EC₅₀s of 4.5 and 9.7 nM, respectively. Schild analysis of the inhibition of CGS 21680, NECA and 2-chloroadenosine induced relaxation of the porcine coronary artery by CGS 15943 (9-chloro-2-(2-furanyl)[1,2,4]triazolo[1,5-C]quinazolin-5-amine), an A₂ receptor antagonist, yielded identical pA₂values for the antagonist (approximately 9.3). This indicates that the same receptor mediates the effects of these three adenosine agonists. NECA and CGS 21680 were equipotent in most vascular preparations except in the canine coronary artery. Porcine coronary arterial rings contracted with PGF_2α were relaxed by NECA or CGS 21680 as well as by nitroprusside; those contracted with KC1 (40 mM) were relaxed only by nitroprusside. In rabbit aorta, contractions induced by phenylephrine or PGF_2αwere inhibited by nitroprusside but not by NECA or CGS 21680. Thus, the adenosine A₂ receptor agonists, NECA and CGS 21680, are potent vasorelaxants that display regional vascular and species variations that differ from those of nitroprusside.

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2017, Molecular Aspects of Medicine
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Interestingly, it has been shown that the ARs involved in these phenomena depend not only on the species but also on the vascular bed studied (Talukder et al., 2002b). For example, in the porcine coronary artery, the nonselective adenosine receptor agonist NECA and the A2AR agonist CGS 21680 induced the relaxation of coronary vessels (Balwierczak et al., 1991). Infusion of CGS 21680 in rats was also associated with coronary vasodilation, decreased blood pressure and increases heart rate (Nekooeian and Tabrizchi, 1996).
Adenosine as well as agonists and antagonists for the four adenosine receptor subtypes (A1R, A2AR, A2BR and A3R) play a role in several key physiological and pathophysiological processes, including the regulation of vascular tone, thrombosis, immune response, inflammation, and angiogenesis. This review focuses on the adenosine-mediated regulation of lipid availability in the cell and in the systemic circulation as well in humans and animal models. Therefore, adenosine, mainly by acting on A1R, inhibits lipolysis activity, leading to reduction of the circulating fatty acid levels. This nucleoside can also participate in the early development of atherosclerosis by inhibiting the formation of foam cells via stimulation of cholesterol efflux through A2AR expressed on macrophages and reduction of the inflammatory process by activating A2AR and A2BR. Adenosine also appears to modulate intracellular cholesterol availability in Niemann-Pick type C1 disease and Alzheimer disease via A2AR and A3, respectively. Remarkably, the role of adenosine receptors in the regulation of plasma total cholesterol and triglyceride levels has been studied in animal models. Thus, an anti-atherogenic role for A2BR as well as a pro-atherogenic role of A2AR and A1 have been proposed; A3R has not been shown to participate in the control of lipid levels or the development of atherosclerosis. Surprisingly, and despite the role of A2A in the inhibition of foam cell formation among isolated cells, this receptor appears to be pro-atherogenic in mice. Remarkably, the role of adenosine receptors in human dyslipidaemia and atherosclerosis must to be elucidated. Additionally, it has been reported that increased lipid levels impair the effects of adenosine/adenosine receptors in controlling vascular tone, and we speculate on the possibility that this impairment could be due to alterations in the composition of the membrane microdomains where the adenosine receptors are located. Finally, a possible role for adenosine/adenosine receptors in the phenomena of dyslipidaemia in pregnancy has been proposed.
Effect of adenosine A<inf>2</inf> receptor stimulation on platelet activation-aggregation: Differences between canine and human models
2008, Thrombosis Research
Citation Excerpt :
After stabilization, all 6 dogs received a 10 min infusion of the adenosine A2 receptor agonist CGS 21680 (0.5 μg/kg/min), administered via a cannula positioned in the left atrium, followed by a 10 min washout period. CGS has a plasma half-life on the order of 19 min and, at this dose, the estimated maximum plasma concentration is 0.45 μM [20,21]. The CGS-treated cohort was part of a larger, randomized 3-group study design, with the remaining dogs assigned to receive 10 min of preconditioning ischemia followed by 10 min of reperfusion (n = 10), or a matched no-intervention control period (n = 12).
Adenosine A₂ agonists improve arterial patency in experimental models of recurrent thrombosis, an effect purportedly triggered by stimulation of platelet A₂ receptors and subsequent down-regulation of platelet function. However: (i) there is no direct evidence to substantiate this premise; and (ii) given the recognized differences among species in platelet signaling, it is possible that the mechanisms of A₂ receptor stimulation may be model-dependent. Accordingly, we applied an integrated in vivo and in vitro approach, using both canine and human models, to test the hypothesis that the anti-thrombotic effects of A₂ agonist treatment are due in part to inhibition of platelet activation.
In Protocol 1, recurrent coronary thrombosis was triggered in anesthetized dogs by application of a stenosis at a site of arterial injury. Coronary patency and flow cytometric indices of platelet activation (P-selectin expression; formation of heterotypic aggregates) were compared in dogs pre-treated with the A₂ agonist CGS 21680 versus controls. In Protocols 2 and 3, blood samples were obtained from dogs and human volunteers. In vitro aggregation and platelet activation (assessed by impedance aggregometry and flow cytometry, respectively) were quantified in paired aliquots pre-incubated with CGS versus vehicle.
In the canine models, CGS improved in vivo coronary patency and attenuated in vitro aggregation but, contrary to our hypothesis, did not evoke a down-regulation in platelet activation. In contrast, in human blood samples, CGS attenuated both in vitro aggregation and flow cytometric markers of platelet activation–aggregation.
The mechanisms contributing to the anti-thrombotic effect of A₂ agonist treatment are species-dependent: adenosine A₂ receptor stimulation inhibits platelet activation in human, but not canine, models.
Ophidian envenomation strategies and the role of purines
2002, Toxicon
Snake envenomation employs three well integrated strategies: prey immobilization via hypotension, prey immobilization via paralysis, and prey digestion. Purines (adenosine, guanosine and inosine) evidently play a central role in the envenomation strategies of most advanced snakes. Purines constitute the perfect multifunctional toxins, participating simultaneously in all three envenomation strategies. Because they are endogenous regulatory compounds in all vertebrates, it is impossible for any prey organism to develop resistance to them. Purine generation from endogenous precursors in the prey explains the presence of many hitherto unexplained enzyme activities in snake venoms: 5′-nucleotidase, endonucleases (including ribonuclease), phosphodiesterase, ATPase, ADPase, phosphomonoesterase, and NADase. Phospholipases A₂, cytotoxins, myotoxins, and heparinase also participate in purine liberation, in addition to their better known functions. Adenosine contributes to prey immobilization by activation of neuronal adenosine A₁ receptors, suppressing acetylcholine release from motor neurons and excitatory neurotransmitters from central sites. It also exacerbates venom-induced hypotension by activating A₂ receptors in the vasculature. Adenosine and inosine both activate mast cell A₃ receptors, liberating vasoactive substances and increasing vascular permeability. Guanosine probably contributes to hypotension, by augmenting vascular endothelial cGMP levels via an unknown mechanism. Novel functions are suggested for toxins that act upon blood coagulation factors, including nitric oxide production, using the prey's carboxypeptidases. Leucine aminopeptidase may link venom hemorrhagic metalloproteases and endogenous chymotrypsin-like proteases with venom L-amino acid oxidase (LAO), accelerating the latter. The primary function of LAO is probably to promote prey hypotension by activating soluble guanylate cyclase in the presence of superoxide dismutase. LAO's apoptotic activity, too slow to be relevant to prey capture, is undoubtedly secondary and probably serves principally a digestive function. It is concluded that the principal function of L-type Ca²⁺ channel antagonists and muscarinic toxins, in Dendroaspis venoms, and acetylcholinesterase in other elapid venoms, is to promote hypotension. Venom dipeptidyl peptidase IV-like enzymes probably also contribute to hypotension by destroying vasoconstrictive peptides such as Peptide YY, neuropeptide Y and substance P. Purines apparently bind to other toxins which then serve as molecular chaperones to deposit the bound purines at specific subsets of purine receptors. The assignment of pharmacological activities such as transient neurotransmitter suppression, histamine release and antinociception, to a variety of proteinaceous toxins, is probably erroneous. Such effects are probably due instead to purines bound to these toxins, and/or to free venom purines.
Effects of adenosine A(2A) receptor agonist, CGS 21680, on blood pressure, cardiac index and arterial conductance in anaesthetized rats
1996, European Journal of Pharmacology
The effects of 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine (CGS 21680) on blood pressure, total peripheral resistance, cardiac index, heart rate and arterial conductance in different vascular beds in the presence and absence of hexamethonium (ganglionic blocker) and phenylephrine (α₁-adrenoceptor agonist) were investigated in pentobarbitone-anaesthetized rats using a radioactive microsphere technique. CGS 21680 (0.1, 0.3 and 1.0 μg/kg/min) significantly decreased blood pressure and total peripheral resistance, and increased heart rate and cardiac index. In addition, after infusion with CGS 21680 (0.1, 0.3 and 1.0 μg/kg/min) arterial conductance in coronary bed significantly increased. However, while CGS 21680 (0.3 and 1.0 μg/kg/min) significantly increased conductance in skeletal muscle, it significantly decreased splenic arterial conductance. Moreover, CGS 21680 (1.0 μg/kg/min) significantly increased conductance in cerebral arterial bed. Infusion with hexamethonium (200 μg/kg/min) resulted in significant reduction in blood pressure, heart rate and cardiac index whereas stroke volume and total peripheral resistance remained unchanged. In animals that were pretreated with hexamethonium (200 μg/kg/min), further administration of CGS 21680 (0.3 μg/kg/min), compared to CGS 21680 alone, significantly reduced blood pressure, heart rate and cardiac index but did not affect total peripheral resistance or conductance in any vascular bed. Administration of phenylephrine (7 μg/kg/min) resulted in a significant increase in blood pressure and total peripheral resistance, and a significant reduction in cardiac index and heart rate. In animals infused with phenylephrine and CGS 21680 combined, in comparison to those animals that received CGS 21680 alone, no significant differences in blood pressure, heart rate, total peripheral resistance, cardiac index or conductance in any vascular beds were found. Our present findings suggest that CGS 21680 decreased blood pressure by decreasing total peripheral resistance, and increased cardiac index possibly through a reflex-mediated increase in heart rate. Moreover the coronary arterial bed is the most sensitive and cerebral arterial bed is the least sensitive to the effects of CGS 21680. In addition, the autonomic nervous system did not appear to play a major role in the actions of CGS 21680 on arterial conductance, and there was no difference in the action of this compound in the states of normal and raised vascular tone.
Differential vasodilatory action of 2-octynyladenosine (YT-146), an adenosine A<inf>2</inf> receptor agonist, in the isolated rat femoral artery and vein
1995, European Journal of Pharmacology
The vasodilatory action of 2-octynyladenosine (YT-146), an adenosine A₂ receptor agonist, was investigated in the isolated rat femoral artery and vein. Exposure to YT-146 resulted in preferential vasodilation; the vein was completely dilated at YT-146 concentrations as low as 10⁻⁷ M; in contrast, a concentration of YT-146 greater than 10⁻⁴ M was necessary to induce complete relaxation in the femoral artery. 2-[p-(2-Carboxyethyl)-phenethylamine]-5′-N-ethylcarboxamidoadenosine (CGS 21680) also evoked stronger dilation in the vein than in the artery. The vasodilatory action of N⁶-cyclopentyladenosine (CPA) was much weaker in the vein than that of YT-146. YT-146-induced vasodilation in the artery was antagonized by neither 10⁻⁷ M 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) nor 3 × 10⁻⁶ M (E)-8-(3,4-dimethoxystylyl)-1,3-dipropyl-7-methylxanthine (KF17837), while the vasodilation in the vein was only antagonized by KF17837, suggesting that the vasodilation may involve adenosine A₂ receptor activation in the vein. However, the present study did not provide evidence of a link between adenosine agonist-induced vasodilation and adenosine A₂ receptor activation in the artery. The addition of 10⁻⁴ M N^ω-nitro-l-arginine partially reversed YT-146-induced vasodilation in the artery, but not in the vein. The reversal of YT-146-induced vasodilation by N^ω-nitro-l-arginine in the artery was attenuated by the addition of 10⁻³ M l-arginine. Removal of the endothelium decreased YT-146-induced vasodilation in the artery, but not in the vein. Prior treatment with 10⁻⁴ M N^ω-nitro-l-arginine decreased YT-146-induced vasodilation in the artery, but not in the vein. These results indicate that adenosine A₂ receptor agonists preferentially dilate the femoral vein rather than the femoral artery of rats and that YT-146-induced vasodilation is partially endothelium-dependent in the femoral artery, but not in the vein.
Characterization of adenosine receptors in the rat isolated aorta
1994, General Pharmacology
- 1.
  1. Adenosine and its analogues relaxed the isolated rat aorta by an endothelium-dependent mechanism with an order of potency of 5′-N-ethylcarboxamidoadenosine (NECA) > 2-(p-(2-carboxyethyl)phenethylamino)-5′-N-ethylcarboxamidoadenosine (CGS 21680) > adenosine = N⁶-(2-(4-aminophenyl)ethyl)adenosine (APNEA = N⁶-cyclopentyladenosine (CPA) > 5′ - methylthioadenosine (MTA), although the maximal response achieved by CGS 21680 was less than that achieved by NECA.
- 2.
  2. Both 8-sulphophenyltheophylline (8-SPT) and MTA antagonized responses to the adenosine analogues, but there were some anomolous features of this antagonism and NECA was inhibited more powerfully than the other agonists. This suggests that as well as A_2a receptors mediating relaxation, the rat aorta may relax to adenosine analogues by other mechanisms.

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^∗: Bausch and Lomb Pharmaceuticals, Clearwater, FL 34622, U.S.A.

^∗∗: Department of Pediatrics, LSU School of Medicine, 1542 Tulane Avenue, New Orleans, LA 70112, U.S.A.

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Comparative effects of a selective adenosine A2 receptor agonist, CGS 21680, and nitroprusside in vascular smooth muscle

Abstract

Phosphorylalion of smooth muscle myosin light chain kinase by the catalytic subunit of adenosine 3':5'-monophosphate-dependent protein kinase

J. Biol. Chem.

Some quantitative uses of drug antagonists

Br. J. Pharmacol. Chemother.

Cardiac nucleotides in hypoxia: Possible role in regulation of coronary blood flow

Am. J. Physiol.

N6[2-(3,5-Dimethoxypheny)-2-(2-methylphenyl)-ethyl]adenosine and it's uronamide derivatives. Novel adenosine agonists with both high affinity and high selectivity for the adenosine A2 receptor

J. Med. Chem.

Adenosine receptor subtypes. Binding studies

Evidence for an A1-receptor in the guinea pig atrium

Br. J. Pharmacol.

The vasodilator role of adenosine

Pharmacol. Ther.

The physiological action of adenine compounds with special reference to their action on the mammalian heart

J. Physiol. (London)

Adenosine receptors mediating cardiac depression

Life Sci.

Pharmacological characterization of CGS 15943A: A novel nonxanthine adenosine antagonist

J. Pharmacol. Exp. Ther.

Basis of pH-inde-pendent inhibitory effects of lactate on 45Ca2+ movements and responses to KC1 and PGF2α in canine coronary arteries