Effects of chronic L-NAME treatment on rat focal cerebral ischemia and cerebral vasoreactivity

doi:10.1016/S0024-3205(01)01292-9

Life Sciences

Volume 69, Issue 19, 28 September 2001, Pages 2203-2216

https://doi.org/10.1016/S0024-3205(01)01292-9 Get rights and content

Abstract

Nitric oxide has been shown to be involved in the regulation of cerebral blood flow and the consequences of cerebral ischemia. Short-term inhibition of its synthesis induces hypertension and increases the cortical infarct volume in focal ischemia. Our purpose was to investigate the influence of the long-term inhibition of nitric oxide synthase on infarct volume due to middle cerebral artery (MCA) occlusion and on the reactivity of cerebral arteries. Sprague Dawley rats were given N^ω-nitro-L-arginine methyl ester (L-NAME) for 2 or 6 weeks and compared to untreated normotensive rats and untreated spontaneously hypertensive rats (SHRs). Brain nitric oxide synthase activity was measured by the ¹⁴C-L-arginine assay. Arterial blood pressure was measured in each group. Independently, the reactivity of MCA trees was studied in vitro by a perfusion technique. Cortical infarct volume was not significantly modified by either 2-week or 6-week L-NAME treatment, despite induced hypertension, whereas it was significantly higher in SHRs than in normotensive rats. The reactivity of the MCA tree was significantly affected by the treatment with a clearcut time-dependency. Compared to normotensive controls, contractility to noradrenaline and serotonin was reduced, more severely at 6 weeks, and while dilatation to acetylcholine and nitroprusside was moderately reduced at 6 weeks, dilatation to papaverine was then increased. A major difference of treated animals compared to SHRs was the decreased response to 5-hydroxytryptamine. We conclude that infarct expansion may be limited in treated animals by a progressive reduction in cerebral artery response to vasoconstrictory neurotransmitters, concomitant with augmented non-guanylate cyclase dilator responses (cf. papaverine) and some recovery of dilatation to acetylcholine.

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Citation Excerpt :
Observations made by others indicate that hypoxia is a stimulus that increases gene expression of α1-adrenoceptors in arterial blood vessels (Eckhart et al., 1996). Our results, however, contrast with those performed in anesthetized newborn pigs where 20 min of global cerebral ischemia induced by intracranial hypertension, followed by 2–3 h or 24 h of reperfusion did not affect the reactivity of pial arteries to noradrenaline (Leffler et al., 1989b), and also with those performed in rats where long-term inhibition of NO synthesis with l-NAME reduced the in vitro cerebral vasoconstrictor response to noradrenaline and the vasodilator response to acetylcholine, after occlusion of the left middle cerebral artery for 8–9 weeks, without reperfusion (Sercombe et al., 2001). The discrepancies between these two studies (Leffler et al., 1989b; Sercombe et al., 2001) and ours may be related to differences in the duration of ischemia, the presence or not of reperfusion, the procedure to examine vascular response, and/or perhaps in species used.
To analyze ischemia-reperfusion effects on the cerebrovascular adrenergic response, the left middle cerebral artery (MCA) of anesthetized goats was occluded for 120 min and reperfused for 60 min. Isolated segments from the left (ischemic) and right (control) MCA exhibited isometric constriction in response to noradrenaline (10^− 8–10^− 4 M, in the presence of β-adrenoceptors blockade), phenylephrine (α₁-adrenoceptors agonist, 10^− 8–10^− 4 M), B-HT-920 (α₂-adrenoceptors agonist, 10^− 7–3 × 10^− 3 M) or tyramine (indirect sympatheticomimetic amine, 10^− 8–10^− 4 M), but this constriction was greater in ischemic arteries. The cyclooxygenase (COX) inhibitor meclofenamate (10^− 5 M) augmented the response to noradrenaline only in control arteries. The prostacyclin (PGI₂) synthesis inhibitor tranylcypromine (TCP, 10^− 5 M) increased the response to noradrenaline in control arteries and reduced it in ischemic arteries. The thromboxane A₂ (TXA₂) synthase inhibitor furegrelate (10^− 6 M) did not modify the noradrenaline effect in both types of arteries, whereas the TXA₂ receptor antagonist SQ 29 548 (10^− 5 M) and the COX-2 inhibitor NS-398 (10^− 6 M) decreased the response to noradrenaline only in ischemic arteries. PGI₂ caused a small relaxation in control arteries and a small contraction in ischemic arteries. α-Adrenoceptors and COX-2 protein expression and the metabolite of PGI₂ were augmented in ischemic arteries. Therefore, ischemia-reperfusion may increase the cerebrovascular responsiveness to noradrenaline, through upregulation of α-adrenoceptors and increased COX-2-derived PGI₂ exerting a vasoconstrictor action. After ischemia-reperfusion, noradrenaline might increase PGI₂ production thus contributing to adrenergic vasoconstriction and/or PGI₂ would potentiate the noradrenaline effects.
Reduction of cerebral infarct size by the AT<inf>1</inf>-receptor blocker candesartan, the HMG-CoA reductase inhibitor rosuvastatin and their combination. An experimental study in rats
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Our purpose was to test the impact of single and/or combined treatment with the AT₁-receptor blocker candesartan and the HMG-CoA reductase inhibitor rosuvastatin on infarct size and neuroscore in transient cerebral ischemia in rats. L-NAME was used to test whether any potential effect was due to activation of endothelial nitric oxide synthase (eNOS). Therefore, the middle cerebral artery was occluded for 1 h (MCAO) followed by 7 days reperfusion. Rats received candesartan 2 h before and daily after MCAO (pretreatment) or daily after MCAO (posttreatment); rosuvastatin was given daily for 7 days before MCAO without or with candesartan pre- and posttreatment. In addition, candesartan and rosuvastatin were combined with L-NAME. Infarct size and neuroscore at day 7 were compared to those of controls. As result, compared to controls (109 ± 12 mm³) infarct size with candesartan (pretreatment: 21 ± 5 mm³; posttreatment: 68 ± 29 mm³; P < 0.05) or rosuvastatin (69 ± 14 mm³; P < 0.05) was smaller. Combined treatment also reduced infarct size (pretreatment: 37 ± 15 mm³; posttreatment 57 ± 20 mm³; P < 0.05); but there was no benefit of combined treatment over candesartan pretreatment alone. Compared to controls (2.08 ± 0.28) only candesartan pretreatment and combined treatment improved the neuroscore (0.97 ± 0.05, 1.10 ± 0.33; P < 0.05). L-NAME abolished the reduction in infarct size and improvement in neuroscore. In conclusion, both, candesartan or rosuvastatin treatment alone reduced infarct size in transient cerebral ischemia, and the best result was achieved with candesartan pretreatment. Combined treatment was superior to rosuvastatin alone, but not to candesartan. The therapeutic benefit of both agents was at least in parts mediated by eNOS-activation.
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2005, Free Radical Biology and Medicine
Nitric oxide produced by the neuronal or inducible isoform of nitric oxide synthase (nNOS, iNOS) is detrimental in acute ischemic stroke (IS), whereas that derived from the endothelial isoform is beneficial. However, experimental studies with nitric oxide synthase inhibitors have given conflicting results. Relevant studies were found from searches of EMBASE, PubMed, and reference lists; of 456 references found, 73 studies involving 2321 animals were included. Data on the effects of NOS inhibition on lesion volume (mm³, %) and cerebral blood flow (CBF; %, ml · min⁻¹ · g⁻¹) were analyzed using the Cochrane Review Manager software. NOS inhibitors reduced total infarct volume in models of permanent (standardized mean difference (SMD) −0.56, 95% confidence interval (95% CI) −0.86, −0.26) and transient (SMD −0.99, 95% CI −1.25, −0.72) ischemia. Cortical CBF was reduced in models of permanent but not transient ischemia. When assessed by type of inhibitor, total lesion volume was reduced in permanent models by nNOS and iNOS inhibitors, but not by nonselective inhibitors. All types of NOS inhibitors reduced infarct volume in transient models. NOS inhibition may have negative effects on CBF but further studies are required. Selective nNOS and iNOS inhibitors are candidate treatments for acute IS.
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Original articlesEffects of chronic L-NAME treatment on rat focal cerebral ischemia and cerebral vasoreactivity

Abstract

Original articles
Effects of chronic L-NAME treatment on rat focal cerebral ischemia and cerebral vasoreactivity