Evidence from its cardiovascular effects that 7-nitroindazole may inhibit endothelial nitric oxide synthase in vivo.
We have examined whether the cardiovascular effects of 7-nitroindazole, a reportedly selective inhibitor of neuronal nitric oxide (NO) synthase, are induced without inhibition of endothelial NO synthase. A significant increase in mean arterial blood pressure but no change in heart rate was observed after 7-nitroindazole administration (50 mg/kg i.p.) in rats anesthetized with urethane or urethane and chloralose, while both an elevation in mean arterial blood pressure and bradycardia were observed in conscious animals after 7-nitroindazole administration (50 mg/kg i.p.). No enhancements in these effects on mean arterial blood pressure and heart rate were observed in urethane-chloralose anesthetized rats treated with a higher dose of 7-nitroindazole (75 mg/kg i.p.). Use of halothane to induce anesthesia abolished the pressor effect of 7-nitroindazole in rats studied under urethane anesthesia. 7-Nitroindazole shortened the duration of the acetylcholine (3 micrograms or 30 micrograms i.v.) but not the sodium nitroprusside (2 micrograms i.v.) induced hypotension in urethane-anesthetized rats. Pretreatment with L-arginine (300 mg/kg i.v.) inhibited the effects of 7-nitroindazole on mean arterial blood pressure and acetylcholine induced hypotension, suggesting involvement of the L-arginine-NO pathway in the effects of 7-nitroindazole. The effects of 7-nitroindazole on blood pressure and on the depressor responses to acetylcholine and sodium nitroprusside are similar to the effects previously observed after non-selective NO synthase inhibition by L-arginine analogs. Our results suggest, therefore, that 7-nitroindazole affects basal endothelial NO formation in vivo. The suppressive action of halothane on the cardiovascular effects of 7-nitroindazole suggests that the influence of anesthetics should be taken into consideration in studies of the cardiovascular effects of NO synthase inhibitors, particularly 7-nitroindazole.
Zagvazdin
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Department of Anatomy and Neurobiology, University of Tennessee, Memphis 38163, USA. AREINER@UTMEM2.UTMEM.EDU
Sancesario
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Wang
Y X
YX
Share
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Fitzgerald
M E
ME
Reiner
A
A
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects*; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007191:Indazoles; D014665:Vasodilator Agents; D001120:Arginine; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; C080122:7-nitroindazole