The actions of the cannabinoid receptor antagonist, SR 141716A, in the rat isolated mesenteric artery.
1. The actions of the cannabinoid receptor antagonist, SR 141716A, were examined in rat isolated mesenteric arteries. At concentrations greater than 3 microM, it caused concentration-dependent, but endothelium-independent, relaxations of both methoxamine- and 60 mM KCl-precontracted vessels. 2. SR 141716A (at 10 microM, but not at 1 microM) inhibited contractions to Ca2+ in methoxamine-stimulated mesenteric arteries previously depleted of intracellular Ca2+ stores. Neither concentration affected the phasic contractions induced by methoxamine in the absence of extracellular Ca2+ 3. SR 141716A (10 microM) caused a 130 fold rightward shift in the concentration-response curve to levcromakalim, a K+ channel activator, but had no effect at I microM. 4. SR 141716A (10 microM) attenuated relaxations to NS 1619 (which activates large conductance. Ca2+-activated K+ channels; BK(Ca)). The inhibitory effect of SR 141716A on NS 1619 was not significantly different f'rom, and was not additive with, that caused by a selective BKc,, inhibitor, iberiotoxin (100 nM). SR 141716A (1 microM) did not effect NS 1619 relaxation. 5. SR 141716A (10 microM) had no effect on relaxations to the nitric oxide donor S-nitroso-N-acetylpenicillamine, or relaxations to carbachol in the presence of 25 mM KCl. 6. The results show that, at concentrations of 10 microM and above. SR 141716A causes endothelium-independent vasorelaxation by inhibition of Ca2+ entry. It also inhibits relaxations mediated by K+ channel activation. This suggests that such concentrations of SR 141716A are not appropriate for investigation of cannabinoid receptor-dependent processes.
White
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Department of Pharmacology, University of Cambridge.
Hiley
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CR
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002186:Cannabinoids / Q000037:antagonists & inhibitors*; D002217:Carbachol / Q000494:pharmacology; D019806:Cromakalim / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D008729:Methoxamine / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D015221:Potassium Channels / Q000819:agonists*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000077285:Rimonabant
D001562:Benzimidazoles; D002186:Cannabinoids; D010880:Piperidines; D015221:Potassium Channels; D011720:Pyrazoles; C110881:S-nitro-N-acetylpenicillamine; D019806:Cromakalim; C086491:NS 1619; D002217:Carbachol; D010396:Penicillamine; D008729:Methoxamine; D000077285:Rimonabant; D002118:Calcium