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 mu M, it caused concentration-dependent, but endothelium-independent, relaxations of both methoxamine- and 60 mM KCl-precontracted vessels. 2 SR 141716A (at 10 mu M, but not at 1 mu M) 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 mu M) caused a 130 fold rightward shift in the concentration-response curve to levcromakalim, a K+ channel activator, but had no effect at 1 mu M 4 SR 141716A (10 mu M) attenuated relaxations to NS 1619 (which activates large conductance, Ca2+ activated K+ channels; BKCa). The inhibitory effect of SR 141716A on NS 1619 was not significantly different from, and was not additive with, that caused by a selective BKCa inhibitor, iberiotoxin (100 nM). SR 141716A (1 mu M) did not effect NS 1619 relaxation. 5 SR 141716A (10 mu M) 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 mu M and above, SR 141716A causes endotheliumin-dependent 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.