Sigma receptor ligands inhibit rat tail artery contractile responses by multiple mechanisms.

The goal of this study was to further explore the mechanism of action by which several sigma ligand inhibit vascular contractile responses. By using the rat tail artery, the following sigma receptor ligands were tested: haloperidol; (+)-3-(3-hydroxyphenyl)-N- (1-propyl)piperidine; 1,3-di-ortho-tolyl-guanidine; cis-9- [3-(3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride; (+/-)-alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; and the two newly identified sigma ligands, N-(1-adamant-1- yl)-N'-(2-iodophenyl)guanidine and 2-amino-(3-phenyl)-3,4-dihydroquinazoline. We first tested the possibility that this inhibitory effect is mediated by an action on muscarinic receptors or an endothelium-dependent mechanism. However, inhibitory responses caused by either haloperidol or (+/-)-alpha-(4-fluorophenyl)- 4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol were unaffected by the muscarinic antagonist atropine, 10(-7) M, or by removal of the endothelium. We then explored the pharmacological profile of the inhibitory effect using several different contractile agents. Except for (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine which did not affect serotonin-evoked contractions, all ligands used caused an inhibition of norepinephrine-, serotonin- and KCl-induced contractile responses. Each sigma ligand exhibited a distinct individual inhibitory profile with respect to preferential actions on either norepinephrine- or serotonin-induced contractions, suggesting that these ligands act by several mechanisms to inhibit contractile responses in the rat tail artery. The multiple functional effects of this group of putative sigma receptor ligands suggests that they have only limited utility for exploration of the potential physiological role of the sigma receptor.