Heavy Alcohol Consumption Attenuates Human Mesenteric Artery Responsiveness to Sigma Receptor-1 Ligands

Sigma receptor agonists are suspected to modulate blood pressure in humans. We investigated how modulation of sigma receptors impacts phenylephrine (PE)-induced contraction in human mesenteric arterial rings obtained from human organ donors. This study also explored the relationship between sigma receptor activation, PE-induced arterial contraction, and the history of the organ donor’s alcohol use. The concentration responsiveness of PE-induced arterial contraction was tested using wire myography in the absence and presence of the sigma receptor agonist PRE-084, and the sigma receptor antagonists BD-1047 and SM-21. Sigma receptor-1 expression in the arteries was also investigated using an automated capillary electrophoresis system. The results show that PRE-084 elicited a downward shift in the PE concentration-response curve. Notably, this trend only occurred in arteries from donors with histories of non-/light drinking or moderate drinking (P<0.05), but not with arteries obtained from donors with histories of heavy or binge drinking. The sigma receptor-1 antagonist BD-1047 elicited an upward shift in the PE concentration-response curve in arteries from non-/light and moderate drinkers, but not from heavy drinkers. Interestingly, the sigma receptor-2 antagonist caused an upward shift in the PE concentration-response curve in arteries from all three groups of donors. Notably, sigma receptor-1 protein levels were decreased in arteries from heavy drinkers compared to the other groups. Collectively, the findings suggest that sigma receptors in human arteries may promote relaxation. However, heavy alcohol consumption reduces arterial sigma receptor-1 expression and impairs its ability to modulate contraction.