Nicotinamide-inhibited vasoconstriction: lack of dependence on agonist signalling pathways

Previously. we have shown that nicotinamide inhibits both high [K+]- and phenylephrine-induced constrictions in a dose-dependent manner in rat tail arteries. We have now investigated the effect of nicotinamide on intracellular signalling pathways in vascular smooth muscle, Nicotinamide (8.2 mM) reduced the response to phenylephrine- and [Arg(8)]vasopressin-induced constrictions by means of 72.9 +/- 6.9 and 51.8 +/- 5.7%, respectively. It also blocked phenylephrine-induced constrictions in the absence of a functional endothelium (P < 0.0136). In addition. pre-treatment of the artery with nifedipine (10 mM) also failed to inhibit nicotinamide's activity (P < 0.0178). Moreover, nicotinamide significantly reduced the sensitivity to phenylephrine in Ca2+-free Krebs solution (P < 0.0152). Continuous perfusion of maximal concentrations of ryanodine or thapsigargin significantly inhibited the response to phenylephrine; the addition of nicotinamide (8.2 mM) caused a significant additional inhibition when compared to the effect of ryanodine (P < 0.0006) or thapsigargin (P < 0.037) alone. In addition, beta-escin (0.02%) permeabilisation and Ca2+ (7.5 mM)-mediated constriction was also significantly attenuated by nicotinamide (P < 0.0001). However, phorbol eater-induced constriction was not attenuated by nicotinamide. This would suggest that nicotinamide directly inhibits vascular smooth muscle cell contraction and is unlikely to act via blockage of external Ca2+ entry or release of Ca2+ from intracellular stores. (C) 1999 Elsevier Science B.V, All rights reserved.