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

Previously. we have shown that nicotinamide inhibits both high [K+]- and ph enylephrine-induced constrictions in a dose-dependent manner in rat tail ar teries. We have now investigated the effect of nicotinamide on intracellula r signalling pathways in vascular smooth muscle, Nicotinamide (8.2 mM) redu ced the response to phenylephrine- and [Arg(8)]vasopressin-induced constric tions by means of 72.9 +/- 6.9 and 51.8 +/- 5.7%, respectively. It also blo cked phenylephrine-induced constrictions in the absence of a functional end othelium (P < 0.0136). In addition. pre-treatment of the artery with nifedi pine (10 mM) also failed to inhibit nicotinamide's activity (P < 0.0178). M oreover, nicotinamide significantly reduced the sensitivity to phenylephrin e in Ca2+-free Krebs solution (P < 0.0152). Continuous perfusion of maximal concentrations of ryanodine or thapsigargin significantly inhibited the re sponse to phenylephrine; the addition of nicotinamide (8.2 mM) caused a sig nificant 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 signifi cantly attenuated by nicotinamide (P < 0.0001). However, phorbol eater-indu ced constriction was not attenuated by nicotinamide. This would suggest tha t nicotinamide directly inhibits vascular smooth muscle cell contraction an d 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 reser ved.