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 [Arg8]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+ (2.5 mM)-mediated constriction was also significantly attenuated by nicotinamide (P < 0.0001). However, phorbol ester-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.
Burns
D M
DM
Radiation Sciences Group, School of Biomedical Sciences, University of Ulster, Northern Ireland, UK.
Ruddock
M W
MW
Walker
M D
MD
Allen
J M
JM
Kennovin
G D
GD
Hirst
D G
DG
D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D020013:Calcium Signaling / Q000502:physiology; D004347:Drug Interactions; D004727:Endothelium / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009536:Niacinamide / Q000494:pharmacology*; D010477:Perfusion; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D014662:Vasoconstrictor Agents; D001127:Arginine Vasopressin; D010656:Phenylephrine; D009536:Niacinamide