Contribution of Na+-Ca2+ exchanger to pinacidil-induced relaxation in the rat mesenteric artery

1 Pinacidil relaxes blood vessels through opening the K-ATP channels with a resultant membrane hyperpolarization and inhibition of Ca2+ influx. The aim of this study was to examine the mechanisms thereby pinacidil induces K+ channel-independent relaxation in isolated endothelium-denuded rat mesenteric artery. 2 Pinacidil-induced relaxation was inhibited by glibenclamide (1-10 muM) in phenylephrine-preconstricted rings, but was unaffected by glibenclamide after inhibition of K+ channels and VGCCs. Pinacidil-induced K+ channel-independent relaxation remained unchanged after treatment with cyclopiazonic acid (10 muM), thapsigargin (1 muM), ouabain (100 muM), propranolol (10 muM), Rp-cAMPS triethylamine (30 muM), L-NNA (100 muM), or ODQ (10 muM). 3 Pinacidil induced more relaxant effect in the presence of nifedipine than in the presence of 60 mm K+ plus nifedipine. Pretreatment with Na+-Ca2+ exchanger inhibitors, nickel (30-300 muM) or benzamil (20 muM) attenuated pinacidil-induced relaxation in normal or in nifedipine-containing solution. Pinacidil (1 muM) produced less relaxant effect with decreasing extracellular Na+ concentration. Na+-free condition abolished the inhibitory effect of benzamil. Both nickel and benzamil inhibited pinacidil-induced relaxation in the presence of glibenclamide (10 mum). Nickel (300 muM) did not affect the relaxant response to sodium nitroprusside. 4 Pinacidil relaxed the rings preconstricted by active phorbol and U46619 with similar potency. 5 The present results indicate that stimulation of the forward mode Na+-Ca2+ exchange pathway is in part responsible for pinacidil-induced K+ channel-independent vasorelaxation. Pinacidil also induces K+ channel-dependent but VGCCs-independent relaxation. The PKC-mediated cellular pathway may be a target site for pinacidil only in higher concentrations.