VASOCONSTRICTOR AND VASODILATOR EFFECTS OF DISOPYRAMIDE ON ISOLATED RAT VASCULAR SMOOTH-MUSCLE

We investigated the effects of disopyramide on the isometric contracti ons and intracellular Ca2+ concentrations ([Ca2+](i)) measured by Fura -2 fluorescence in isolated rat aorta and portal veins. Disopyramide a t concentrations greater than or equal to 10(-5) M in creased the dura tion and complexity of the spontaneous contractions in rat portal vein s. At >10(-6) M, it induced a concentration-dependent contraction in t he rat aorta. This effect was endothelium independent, associated with an increase in [Ca2+](i) and abolished in aortic rings incubated in C a2+-free solution or pretreated with 10(-7) M nifedipine, suggesting t hat disopyramide increased [Ca2+](i) through the activation of L-type Ca2+ channels. In aortic rings precontracted by KCl (30 and 80 mM), 80 mM KCl in a low-concentration (26.2 mM) Na+ solution or 10(-5) M nora drenaline, disopyramide induced a concentration-dependent relaxation. The relaxant response in 80 mM KCl-precontracted arteries was associat ed with a parallel reduction in [Ca2+](i), an effect attributable to i ts Ca2+ channel blocking properties. In contrast, disopyramide had no effect on the concentration-response curves to noradrenaline in the pr esence of nifedipine. Disopyramide also inhibited in a concentration-d ependent manner the relaxation induced by levcromakalim in aortic ring s precontracted by 30 mM KCl because of its inhibitory action on K-ATP channels, whereas it had no effect on the relaxant response to sodium nitroprusside. These effects, together with the negative inotropic ef fects of the drug, may account for the increase in mean arterial press ure observed in disopyramide-treated patients and the profound hypoten sion observed after overdosages of disopyramide.