Vasoconstrictor and vasodilator effects of disopyramide on isolated rat vascular smooth muscle.
We investigated the effects of disopyramide on the isometric contractions and intracellular Ca2+ concentrations ([Ca2+]i) measured by Fura-2 fluorescence in isolated rat aorta and portal veins. Disopyramide at concentrations > or = 10(-5) M increased the duration and complexity of the spontaneous contractions in rat portal veins. At > 10(-6) M, it induced a concentration-dependent contraction in the rat aorta. This effect was endothelium independent, associated with an increase in [Ca2+]i and abolished in aortic rings incubated in Ca2+-free solution or pretreated with 10(-7) M nifedipine, suggesting that 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 noradrenaline, disopyramide induced a concentration-dependent relaxation. The relaxant response in 80 mM KCl-precontracted arteries was associated with a parallel reduction in [Ca2+]i, an effect attributable to its Ca2+ channel blocking properties. In contrast, disopyramide had no effect on the concentration-response curves to noradrenaline in the presence of nifedipine. Disopyramide also inhibited in a concentration-dependent manner the relaxation induced by levcromakalim in aortic rings 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 effects of the drug, may account for the increase in mean arterial pressure observed in disopyramide-treated patients and the profound hypotension observed after overdosages of disopyramide.
Pérez-Vizcaíno
F
F
Department of Pharmacology, Institute of Pharmacology and Toxicology (CSIC/UCM), School of Medicine, Complutense University of Madrid, Spain.
Fernández
C
C
Fernández del Pozo
B
B
Cogolludo
A
A
Zaragozá
F
F
Tamargo
J
J
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D004206:Disopyramide / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D011189:Potassium Chloride; D012964:Sodium; D004206:Disopyramide; D002118:Calcium; D009638:Norepinephrine