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.

Effects of several class I antiarrhythmic drugs on isolated rat aortic vascular smooth muscle.

1. The vasorelaxant effects of seven NA+ channel blockers (i.e., class I antiarrhythmic agents), quinidine, disopyramide, imipramine, lidocaine, mexiletine, flecainide, and desipramine, were investigated in isolated endothelium-denuded rat aorta. 2. All drugs induced a concentration-dependent relaxation in aorta precontracted with either 80 mM KCl or 10(-5) M noradrenaline and, with the exception of mexiletine, they were more potent in inhibiting KCl-induced contractions. 3. The degree of inhibition of high KCl-induced contractions produced by quinidine and desipramine increased with the time of depolarization. Furthermore, the inhibitory effect of quinidine also increased in aorta preincubated in 40 mM KCl, whereas the inhibitory effects of other antiarrhythmics were almost similar in 5 or 40 mM KCl solution. 4. In conclusion, all these class I antiarrhythmic drugs inhibited Ca2+ entry through voltage- and receptor-gated channels as well as Ca2+ release from intracellular stores. As a consequence, they decrease the availability of intracellular free Ca2+ required for vascular smooth muscle contraction.

Lack of endotoxin-induced hyporesponsiveness to U46619 in isolated neonatal porcine pulmonary but not mesenteric arteries.

The effects of endotoxin from Escherichia coli on the vasoconstrictor responses to noradrenaline (10 nM-100 microM) and the thromboxane A2 analog U46619 (100 pM-1 microM) were evaluated on isolated pulmonary and mesenteric arteries from neonatal piglets. Incubation for 20 h with endotoxin (1 microgram ml-1) induced a decrease in the contractile responses to noradrenaline in both arteries (p < 0.05) which was inhibited by NG-nitro-L-arginine-methyl ester (L-NAME, 100 microM). Endotoxin-treated mesenteric arteries also showed a reduction of the maximal contractions induced by U46619 (p < 0.05) and this effect was inhibited by L-NAME. In contrast, the contractile responses to U46619 were similar in control and endotoxin-treated pulmonary arteries. In endothelium-denuded pulmonary rings, endotoxin was also unable to modify the contractile responses to U46619. In pulmonary rings, the contractions induced by U46619 (100 nM) were much less sensitive to sodium nitroprusside, 8-bromo-cyclic GMP or dipyridamole than those induced by 10 microM noradrenaline. In conclusion, endotoxin-treated pulmonary arteries exhibited decreased responses to noradrenaline due to enhanced nitric oxide release but not to the thromboxane A2 analog U46619. This lack of hyporesponsiveness to U46619 in pulmonary arteries may be attributed to a relative insensitivity to nitric oxide. The absence of pulmonary hyporesponsiveness to U46619 may explain why pulmonary hypertension occurs in septic shock despite Ca(2+)-independent nitric oxide synthase induction in the lung.

Voltage- and time-dependent inhibitory effects on rat aortic and porcine coronary artery contraction induced by propafenone and quinidine.

1. Class I antiarrhythmic drugs (e.g. Na+ channel blockers) such as propafenone and quinidine also inhibit voltage-gated Ca2+ and K+ channels. In the present paper the voltage- and time-dependent inhibitory effects of propafenone and quinidine were studied on depolarization-induced vascular contractions and 45Ca2+ uptake in isolated endothelium denuded rat aorta and pig left descending coronary artery. 2. Quinidine and propafenone (10(-7) M -5 x 10(-5) M) produced a concentration-dependent relaxation of the contractions induced by 80 mM KCl. Propafenone was significantly more potent (P < 0.05) than quinidine in both rat aorta and pig coronary arteries but both drugs more potent (P < 0.05) in relaxing rat aorta than pig coronary arteries. In rat aortic rings, the relaxant effects of propafenone were unaffected by pretreatment with the Na+ channel blocker, tetrodotoxin. 3. The degree of inhibition produced after prolonged exposure (40 min) to propafenone and quinidine differed as the time of depolarization with 80 mM KCl was increased. Quinidine (3 x 10(-6) M, 10(-5) M and 3 x 10(-5) M) not only produced an inhibition at the very early stage of contraction, but also a time-dependent inhibition was observed. In contrast, propafenone (10(-6) M, 3 x 10(-6) M and 10(-5) M) produced a more marked concentration-dependent early block but only a mild time-dependent inhibition.4. The voltage-dependence of propafenone- and quinidine-induced inhibition, was studied in rat aorta and coronary arteries which had been incubated in 5 or 40mM KCl Ca2+-free solution and then contracted by changing the bath solution to 100 mM KCI and 2 mM CaCl2 solution. The inhibitor effects of quinidine were significantly enhanced (P <0.05) when the preparations were preincubated in 40 mMKCl (depolarizing) solution. In contrast, the effects of propafenone were quite similar in 5 or in 40 mMKCI solution.5. Quinidine, 10-5 M, produced a greater inhibition (P<0.05) of 100 mM KCl-stimulated 45Ca2+ uptake in aortic rings preincubated in depolarizing as compared to normal solution. In contrast, the inhibition produced by 3 x 10-6 M propafenone was similar in aortic rings incubated in 5 or 40 mM KCl solution.6.It is concluded that both quinidine and propafenone inhibited vascular smooth muscle contraction which could be attributed to reduced Ca2+ entry. The voltage- and time-dependent inhibitory effects of quinidine may reflect an increased binding of the drug to Ca2+ channels at depolarized potentials.