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-M) produced a concentration-dependent relaxation of the contractions induced by 80mM KCL. Propafenone was significantly more potent (P<0.05) than quinidine in both rat aorta and pig coronary arteries but both drugs were 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-S M and 3 X 10-5M) 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 mM KCl (depolarizing) solution. In contrast, the effects of propafenone were quite similar in 5 or in 40 mM KCI 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.

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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.

1. The effects of the two enantiomers, quinidine and quinine, were studied on depolarization- and agonist-induced isometric contractions in rat isolated thoracic aortic rings. 2. Quinidine or quinine (10(-6)M-3 x 10(-4)M) produced a concentration-dependent relaxation of 80 mM KCl-contracted rings, the pD2 values being 4.89 and 4.23, respectively. Thus, quinidine was about 4-5 times more potent than quinine. 3. The voltage-dependence of quinidine- and quinine-induced inhibition was studied in rings that had been incubated in 5 or 40 mM KCl Ca(2+)-free solution and then contracted by changing the bath solution to 100 mM KCl and 2 mM Ca2+. The inhibitory effects of quinidine were significantly enhanced when the rings were preincubated in 40 mM KCl (depolarizing conditions), when compared to normally polarized rings. In contrast, the effects of quinine were similar in 5 or 40 mM KCl solution. 4. The antagonism of noradrenaline (NA)-induced contractions by low concentrations of quinidine (< 10(-4)M) and quinine (< 3 x 10(-4)M) was competitive, as demonstrated by the concentration-dependent parallel rightward shift of the NA concentration-response curves (pA2 values 6.20 and 5.68, respectively, P < 0.05). 5. At low concentrations (< or = 3 x 10(-5)M), quinidine and quinine did not shift the concentration-response curve to 5-hydroxytryptamine (5-HT) or endothelin-1, whereas at higher concentrations they produced a downward shift of these curves. Quinidine and quinine (> 10(-4)M) inhibited to a similar extent both the phasic (induced in Ca(2+)-free media) and tonic responses (after restoring extracellular Ca2+) induced by 5-HT. 6. In conclusion, quinidine and quinine produced a stereoselective inhibition of depolarization and NA-induced contractions, quinidine being more potent than quinine. The inhibition of KCl-induced contractions could be attributed to inhibition of Ca2+ entry. Both drugs also behaved as competitive antagonists of alpha 1D-adrenoceptors. At high concentrations, quinidine and quinine also decreased the contractions induced by endothelin-1 and 5-HT in a non-stereoselective manner.

The effects of endotoxin from Escherichia coli on the vasoconstrictor responses to noradrenaline (10 nM–100 µM) and the thromboxane A₂ analog U46619 (100 pM–1 µM) were evaluated on isolated pulmonary and mesenteric arteries from neonatal piglets. Incubation for 20 h with endotoxin (1 µg ml^–1) induced a decrease in the contractile responses to noradrenaline in both arteries (p < 0.05) which was inhibited by N^G-nitro-L-arginine-methyl ester (L-NAME, 100 µM). 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 nitroprus-side, 8-bromo-cyclic GMP or dipyridamole than those induced by 10 µM 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 Ca²⁺-inde-pendent nitric oxide synthase induction in the lung.