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.
Pérez-Vizcaíno
F
F
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.
Fernández del Pozo
B
B
Zaragozá
F
F
Tamargo
J
J
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002132:Calcium Radioisotopes; D003331:Coronary Vessels / Q000187:drug effects*; D004594:Electrophysiology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011189:Potassium Chloride / Q000494:pharmacology; D011405:Propafenone / Q000494:pharmacology*; D011802:Quinidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D013997:Time Factors
D002132:Calcium Radioisotopes; D011189:Potassium Chloride; D011405:Propafenone; D011802:Quinidine; D002118:Calcium