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

Abstract

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.

Evidence for the possible involvement of Ca 2+ entry blockade in the relaxation by class I antiarrhythmic drugs in the isolated pig coronary smooth muscle

“…Voltage-and time-dependent property of quinidine-induced relaxation of high-KCl-induced contraction was also reported in rat aorta as well as pig coronary artery (Fernández del Pozo et al 1997;Pérez-Vizcaíno et al 1994). If we assume that the (direct) targeted protein of vascular smooth muscle cells for class I antiarrhythmics is voltage-gated L-type Ca 2+ channel, it is conceivable that the binding of these drugs within the channel is modulated by the membrane potential-determinant conformational change of the channel stage (resting, activated, inactivated).…”

“…Consistent with this in vivo views, class Ia (disopyramide, imipramine, quinidine), class Ib (lidocaine, mexiletine) and class Ic (flecainide, desipramine, propafenone) have been reported to inhibit highKCl-induced contractions of the isolated rat aorta and pig coronary artery (Fernández del Pozo et al 1997;Pérez-Vizcaíno et al 1994). Since quinidine and propafenone block 45 Ca 2+ uptake and their potencies to inhibit vascular contractions are very close to those of cardiac myocytes L-type Ca 2+ channel currents, the blockade of transmembrane Ca 2+ influx through L-type Ca 2+ channel is likely to be involved in the mechanism for their vascular actions (Pérez-Vizcaíno et al 1994). However, at present, there are few studies on the effects of class I antiarrhythmic drugs on the Ca 2+ mobilization in coronary smooth muscles.…”

“…The existence of Na + channels either sensitive or relatively insensitive to TTX in vascular smooth muscle has rarely been reported (Sturek and Hermsmeyer 1986). The relaxations by propafenone of isolated rat aorta have been reported not to be affected by TTX (3×10 -5 M; Pérez-Vizcaíno et al 1994). In the present experiments, TTX (3×10 -5 M) did not affect coronary relaxations to tested class I antiarrhythmic drugs in the muscle contracted due to membrane depolarization.…”

Design, synthesis and biological activity of phenylpropiofenone aminoalcoxy derivatives

“…U terapijskim koncentracijama, propafenon inhibira i nekoliko K + struja u srcu: I TO Propafenon redukuje postojeću I Ca struju, ali ne utiče na njenu aktivaciju 218 . Ovaj efekat u miocitima pretkomora i komora dovodi do produženog trajanja AP-a i refraktarnog perioda, dok u glatkim mišićima krvnih sudova dovodi do vazodilatacije [219][220][221][222] .…”

“…Efekti propafenona na jonskim kanalima do skora su se zasnivali samo na elektrofiziološkim ili in vitro animalnim modelima [21][22][219][220][221][222]228 . Poslednjih godina QSAR studije sve više dobijaju na značaju i uglavnom su vezane za interakciju sa hERG kanalom 212,214,[244][245] .…”