Effects of flecainide on isolated vascular smooth muscles of rat

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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.

Section: Discussionsupporting

confidence: 87%

“…In contrast, the inhibition of 45Ca2+ uptake produced by 3 x 10-6 M propafenone was not different in aortic rings incubated in 5 or 40 mM KCI PSS. (Cauvin et al, 1983;Godfraind et al, 1986 (Carron et al, 1991;Perez-Vizcaino et al, 1991 Fei et al, 1993) and quinidine (pD2 = 5.0. Scamps et al, 1989).…”

Section: Inhibition Of'5ca2+ Influxmentioning

confidence: 99%

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

Pérez-Vizcaíno

Pozo

Zaragozá

et al. 1994

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“…Contractions induced by depolarization with KCl have been shown to depend on Ca2`entry through voltage-dependent Ca2+ channels (Bolton, 1979). In previous experiments in this laboratory and others, it has been demonstrated that some class I antiarrhythmic drugs (i.e., propafenone, flecainide, quinidine, mexiletine, imipramine and desipramine) produced vasorelaxant effects that can be attributed to Ca2+ entry blockade (Carron et al, 1991;Perez Vizcaino et al, 1991;Dohi et al, 1994;Fernandez del Pozo et al, 1994). In the present study, quinidine and quinine inhibited in a concentrationdependent manner KCl-induced contractions, an effect that can be related to their ability to inhibit Ca2+ entry through L-type Ca21 channels.…”

Section: Discussionmentioning

confidence: 93%

Stereoselective effects of the enantiomers, quinidine and quinine, on depolarization‐ and agonist‐mediated responses in rat isolated aorta

Pozo

Pérez‐Vizcaíno

Villamor

et al. 1996

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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.

“…After excess of fat and connective tissue were removed, the aortae were cut into rings (4-5 mm in length). Aortic rings were mounted under the tension of 1 g by two parallel L-shaped stainless-steel holders inserted into the lumen and longitudinal portal vein segments (15 mm in length) were mounted vertically under the basal tension of 1 g in 20 ml organ baths containing PSS and attached to a force-displacement transducer (Grass FT07) to measure isometric contractile force as previously described (Perez-Vizcaino et al, 1991;. The tissue bath was maintained at 37C and bubbled with 95% 02:5% CO2 gas mixture.…”

Section: Methodsmentioning

confidence: 99%

Effects of the novel potassium channel opener, UR‐8225, on contractile responses in rat isolated smooth muscle

Pérez‐Vizcaíno

Casis

Rodríguez

et al. 1993

1 The effects of UR-8225 [(1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-1-oxonaphthalen-6-carbonitrile)] and levcromakalim were studied on the electrical and contractile responses induced by noradrenaline and KCI and on 86Rb+ efflux in rat aortic rings and on spontaneous mechanical activity in rat portal vein segments.2 UR-8225 and levcromakalim, 10-9M-10-SM, relaxed the contractile responses induced by noradrenaline (IC50 = 2.7 ± 0.4 x 10-6 M and 6.6 ± 1.3 x I0-M, respectively) or 30mM KCI (IC, = 1.4 ± 0.2 x 10-7 M and 9.4 ± 1.3 x 10-8 M, respectively) more effectively than those induced by 80 mM KCI. The relaxant effect on noradrenaline-induced contractions was independent of the presence or absence of functional endothelium. 3 The vasorelaxant effect of UR-8225 and levcromakalim can be competitively antagonized by glibenclamide, an ATP-sensitive K+ channel blocker. There were no differences in the calculated pA2 values for glibenclamide to inhibit UR-8225-and levcromakalim-induced relaxations (7.61 ± 0.08 and 7.69 ± 0.10, respectively). The slope of the Schild plot yielded values not significantly different from unity (0.95 ± 0.06 and 0.96 ± 0.05, respectively). 4 UR-8225 (10-5 M) hyperpolarized the resting aortic membrane potential from -50.7 ± 0.7 mV to -66.0 ± 2.0 mV and stimulated 86Rb+ efflux.5 UR-8225 and levcromakalim inhibited the contractions induced by Ca2" in aortae incubated in Ca2"-free PSS containing methoxyverapamil in the presence of noradrenaline.6 Both drugs inhibited the amplitude of spontaneous activity in portal veins (IC50 = 5.1 + 1.4 x 10-8 M and 1.5 ± 0.7 x 10-8 M, respectively), this effect being competitively antagonized by glibenclamide. 7 These results indicated that UR-8225 exhibited qualitatively similar, but slightly less potent, vasorelaxant effects than those exerted by levcromakalim, which suggests that they can be related to its ability to activate ATP-sensitive K+ channels in vascular smooth muscle cells.