Vol. 287, Issue 1, 81-86, October 1998

Antagonism by Class I Antiarrhythmic Drugs of Levcromakalim-Induced Relaxation in Isolated Rat Aorta¹

Angel L. Cogolludo, Francisco Perez-Vizcaino and Juan Tamargo

Department of Pharmacology, Institute of Pharmacology and Toxicology (CSIC/UCM), School of Medicine, University Complutense of Madrid, 28040 Madrid, Spain

We have analyzed the effects of several class I antiarrhythmic drugs (propafenone, quinidine, its enantiomer quinine, disopyramide, flecainide and mexiletine), tetraethylammonium (TEA) and glibenclamide on the vasodilator effects of the adenosine 5'-triphosphate-dependent K⁺ channels channel opener levcromakalim in isolated rat aorta precontracted by 30 mM KCl. TEA (>1 mM) and disopyramide (10 µM), induced a sustained contraction in resting aortic rings. Propafenone (3 µM), quinidine (30 µM), disopyramide (100 µM) and flecainide (100 µM) but not the other drugs decreased the contraction induced by 30 mM KCl in a concentration-dependent manner. Propafenone (1 µM), quinidine (10 µM), quinine (1 µM), disopyramide (3 µM), flecainide (100 µM), mexiletine (3 µM), TEA (0.3 mM) and glibenclamide (0.1 µM) caused a concentration-dependent inhibition of the vasodilation induced by levcromakalim in rat aortic rings. The order of potency of the drugs, expressed as pD₂ values, to inhibit the vasodilation induced by 0.3 µM levcromakalim was the following: glibenclamide (6.84) > quinine (6.14) > propafenone (5.27) > disopyramide (5.03) > quinidine (4.80) > mexiletine (4.68) > flecainide (3.37) > TEA (3.20). With the exception of flecainide and mexiletine, the slopes of the Schild plots were similar to unity. Based on the mode of antagonism these drugs could be classified in four groups: 1) glibenclamide which only shifted the curves to the right, 2) quinidine and disopyramide that, at low concentrations, shifted the curve to the right but, at higher concentrations, it also reduced the maximal relaxant effect, 3) propafenone, quinine and TEA that shifted the curve rightwards and reduced the maximal relaxation at all concentrations and 4) flecainide and mexiletine whose Schild slopes were clearly different from unity. In conclusion, class I antiarrhythmic drugs inhibited levcromakalim-induced relaxation in isolated rat aorta. The concentrations at which these effects were observed were within the therapeutic range (except for flecainide) and similar to those reported to inhibit adenosine 5'-triphosphate-dependent K⁺ channel currents. Analysis of the concentration-response curves revealed that these drugs produced a noncompetitive antagonism of levcromakalim-induced relaxations.