Modulation of the contractility of guinea pig papillary muscle by the activation of ATP-sensitive K + channels

Abstract

The influence of activation of ATP-sensitive K + channels on the positive inotropic action of l-isoproterenol d-bitartrate (isoprenaline), 12b-hydroxydigitoxin (digoxin), 5-amino-[3,4′-bipyridin]-6[1 H]-one (amrinone), 1,6-dihydro-2-methyl-6-oxo 3,4-bipyridine-5-carbonitrile (milrinone) and UD-CG 115 BS; 4,5-dihydro-6[2-(4-methoxyphenyl)-1 H-benzimidazol-5-yl]-5-methyl-3(2 H)pyridazinone (pimobendan) was investigated in guinea pig papillary muscle. The force of contraction (d F) and the rate of rise of force of contraction ( dF dt ) were measured. After activation of ATP-sensitive K + channels by 1 μM of (3 S,4 R)-3-hydroxy-2,2-dimethyl-4-(oxo-1 pyrrolidinyl)-6-phenyl-sulfonylchroman hemihydrate (HOE 234) the dose-response curves for isoprenaline were shifted to the right (about 9-fold). The positive inotropic action of digoxin and milrinone was significantly enhanced (about 5-fold). The inotropic action of amrinone and pimobendan before and after pretreament with HOE 234 was not significantly different. HOE 234 pretreatment decreased irreversibly the maximum effect ( E max) of isoprenaline only for the amplitude of force of contraction, but not for the rate of rise of force. Opposite to this, activation of ATP-sensitive K + channels evidently enhanced the positive inotropic effects of digoxin and milrinone. In the case of milrinone, the E max for both parameters (d F and dF dt ) was greater after HOE 234 pretreatment. Only the E max of digoxin for the amplitude of the force of contraction was significantly increased in the presence of HOE 234. The above mentioned results indicate that activation of ATP-sensitive K + channels by HOE 234 modulates the positive inotropic action of cardiotonic drugs. This change may be expressed as potentiation (digoxin, milrinone) or attenuation (isoprenaline) of the positive inotropic effects, depending on the mechanism of action.