Potassium changes the relationship between receptor occupancy and the inotropic effect of cardiac glycosides in guinea-pig myocardium

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Abstract
1 K+ (2.4–15.6 mmol l−1) antagonized the positive inotropic effect of dihydro-ouabain. The concentration-effect curves became steeper with the shift to higher concentrations of the glycoside. At 1.2 mmol l−1 Ca2+, an increase in K+ from 2.4 to 12 mmol l−1 required tenfold higher concentrations of dihydro-ouabain to produce equal inotropic effects. This factor was reduced to four at 3.2 mmol l−1 Ca2+. The same change in K+ concentration, at 1.2 mmol l−1 Ca2+, diminished the inotropic effect of ouabain on rested-state contractions by a factor of six. 2 The positive inotropic effect of Ca2+ was also antagonized by K+ (1.2–12 mmol l−1). Reduction of Na+ from 140 to 70 mmol l−1 abolished the antagonistic action of K+ (1.2–8.0 mmol l−1) Moreover the inotropic effect of Ca2+ was enhanced. 3 Reduction of Na+, from 140 to 70 mmol l−1, antagonized the positive inotropic effect of dihydro-ouabain more at low (2.4 mmol l−1) than at high (8.0 mmol l−1) K+. Accordingly, the extent of the dihydro-ouabain-K+ antagonism was reduced. 4 When the K+ concentration was increased from 2.4 to 12 mmol l−1, [3H]-ouabain binding was reduced by a factor of three. This is less than the reduction in the inotropic effectiveness of ouabain or dihydro-ouabain. 5 Reduction of stimulation frequency from 1 to 0.1215 Hz did not significantly alter the antagonistic effect of K+. Diminution of of the action potential was observed only at K+ concentrations greater than 5.9 mmol 1−1, whereas the resting membrane potential was continuously depolarized over the entire range of K+ concentrations. 6 The results support the view that the reduction in receptor affinity cannot be the sole cause of the antagonism between the glycoside and K+. Impairment of passive Na+ influx during diastole, due to the K+-dependent depolarization of the resting membrane potential, contributed to about one half of the glycoside-K+ antagonism.

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