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

Abstract

I K+ (2.4-15.6mmoll-') 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 1-Ca2+, an increase in K+ from 2.4 to 12 mmol 1-P' required tenfold higher concentrations of dihydro-ouabain to produce equal inotropic effects. This factor was reduced to four at 3.2 mmol I-, Ca2+ . The same change in K+ concentration, at 1.2 mmol 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 1-'). Reduction of Na+ from 140 to 70 mmol 1-' abolished the antagonistic action of K+ (1.2-8.0 mmol 1-'). Moreover the inotropic effect of Ca2" was enhanced.3 Reduction of Na+, from 140 to 70 mmol -', antagonized the positive inotropic effect of dihydroouabain more at low (2.4 mmol l') than at high (8.0 mmol I') K+. Accordingly, the extent of the dihydro-ouabain-K+ antagonism was reduced. 4 When the K+ concentration was increased from 2.4 to 12mmoll-', [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 Vmax of the action potential was observed only at K+ concentrations greater than 5.9 mmol 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.

Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels

“…Digibind is an inactivating Fab fragment antibody against the digitalis pharmacophore, which is widely available in all poison control centers. In fact, the NaKATPase hypothesis for the regulation of positive inotropic effects of cardiac glycosides has been under continuous questioning by investigators for many years without compelling resolution (11)(12)(13)(14)(15)(16). Non-NaKATPase effects also have been observed.…”

Effects of ouabain and low-Na+ perfusion on rest-decay and post-rest recovery of cellular Ca content in ventricular muscle of guinea-pig heart

“…This shift would act synergistically with ouabain and low-Na perfusion. On the other hand, the high [K+]o depolarization decreases Na + inward current and promotes Na + extrusion, decreasing [Na+]i (1,7,9,12). Moreover, increased [K+]o should decrease the binding of ouabain to its receptors (1).…”

“…On the other hand, the high [K+]o depolarization decreases Na + inward current and promotes Na + extrusion, decreasing [Na+]i (1,7,9,12). Moreover, increased [K+]o should decrease the binding of ouabain to its receptors (1). Due to these multidirectional actions of elevated [K+]o, it is difficult to tell what its net effect should be on the influence of ouabain and low-Na perfusion on 45Ca extrusion.…”