RESTORATION OF SLOW RESPONSES IN HYPOXIC HEART-MUSCLE BY ALKALINE PH

Hypoxia, metabolic poisons, and acid pH were shown to depress the inward slow current in myocardial cells. In the present study, the rate of inhibition of the slow responses (dependent on Ca2+ and Na+) during hypoxia was determined at different pH values in isolated guinea pig papillary muscles. To study the slow responses, the fast Na+ current was first voltage-inactivated by partial depolarization to about -45 mV using an elevated (25 mm) K+ solution. Under these conditions, the muscles became inexcitable and did not contract. Isoproterenol (10-6m) or elevated Ca2+ (7 mm) allowed slowly-rising overshooting electrical responses accompanied by contractions to be elicited by electrical stimulation. In normoxia (Po2 of 576 ± 18 mmHg), the maximal upstroke velocity (+ V ̇max) and peak overshoot of the control slow responses recorded at pH 7.4 did not change significantly when the pH was varied to 6.8 or 8.0. Although hypoxia (Po2 of 23 ± 1 mmHg) caused slow response blockade irrespective of the pH value used, the rate of blockade was slower at more alkaline pH levels. The times to 90% inhibition were 15 min, 25 min, and 65 min at pH 6.8, 7.4, and 8.0, respectively. The developed tension declined concomitantly with + V ̇max of the slow response. Raising the pH of the hypoxic solution to 8.0 allowed partial (and temporary) restoration of slow responses and contractions that had been blocked at pH 7.4 or 6.8. This effect may be mediated by reversal of the acidosis normally produced by hypoxia. The results suggest that the slow current is depressed only gradually at low Po2 values if the cells are exposed to alkaline pH, and may explain the well-known fact that alkaline pH improves mechanical performance of ventricular muscle during hypoxia. These findings are consistent with a role of acidosis in inhibition of metabolically-dependent myocardial slow channels under adverse conditions such as hypoxia. However, an additional factor could be a change in K+ conductance during hypoxia and acidosis. © 1979.