Propranolol withdrawal-induced supersensitivity to the chronotropic effects of isoproterenol in the conscious rabbit.

The present study was undertaken to determine if chronic administration and abrupt withdrawal of propranolol would induce supersensitivity to the chronotropic effects of isoproterenol in the conscious rabbit. Eight rabbits were pretreated with propranolol (40 mg/kg/day, i.p.) for one week. Dose-response curves were obtained one week prior to pretreatment and 24, 48, 72 and 168 hours after the last dose of propranolol. Isoproterenol (0.01 to 10 micrograms/kg) was injected via the marginal ear vein and heart rate was monitored continuously by recording the ECG. During the withdrawal period no significant rebound increase in basal heart rate was noted. Geometric mean ED50 values and their corresponding 95% confidence intervals were calculated and used as an index of potency. Twenty-four hours after withdrawal of propranolol pretreatment, the ED50 value for isoproterenol was significantly greater than control indicating continued surmountable beta-adrenoceptor blockade. In contrast, 72 hours after withdrawal, the geometric mean ED50 value was significantly less than control. The maximum chronotropic response to isoproterenol was not found to be different from control at any time during the withdrawal period indicating that a change in responsiveness was not induced. These data are interpreted as evidence of a true supersensitivity to the chronotropic effects of isoproterenol in the conscious rabbit following propranolol withdrawal.