Biochemical and physiological adaptation to chronic propranolol treatment in the rat.

The biochemical and physiological aspects of isoprenaline sensitivity in normotensive rats were examined during and after abrupt withdrawal of chronic propranolol treatment. Serum propranolol concentrations in rats chronically treated for one month (0.125% propranolol in drinking water: 75-100 mg/kg/day) ranged from 7 to 23 ng/ml. At the height of the blockade, rats showed a decreased responsiveness in vivo to isoprenaline-induced increase in heart rate and fall in blood pressure; the ED50 values for isoprenaline being increased some 20- and 4-fold respectively. There was a 180% increase in beta-receptor number in sarcolemmal membranes isolated from ventricular muscle of these animals, together with increased basal (290%), fluoride- (100%), forskolin- (80%) and isoprenaline-stimulated (125%) adenylate cyclase activity. Twenty-four hours after propranolol withdrawal, serum propranolol concentrations were reduced by over 95%. At this time rats exhibited increased chronotropic and blood pressure responses to i.v. isoprenaline, indicated by the reduced ED50 values (2-fold and 12-fold respectively compared to controls). In addition, cardiac sarcolemmal beta-receptor number and adenylate cyclase activities were still significantly elevated above those of controls; 35% increase in beta-receptor number and increases of 96, 26, 13 and 37% in basal, fluoride-, forskolin- and isoprenaline-stimulated adenylate cyclase activities respectively. Forty-eight hours after drug withdrawal serum propranolol concentrations were only just detectable at 0.5 +/- 0.1 ng/ml. Although sarcolemmal beta-receptor numbers were still elevated (23%) isoprenaline-stimulated adenylate cyclase activity had returned to control values. However, both the fluoride- and forskolin-stimulated enzyme activities were decreased below control values by 12 and 23% respectively, suggestive of a reduction in the catalytic capacity of the adenylate cyclase complex. In parallel with the reduction in beta-receptor number and adenylate cyclase activity, the chronotropic response to i.v. isoprenaline had also returned to control values. In contrast, the blood pressure response to i.v. isoprenaline was still elevated in these animals indicated by the 5-fold reduction in the ED50 value compared with control animals.