BETA-ADRENOCEPTOR REGULATION IN RAT-HEART, LUNG AND SKIN AFTER CHRONIC TREATMENT WITH (-)-TERTATOLOL OR (-)-PROPRANOLOL

1. The effect of long-term treatment with the beta-adrenoceptor antago nists (-)-tertatolol and (-)-propranolol was studied. Sprague-Dawley r ats were treated with either(-)-tertatolol (50 mu g kg(-1) hr(-1)), (- )-propranolol (250 mu g kg(-1) hr(-1)) or vehicle (1 mM HCl) for 14 da ys with osmotic minipumps implanted subcutaneously. 2. The mean daily systolic blood pressure and heart rate of rats treated with either (-) -tertatolol (108 +/- 1 mmHg/330 +/- 3 bpm) or (-)-propranolol (103 +/- 1 mmHg/330 +/- 2 bpm) were lower than in the control (126 +/- 1 mmHg/ 405 +/- 3 bpm, P < 0.001, n = 8-10) indicating the effectiveness of dr ug delivery. 3. Autoradiographic studies in areas of heart, lung and s kin showed that beta-adrenoceptor populations were not significantly a ffected by the drug treatment (all regions P > 0.05). Nevertheless, th e receptor population in the homogenates of(-)-tertatolol treated lung were halved (194 +/- 28 fmol mg protein(-1) compared with a control v alue of 388 +/- 54 fmol mg protein(-1), P < 0.01, n = 6). 4. In the pr esence of CGP 20712A, the left atrial inotropic and right atrial chron otropic responsiveness to (-)-isoprenaline were hypersensitive in both (-)-tertatolol and (-)-propranolol-treated groups (P < 0.005, ANCOVA) . 5. (-)-Propranolol treated left ventricular free wall had lower basa l [H-3]-forskolin binding to adenylate cyclase (14.45 +/- 1.20 fmol mg protein(-1) compared with a control value of 18.91 +/- 0.78 fmol mg p rotein(-1), P = 0.01, n = 6). (-)-Tertatolol treatment had no effect o n the basal binding. In the presence of the G-protein activators NaF a nd Gpp(NH)p, the enhancement of [H-3]-forskolin binding did not differ between control and the drug treated groups. 6. Chronic (-)-tertatolo l or(-)-propranolol treatment therefore did not produce an increase in receptors in heart, lung or skin but the beta-adrenoceptor-mediated r esponses were enhanced. In addition, [H-3]-forskolin binding did not i ncrease suggesting that the hypersensitivity was not due to changes in the number of receptors or adenylate cyclase. Hypersensitivity follow ing beta-adrenoreceptor antagonist administration may therefore involv e enhanced coupling of receptors to G-proteins.