Several clinical reports have suggested that patients abruptly withdrawn from propranolol therapy are subject to increased severity of angina pectoris, arrhythmias, myocardial infarction and sudden death. Unfortunately, there has been no good animal model available for studying this phenomenon. Animal studies have reported increased numbers of cardiac Beta adrenoceptors and potentiated levels of isoproterenol-induced cardiac cyclic AMP after abrupt withdrawal of propranolol; however, these studies do not correlate the altered biochemical events with physiological and pathophysiological responses. The principal investigator has observed that following abrupt cessation of chronic propranolol pretreatment, supersensitivity to the cardiovascular actions of isoproterenol can be demonstrated under both in vivo (conscious rabbit) and in vitro (isolated rat heart and vasculature) conditions. The objective of the present proposal is to study the possible mechanisms by which chronic propranolol pretreatment and its abrupt withdrawal induce a supersensitivity phenomenon. The first series of experiments will result in a complete characterization of the phenomenon in the rabbit (in vivo and in vitro) to firmly establish the animal model. The second series of experiments will determine the propensity of several Beta-adrenoceptor antagonists, which possess characteristic pharmacodynamic properties, to induce supersensitivity. A third series of experiments will determine if biochemical alterations are associated with the development and extinction of the supersensitivity phenomenon induced by the various Beta-adrenoceptor antagonists tested. Of major interest will be the proposed changes in Beta-adrenoceptor number, cyclic AMP content and adenylate cyclase or phosphodiesterase activity. Finally, the specificity of the phenomenon for the Beta-adrenoceptor system will be tested. In an effort to insure that the results of these studies are not strictly species dependent, selected key experiments will be repeated in rats and dogs to confirm data crucial to understanding the mechanism of the phenomenon obtained in rabbits. The significance of the present proposal will rest in the demonstration of the cellular mechanism(s) responsible for the supersensitivity phenomenon. This information plus the study of various Beta-adrenoceptor antagonists should identify drugs which will not induce supersensitivity while retaining the therapeutically desirable effects of Beta-adrenoceptor antagonists.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Pharmacology A Study Section (PHRA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Texas Tech University
Schools of Medicine
United States
Zip Code
Tenner Jr, T E; Buddingh, F; Yang, M L et al. (1989) Dietary calcium and development of hypertension in spontaneously hypertensive rats. Magnesium 8:288-98
Tenner Jr, T E; Young, J A; Earley, K J et al. (1989) Functional characterization of beta-adrenoceptor subtypes in rabbit right atria. Life Sci 44:651-60
Tenner Jr, T E; Earley, K J; Young, J A (1989) Characterization of beta-adrenoceptor subtypes in rabbit mononuclear leukocytes. Eur J Pharmacol 160:291-3
Earley, K J; Gunasegaram, S; Tenner Jr, T E (1988) Determination of beta adrenoceptor density on rabbit mononuclear leukocytes. J Pharmacol Methods 19:193-203
Tenner Jr, T E; Young, J; Riker, B J et al. (1988) Nonspecific supersensitivity induced by reserpine in guinea pig cardiac ventricle tissue. J Pharmacol Exp Ther 246:1-6
Ramanadham, S; Tenner Jr, T E (1987) Alterations in the myocardial beta-adrenoceptor system of streptozotocin-diabetic rats. Eur J Pharmacol 136:377-89
Ramanadham, S; Young, J; Tenner Jr, T E (1987) Prevention of streptozotocin-induced alterations in the rat heart by 3-O-methyl glucose and insulin treatments. J Cardiovasc Pharmacol 9:291-7
Ramanadham, S; Tenner Jr, T E (1986) Chronic effects of streptozotocin diabetes on myocardial sensitivity in the rat. Diabetologia 29:741-8
Ramanadham, S; McNeill, J H; Tenner Jr, T E (1986) Experimentally induced effects of diabetes on the rat myocardial beta-adrenoceptor system. Proc West Pharmacol Soc 29:23-5
Hester, R K; Tenner Jr, T E (1986) Review of the basic principles of drug action. Semin Nephrol 6:189-99