The influence of diabetes on cardiac b-adrenoceptor subtypes V. Melih Altan Ebru Arioglu Sahika Guner A. Tanju Ozcelikay Received: 28 December 2006 / Accepted: 13 February 2007 / Published online: 16 March 2007 Ó Springer Science+Business Media, LLC 2007 Abstract Despite the significant developments in the treatment of diabetes mellitus, diabetic patients still con- tinue to suffer from cardiac complications. The increase of cardiac adrenergic drive may ultimately contribute to the development and progression of diabetic cardiomyopathy. b-Adrenoceptors play an important role in the regulation of heart function. However, responsiveness of diabetic heart to b-adrenoceptor agonist stimulation is diminished. The chronotropic responses mediated by b 1 -subtype, which is mainly responsible for cardiac effects of catecholamines are decreased in the atria of diabetic rats. The expression of cardiac b 1 -subtype is significantly decreased in diabetic rats as well. b 2 -Adrenoceptors also increase cardiac func- tion. Although the expression of this subtype is slightly decreased in diabetic rat hearts, b 2 -mediated chronotropic responses are preserved. On the other hand, functional b 3 - adrenoceptor subtype was characterized in human heart. Interestingly, stimulation of cardiac b 3 -adrenoceptors, on the contrary of b 1 - and b 2 -subtypes, mediates negative inotropic effect in human ventricular muscle. Cardiac b 3 - adrenoceptors are upregulated in experimental diabetes as well as in human heart failure. These findings suggest that each b-adrenoceptor subtype may play an important role in the pathophysiology of diabetes-induced heart disease. However, it is still not known whether the changes in the expression and/or responsiveness of b-adrenoceptors are adaptive or maladaptive. Therefore, this review outlines the potential roles of these receptor subtypes in cardiac pathologies of diabetes. Keywords Diabetes Á b-Adrenoceptor Á Heart failure Á Gi-protein Á Gs-protein Á Sympathetic nervous system Introduction The introduction of insulin for clinical use some 80 years ago, offered diabetic patients the opportunity of living such a normal life. However, several degenerative complications may frequently occur in those patients as the disease pro- gressed. Diabetic ketoacidosis, infections, and cardiovas- cular disease were the leading causes of diabetic deaths before the discovery of insulin. Death from diabetic coma has been almost removed and death from infections has been sharply decreased by the use of insulin. As a result, the cardiovascular problems have now become the major causes of diabetic morbidity and mortality. As is well known, diabetics have a significantly greater incidence of angina, acute myocardial infarction, congestive heart fail- ure, and other manifestations of atherosclerosis compared to nondiabetics [1] Heart disease, often presented as car- diomyopathy, is one of the most important complications associated with diabetes. These patients appear particularly susceptible to congestive heart failure. Indeed, diabetics comprise approximately 30% of the congestive heart fail- ure population [2]. On the other hand, progression to heart failure in diabetic patients who survive myocardial infarction is also more frequent than nondiabetics [3]. The combination of hyperglycemia, hypertension, obesity, and atherosclerosis has been reported to increase the risk of congestive heart failure in diabetic patients [4, 5]. Many patients with severe chronic heart failure, on the other hand, have been demonstrated to have hyperinsulinaemia and insulin resistance even in the absence of hyperglyce- mia [6]. Diabetic heart disease may be a consequence of V. M. Altan (&) Á E. Arioglu Á S. Guner Á A. T. Ozcelikay Department of Pharmacology, Faculty of Pharmacy, University of Ankara, Tandogan, Ankara 06100, Turkey e-mail: maltan@pharmacy.ankara.edu.tr 123 Heart Fail Rev (2007) 12:58–65 DOI 10.1007/s10741-007-9005-6