Upregulation of b3-Adrenoceptors and Altered Contractile Response to Inotropic Amines in Human Failing Myocardium

Background—Contrary to b1and b2-adrenoceptors, b3-adrenoceptors mediate a negative inotropic effect in human ventricular muscle. To assess their functional role in heart failure, our purpose was to compare the expression and contractile effect of b3-adrenoceptors in nonfailing and failing human hearts. Methods and Results—We analyzed left ventricular samples from 29 failing (16 ischemic and 13 dilated cardiomyopathic) hearts (ejection fraction 18.662%) and 25 nonfailing (including 12 innervated) explanted hearts (ejection fraction 64.263%). b3-Adrenoceptor proteins were identified by immunohistochemistry in ventricular cardiomyocytes from nonfailing and failing hearts. Contrary to b1-adrenoceptor mRNA, Western blot analysis of b3-adrenoceptor proteins showed a 2to 3-fold increase in failing compared with nonfailing hearts. A similar increase was observed for Gai-2 proteins that couple b3-adrenoceptors to their negative inotropic effect. Contractile tension was measured in electrically stimulated myocardial samples ex vivo. In failing hearts, the positive inotropic effect of the nonspecific amine isoprenaline was reduced by 75% compared with that observed in nonfailing hearts. By contrast, the negative inotropic effect of b3-preferential agonists was only mildly reduced. Conclusions—Opposite changes occur in b1and b3-adrenoceptor abundance in the failing left ventricle, with an imbalance between their inotropic influences that may underlie the functional degradation of the human failing heart. (Circulation. 2001;103:1649-1655.)