Upregulation of beta(2)-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium

Background-Contrary to beta (1)- and beta (2)-adrenoceptors, beta (3)-adren oceptors mediate a negative inotropic effect in human ventricular muscle. T o assess their functional role in heart failure, our purpose was to compare the expression and contractile effect of beta (3)-adrenoceptors in nonfail ing and failing human hearts. Methods and Results-We analyzed left ventricular samples from 29 failing (1 6 ischemic and 13 dilated cardiomyopathic) hearts (ejection fraction 18.6 /-2%) and 25 nonfailing (including 12 innervated) explanted hearts (ejectio n fraction 64.2 +/-3%). beta (3)-Adrenoceptor proteins were identified by i mmunohistochemistry in ventricular cardiomyocytes from nonfailing and faili ng hearts. Contrary to beta (1)-adrenoceptor mRNA, Western blot analysis of beta (3)-adrenoceptor proteins showed a 2- to 3-fold increase in failing c ompared with nonfailing hearts. A similar increase was observed for Gari, p roteins that couple beta (3)-adrenoceptors to their negative inotropic effe ct, Contractile tension was measured in electrically stimulated myocardial samples ex vivo. In failing hearts, the positive inotropic effect of the no nspecific amine isoprenaline was reduced by 75% compared with that observed in nonfailing hearts. By contrast, the negative inotropic effect of beta ( 3)-preferential agonists was only mildly reduced. Conclusions-Opposite changes occur in beta (1)- and beta (3)-adrenoceptor a bundance in the failing left ventricle, with an imbalance between their ino tropic influences that may underlie the functional degradation of the human failing heart.