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

[摘要] Background-Contrary to beta (1)- and beta (2)-adrenoceptors, beta (3)-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 beta (3)-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 18.6 +/-2%) and 25 nonfailing (including 12 innervated) explanted hearts (ejection fraction 64.2 +/-3%). beta (3)-Adrenoceptor proteins were identified by immunohistochemistry in ventricular cardiomyocytes from nonfailing and failing hearts. Contrary to beta (1)-adrenoceptor mRNA, Western blot analysis of beta (3)-adrenoceptor proteins showed a 2- to 3-fold increase in failing compared with nonfailing hearts. A similar increase was observed for Gari, proteins that couple beta (3)-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 beta (3)-preferential agonists was only mildly reduced. Conclusions-Opposite changes occur in beta (1)- and beta (3)-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.

[关键词] RECEPTOR MESSENGER-RNA;NITRIC-OXIDE SYNTHASE;HUMAN VENTRICULAR MYOCARDIUM;CHRONIC HEART-FAILURE;BETA-3-ADRENERGIC RECEPTOR;DILATED CARDIOMYOPATHY;TISSUE DISTRIBUTION;TRANSGENIC MICE;BETA(3)-ADRENOCEPTOR;ALPHA