Selective downregulation of the angiotensin II AT1-receptor subtype in failing human ventricular myocardium
Asano, K.; Dutcher, D.L.; Port, J.D.; Minobe, W.A.; Tremmel, K.D.; Roden, R.L.; Bohlmeyer, T.J.; Bush, E.W.; Jenkin, M.J.; Abraham, W.T.; Raynolds, M.V.; Zisman, L.S.; Perryman, M.B.; Bristow, M.R.
Circulation 95(5): 1193-1200
1997
ISSN/ISBN: 0009-7322 PMID: 9054849 Document Number: 475496
Background. The regulation of angiotensin II receptors and the two major subtypes (AT-1 and AT-2) in chronically failing human ventricular myocardium has not been previously examined. Methods and Results. Angiotensin II receptors were measured by saturation binding of 125I-(Sar-1,Ile-8)angiotensin II in crude membranes from nonfailing (n = 19) and failing human left ventricles with idiopathic dilated cardiomyopathy (IDC; n=31) or ischemic cardiomyopathy (ISC; n=21) and membranes from a limited number of right ventricles in each category. The AT-1 and AT-2 fractions were determined by use of an AT-1-selective antagonist, losartan. beta-Adrenergic receptors were also measured by binding of 125I-iodocyanopindolol with the beta-1 and beta-2 fractions determined by use of a beta-1-selective antagonist, CGP20712A. AT-1 but not AT-2 density was significantly decreased in the combined (IDC+ISC) failing left ventricles (nonfailing: AT-1 4.66+-0.48, AT-2 2.73+-0.39; failing: AT-1 3.20+-0.29, AT-2 2.70+-0.33 fmol/mg protein; mean+-SE). The decrease in AT-1 density was greater in the IDC than in the ISC left ventricles (IDC: 2.73+-0.40, P lt .01; ISC: 3.89+-0.39 fmol/mg protein, P=NS versus nonfailing). beta-1 but not beta-2 density was decreased in the failing left ventricles. AT-1 density was correlated with beta-1 density in all left ventricles (r=.43). AT-1 density was also decreased in IDC right ventricles. In situ reverse transcription-polymerase chain reaction in sections of nonfailing and failing ventricles indicated that AT-1 mRNA was present in both myocytes and nonmyocytes. Conclusions. AT-1 receptors are selectively downregulated in failing human ventricles, similar to the selective downregulation of 81 receptors. The relative lack of AT-1 downregulation in ISC hearts may be related to differences in the degree of ventricular dysfunction.