Identification of alpha 1-adrenergic receptors on sarcolemma from normal subjects and patients with idiopathic dilated cardiomyopathy: characteristics and linkage to GTP-binding protein.

Abstract

Discontinuous density sucrose gradient centrifugation was used to isolate membrane vesicles from the left ventricle of three normal subjects (one prospective organ donor and two traffic victims whose hearts were obtained 1 hour after death) and nine patients undergoing cardiac transplantation as a consequence of idiopathic dilated cardiomyopathy. Sarcolemma-enriched subcellular fractions, detected in the interface between 8.55% and 25% sucrose, were identified by the increased activity of Na+,K+-ATPase and by enrichment in beta-adrenergic receptor density. The density of beta-adrenergic receptors was lower in vesicles from diseased hearts (610 +/- 71 fmol/mg protein) than in vesicles from normal hearts (1,410 +/- 226 fmol/mg protein; p less than 0.01). alpha 1-Adrenergic receptors were identified in these membrane vesicles by [3H]prazosin binding. Specific binding of [3H]prazosin was about 50% of the total binding at 1 nM, and alpha 1-adrenergic binding sites were saturable at approximately 3 nM. Scatchard analysis revealed 58 +/- 5 fmol/mg protein (KD = 0.90 +/- 0.08 nM) in pathological hearts and 30 +/- 5 fmol/mg protein (KD = 0.90 +/- 0.03 nM) in normal hearts (p less than 0.01). The displacement curve of (-)-norepinephrine in membrane vesicles from normal hearts delineated one subpopulation of alpha 1-adrenergic receptors; the addition of 0.1 mM GTP did not cause right shift. In membrane vesicles from diseased heart, the displacement curve of (-)-norepinephrine disclosed two subpopulations of alpha 1-adrenergic receptors. A right shift that occurred after addition of GTP showed that in this case alpha 1-adrenergic receptors were functionally coupled with GTP-binding protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional Effects of Endothelin and Regulation of Endothelin Receptors in Isolated Human Nonfailing and Failing Myocardium

“…In contrast to observations in the ␤-adrenergic receptor system, 30 but similar to ␣-adrenergic receptors, 31 the present study shows increased cardiac ET receptor densities in DCM without changes in the affinity of the receptors for their ligands. The upregulation of ET receptors was due to a selective upregulation of ET A receptors with no change in ET B receptor density.…”

Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic β-adrenoreceptor activation

“…Previous studies have demonstrated that, despite myocardial ␤-AR downregulation following chronic Iso administration, ␣-AR-induced inotropic upregulation may occur (6,24). These changes may be mediated by an increased density of myocardial ␣ 1 -ARs (17,18,29,33).…”

Myocardial beta-adrenergic receptor function during the development of pacing-induced heart failure.

“…Myocardial /-adrenergic receptor density has been demonstrated to be increased (5, 6), unchanged (7), or decreased (8)(9)(10)(11) in experimental animals with heart failure. and others (15)(16)(17) have consistently shown a reduction in the number of 3-adrenergic receptors, particularly of the A, subtype ( 1 1, 12, 17), in the left ventricle of failing human hearts. Most prior studies have exam-ined the advanced or terminal stages of heart failure, or examined a single component of the d receptor-GTP-stimulatory protein (Gj) '-adenylyl cyclase pathway, leaving an incomplete picture as to the development of the abnormalities in 3-adrenergic signal transduction.…”