Resting Hemodynamic and Plasma Catecholamine Levels in Patients After Heart Transplant and in Patients With Idiopathic Cardiomyopathy Heart Normal Transplant

To test the hypothesis that there is up-regulation of /-adrenergic receptor density or supersensitivity of ,-adrenergic receptor-stimulated adenylate cyclase in the denervated transplanted human heart, we studied myocardium from transplanted, normal, and failing hearts. Myocardium was obtained from 10 patients 9±3 months after cardiac transplantation, from 10 patients without cardiac disease, and from eight patients with symptomatic congestive heart failure due to idiopathic cardiomyopathy. f-Adrenergic receptor density in transplanted myocardium (15+±3 fmol/mg protein, 1.20+0.14 fmol/mg DNA) was not dilferent from that in normal myocardium (22+±3 fmol/mg protein, 1.46±0.13 fmol/mg DNA; p=NS for both). In myocardium from cardiomyopathic hearts, f3-adrenergic receptor density was markedly reduced (8±2 fmol/mg protein, 0.84±0.13 fmol/mg DNA; p<0.05 and p<0.01 vs. normal myocardium, respectively). Likewise, the response of adenylate cyclase to isoproterenol in transplanted myocardium was not significantly different from that in normal myocardium, but the response was markedly depressed in cardiomyopathic myocardium. Although forskolinstimulated adenylate cyclase activity was similar in all three groups, guanine nucleotidestimulated adenylate cyclase activity was markedly reduced in transplanted myocardium (20±17 vs. 78±+13 pmol/mg/min for normal myocardium, p<0.01) and to a lesser degree in cardiomyopathic myocardium (39±+14 pmol/mg/min, p<0.03 vs. normal myocardium). Thus, there is no evidence of ,B-adrenergic receptor up-regulation or supersensitivity in denervated transplanted human myocardium. Moreover, the depressed adenylate cyclase response to guanine nucleotide stimulation in transplanted and cardiomyopathic myocardium indicates that in these conditions there may be an alteration in the expression or function of one or more guanine nucleotide regulatory proteins. (Circulation 1989;79:1028-1034)

[1]  M. Creager,et al.  Mechanism of the attenuated peak heart rate response to exercise after orthotopic cardiac transplantation. , 1989, Journal of the American College of Cardiology.

[2]  P. Allen,et al.  Distribution and function of human ventricular beta adrenergic receptors in congestive heart failure. , 1989, Journal of molecular and cellular cardiology.

[3]  W. Baumgartner,et al.  Increase of the 40,000-mol wt pertussis toxin substrate (G protein) in the failing human heart. , 1988, The Journal of clinical investigation.

[4]  L. Brunton,et al.  Association of Decreased Myocardial β‐Receptors and Chronotropic Response to Isoproterenol and Exercise in Pigs Following Chronic Dynamic Exercise , 1987, Circulation research.

[5]  M. Bristow,et al.  Assessment of the beta-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response. , 1986, Circulation.

[6]  S. Jamieson,et al.  Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure. , 1986, Circulation research.

[7]  E. Neer,et al.  Development of muscarinic cholinergic inhibition of adenylate cyclase in embryonic chick heart. Its relationship to changes in the inhibitory guanine nucleotide regulatory protein. , 1986, The Journal of biological chemistry.

[8]  S. Morris,et al.  Modifications of the adenylate cyclase complex during differentiation of cultured myoblasts , 1986, Journal of cellular physiology.

[9]  J. Cohn,et al.  The autonomic nervous system in congestive heart failure. , 1986, Annual review of medicine.

[10]  S. Vatner,et al.  Mechanisms of Supersensitivity to Sympathomimetic Amines in the Chronically Denervated Heart of the Conscious Dog , 1985, Circulation research.

[11]  M. Yacoub,et al.  Left ventricular contractility and contractile reserve in humans after cardiac transplantation. , 1985, Circulation.

[12]  T. Smith,et al.  Receptors for beta-adrenergic agonists in cultured chick ventricular cells. Relationship between agonist binding and physiologic effect. , 1985, Molecular pharmacology.

[13]  R. Lefkowitz,et al.  Regulation of β-Adrenergic Receptors by Steroid Hormones , 1984 .

[14]  A. Gilman.  Guanine nucleotide-binding regulatory proteins and dual control of adenylate cyclase. , 1984, The Journal of clinical investigation.

[15]  K. Lurie,et al.  Increased beta-adrenergic receptor density in an experimental model of cardiac transplantation. , 1983, The Journal of thoracic and cardiovascular surgery.

[16]  M. Caron,et al.  Adenylate cyclase-coupled beta-adrenergic receptors: structure and mechanisms of activation and desensitization. , 1983, Annual review of biochemistry.

[17]  D C Harrison,et al.  Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. , 1982, The New England journal of medicine.

[18]  J. Venter,et al.  The synthesis of beta-adrenergic receptors in cultured human lung cells: induction by glucocorticoids. , 1980, Biochemical and biophysical research communications.

[19]  K. Paigen,et al.  A simple, rapid, and sensitive DNA assay procedure. , 1980, Analytical biochemistry.

[20]  E. Neer.  The vasopressin-sensitive adenylate cyclase of the rat renal medulla. , 1973, Journal of Biological Chemistry.

[21]  D. Cooley,et al.  Cardiac transplantation. , 1986, The Surgical clinics of North America.

[22]  B B Brodie,et al.  A simple, sensitive method for the assay of adenyl cyclase. , 1968, The Journal of pharmacology and experimental therapeutics.

[23]  CHRISTOPHER J. MATHIAS,et al.  Increased sensitivity of the denervated , .