guanylyl-imidodiphosphate and Cardiomegaly

The present study investigated whether high salt intake (8%) in Dahl salt-sensitive and salt-resistant rats with and without hypertension produces a heterologous desensitization of cardiac adenylyl cyclase as observed in various types of hypertension and human heart failure. In membranes from Dahl salt-sensitive rats on a high-salt diet (8%) basal, isoproterenol-, 5'-guanylylimidodiphosphate-, and forskolin-stimulated adenylyl cyclase was reduced compared with the low-salt (0.4%) group and Dahl salt-resistant rats on either 0.4% or 8% sodium chloride. The activity of the catalyst was depressed, and the expression of the immunodetectable inhibitory G proteins Gi alpha was increased in Dahl salt-sensitive rats on 8% sodium chloride, whereas the density of beta-adrenergic receptors and the activity of the stimulatory G protein Gs alpha reconstituted into Gs alpha-deficient S49 cyc- mouse lymphoma cell membranes were unchanged in any condition studied. We conclude that high salt intake in salt-sensitive hypertensive Dahl rats produces hypertension, cardiac hypertrophy, and heterologous desensitization of cardiac adenylyl cyclase. The latter alteration is due to an increase of Gi alpha proteins and a depressed catalyst activity of adenylyl cyclase. The results demonstrate that heterologous adenylyl cyclase desensitization can precede the development of contractile dysfunction in later stages and can occur independently of changes in beta-adrenergic receptors.

Topics: Adenosine Diphosphate Ribose; Adenylate Cyclase Toxin; Adenylyl Cyclases; Amino Acid Sequence; Animals; Blood Pressure; Cardiomegaly; Cell Membrane; Colforsin; GTP-Binding Proteins; Guanylyl Imidodiphosphate; Humans; Hypertension; Immune Sera; Kinetics; Lymphoma; Male; Mice; Molecular Sequence Data; Myocardium; NAD; Oligopeptides; Radioimmunoassay; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Adrenergic, beta; Recombinant Proteins; Sodium Chloride; Transducin; Transfection; Tumor Cells, Cultured; Virulence Factors, Bordetella

Recent reports suggested that a complex alteration in beta-receptor function occurs in failing human myocardium. We evaluated beta-receptor-subtype activity in an experimental model of monocrotaline (MCT)-induced cardiomyopathy in the rat. Through pulmonary hypertension, MCT causes right ventricular hypertrophy (RVH), either associated with heart failure or not, beta-Receptor function was evaluated in both failing-hypertrophic and hypertrophic hearts in binding studies with [125I]iodocyanopindolol (ICYP) and by measuring adenylate cyclase (AC) activity. In the right failing ventricle, beta 1- but not beta 2-receptor density was decreased. Lesion-associated modifications in the adenylate cyclase system were also observed: isoproterenol- and guanosine 5' [beta, gamma-imido]triphosphate [Gpp(NH)p]-stimulated cyclic AMP formation was reduced in the right failing ventricle, while the cyclic AMP responses to NaF and forskolin were unchanged. On the other hand, no changes in either beta-receptor density or function were found in hypertrophic ventricles. MCT-induced heart failure in the rat is thus associated with a selective decrease of beta 1-receptor density and function. These results suggest that MCT-induced cardiac failure may be an appropriate model in which to investigate heart insufficiency further.

Topics: Adenylyl Cyclases; Animals; Autoradiography; Cardiac Output, Low; Cardiomegaly; Cardiomyopathies; Female; GTP-Binding Proteins; Guanylyl Imidodiphosphate; Iodocyanopindolol; Monocrotaline; Pindolol; Pyrrolizidine Alkaloids; Rats; Rats, Inbred Strains; Receptors, Adrenergic, beta

High-altitude pulmonary arterial hypertension affects people with a long-term residence at altitudes over 2500 m above the sea level and is characterized by elevated pulmonary artery pressure (over 35/15 mmHg). In order to assess the role of beta-adrenoreceptors in the development of high-altitude pulmonary arterial hypertension, we studied the beta-adrenoreceptor density on mononuclear leukocytes in Kirghiz male natives of Eastern Pamir (3600-4200 m above sea level) with the diagnosis of high-altitude pulmonary arterial hypertension, and in healthy men. It was shown that patients with signs of right ventricular hypertrophy (RVH) of the second and third grade have beta-adrenoreceptor density 4.5 times lower than control (2.27 +/- 0.22 vs. 9.85 +/- 1.28 fmol/10(6) cells). Values of Kd also proved to be lower, by 2.5 times (0.57 +/- 0.14 vs. 1.44 +/- 0.18 nM). Stimulation of adenylate cyclase by isoproterenol and other beta-agonists was lower in patients than in controls (+33% and +120%, respectively). These results demonstrate that the desensitization of beta-adrenoreceptors is present in patients with high-altitude pulmonary arterial hypertension associated with severe right ventricular hypertrophy. Patients with pulmonary arterial hypertension due to mitral stenosis do not have any signs of beta-adrenoreceptor desensitization associated with high plasma levels of catecholamines.

Topics: Adenylyl Cyclases; Adult; Altitude; Animals; Cardiomegaly; Cyclic AMP; Dihydroalprenolol; Guanylyl Imidodiphosphate; Humans; Hypertension, Pulmonary; In Vitro Techniques; Leukocytes, Mononuclear; Mice; Middle Aged; Receptors, Adrenergic, beta

The effects of chronic MtTW15 pituitary adenoma implantation on beta-adrenergic responsiveness, cardiac beta-adrenoreceptors, and muscarinic receptors were studied in the rat. Five weeks after s.c. administration of tissue fragments of the MtTW15 adenoma, there was a 51 and 20% increase in the heart weight and body weight, respectively, and a 49-fold increase in the serum prolactin level as compared to the controls. At this time there was also an attenuation in the adenoma-bearing group of the ability of isoproterenol to produce a dipsogenic response and to increase the heart rate. In contrast, isoproterenol stimulated cardiac ornithine decarboxylase (ODC) activity 4.2-fold in both the control and adenoma-bearing groups. There was no change between the two groups in the cardiac ventricular beta-adrenoreceptor or muscarinic receptor concentration as measured by specific (-)-[125I]iodocyanopindolol (CYP) and (-)-[3H]quinuclidinyl benzilate (QNB) respectively. In addition, the concentrations of isoproterenol and carbachol required to inhibit by 50% (IC50) [125I]CYP and [3H]QNB binding, respectively, in the absence of 5'-guanylylimidodiphosphate (Gpp(NH)p) were not different between the two groups. In the presence of Gpp(NH)p, the isoproterenol IC50 value was not different between the two groups, whereas the carbachol IC50 value was increased slightly in the adenoma-bearing group. The data indicate that chronic MtTW15 adenoma implantation attenuated beta-mediated dipsogenic and heart rate responses but had little or no effect on cardiac ODC activity or cardiac autonomic receptor concentrations and agonist binding properties.

Topics: Adenoma; Animals; Cardiomegaly; Drinking; Guanylyl Imidodiphosphate; Heart Rate; Hypothyroidism; Isoproterenol; Male; Myocardium; Neoplasm Transplantation; Ornithine Decarboxylase; Pituitary Neoplasms; Rats; Rats, Inbred Strains; Receptors, Adrenergic, beta; Receptors, Muscarinic