Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated alterations in beta-adrenergic receptors and adenylate cyclase activity in myocardial membranes from normal and alloxan-treated diabetic rats. Saturation curves of [3H]dihydroalprenolol binding yielded a Bmax of 96.3 +/- 3.9 fmol/mg protein in normal membranes and 47.6 +/- 3.9 fmol/mg protein in diabetic membranes. Decreased receptor number in membranes from diabetic animals was not accompanied by alteration in receptor affinity for either antagonists or agonists to the beta-receptor. We were unable to detect any alteration in adenylate cyclase activity in similar ventricular membranes. Adenylate cyclase activity in the basal state or in the presence of sodium fluoride, guanyl-5'-yl imidodiphosphate, or isoproterenol, with or without GTP, was not altered by the alloxan-induced diabetic state. Stimulation of adenylate cyclase activity by forskolin, the novel diterpene activator, also was not altered by diabetes. The results suggest that while diabetes reduced beta-receptor number, this is not reflected in any other component of the adenylate cyclase complex.
J Cardiovasc Pharmacol
PMID:Alloxan-induced diabetes reduces beta-adrenergic receptor number without affecting adenylate cyclase in rat ventricular membranes. 619 Nov 47

We determined stimulation rates of cardiac adenylate cyclase activity by isoproterenol and impromidine in particulate sarcolemmal membrane preparations from human papillary muscles resected during open heart replacement of mitral and aortic valves. In addition, specific receptor binding studies with [3H]dihydroalprenolol [( 3H]DHA) to cardiac beta-receptors and [3H]tiotidine [( 3H]TIOT) to cardiac H2-receptors were carried out in the same preparations. Compared with the response in patients with pure mitral valve stenosis, the response of cardiac adenylate cyclase activity to isoproterenol showed a marked decrease (-90%) in patients with combined mitral and aortic valve disease, corresponding to the severity of degree of insufficiency at both valves. Similar changes were observed in receptor binding studies with [3H]DHA, in which the reduction of beta-receptor density was of the same order of magnitude. In contrast, stimulation of the enzyme by impromidine and binding capacity of [3H]TIOT to cardiac H2-receptors were found to be unaltered in the same membrane preparations of all 16 patients. We conclude that treatment with H2-agonists may be a new therapeutic approach to congestive heart failure, especially in patients not responding to beta-adrenoceptor stimulation with beta-sympathomimetic drugs.
J Cardiovasc Pharmacol
PMID:Effects of the H2-receptor agonist impromidine in human myocardium from patients with heart failure due to mitral and aortic valve disease. 619 60

A decrease in isoproterenol-stimulated adenylate cyclase activity has been shown in various tissues of hypertensive rats, a finding often associated with decreased beta-adrenoceptor number. The present study was undertaken to investigate whether adenylate cyclase stimulation by other hormones is similarly affected. Adenylate cyclase activity in cerebral microvessels under control conditions and following stimulation by isoproterenol, prostaglandin E1, and the adenosine analog 5'-(N-ethylcarboxamide)-adenosine (NECA) was significantly diminished in deoxycorticosterone acetate (DOCA)-hypertensive rats as compared with control rats, as was adenylate cyclase stimulation by GTP, fluoride, and forskolin. Similar results were obtained in cardiac ventricular membranes, apart from the fact that NECA did not influence adenylate cyclase activity in the heart, either in normotensive or in hypertensive rats. In both the heart preparation and the microvessel preparation, beta-adrenoceptor numbers were reduced in DOCA-hypertensive rats. Because the adenylate cyclase data also pointed to functional alteration at the guanine nucleotide regulatory site of the adenylate cyclase complex, the influence of DOCA hypertension on receptor-adenylate cyclase coupling was investigated by competition studies for beta-adrenoceptor binding. In ventricular membranes prepared from DOCA-hypertensive rats, the isoproterenol competition curve for [125I]iodocyanopindolol binding was only slightly altered in the presence of guanylyl imidodiphosphate (50 microM), in contrast to normotensive control rats, in which it was shifted to the right and became significantly steeper. These results are suggestive of decreased guanine nucleotide sensitivity of adenylate cyclase-coupled receptors in DOCA hypertension.
J Cardiovasc Pharmacol
PMID:The cardiac and brain microvessel adenylate cyclase system in deoxycorticosterone acetate-hypertensive rats. 620 Jul 23

Adrenergic receptor response coupling pathways have been shown to differ in hypertrophied hearts in different models of hypertension. To mimic this, chronic subcutaneous infusions of epinephrine (80 nmol/h for up to 13 days) and angiotensin II (AII) (4.3 nmol/h for up to 4 weeks) were given. Myocardial-, basal-, and isoproterenol-, glucagon-, forskolin-, and Gpp(NH)p-stimulated adenylate cyclase were measured. No changes in enzyme activity were seen following AII infusion, even though myocardial hypertrophy was significant. After epinephrine infusion for 6 days, there was a decrease in isoproterenol stimulated enzyme. After 13 days of infusion, cyclase activity, both basal and stimulated, was reduced. We conclude that in hearts from different models of experimental hypertension associated with cardiac hypertrophy, there are different biochemical alterations in the beta-adrenergic receptor response coupling mechanism.
J Cardiovasc Pharmacol
PMID:Adenylate cyclase activity in rat myocardium following chronic infusions of angiotensin II and epinephrine. 620 77

We examined the effects of prolonged exposure of cardiac cells in primary culture to the partial beta-adrenoceptor agonist prenalterol and inhibitors of phosphodiesterase on their subsequent ability to increase intracellular cyclic AMP during a 5-min exposure to 50 microM isoprenaline (receptor responsiveness). Although prenalterol possesses only 7% of the agonist activity of isoprenaline on adenylate cyclase, it induces extensive beta-adrenoceptor desensitization. Three hours after exposing the cells to 1 microM prenalterol, beta-adrenoceptor responsiveness was reduced by 40% (p less than 0.05), whereas after 12 h the reduction averaged 55%. Prolonging the incubation time to 48 h had no further effect on the magnitude of receptor desensitization. The magnitude of the desensitization was concentration dependent. On exposure of cells to 10(-8) M prenalterol for 16 h, receptor responsiveness was reduced by 19%, and at concentrations of 1 microM and higher responsiveness was reduced by 60% (p less than 0.01). Receptor desensitization appeared to be due to an inability of receptors to activate adenylate cyclase as well as to receptor loss. To investigate if beta-adrenoceptor desensitization as well as receptor loss could be mediated by cyclic AMP, the cells were exposed for 16 h to inhibitors of phosphodiesterase. Exposure of cells to the phosphodiesterase inhibitor isobutylmethylxanthine (0.1 mM) (which increased intracellular cyclic AMP by between 50 and 150%) also induced receptor desensitization. The reduction in receptor responsiveness averaged 62% (p less than 0.01). The loss in responsiveness could be accounted for by an inability of receptors to activate adenylate cyclase as well as by receptor loss.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol
PMID:Role of cyclic AMP in cardiac beta-adrenoceptor desensitization: studies using prenalterol and inhibitors of phosphodiesterase. 620 82

Properties of cardiac beta-adrenergic receptors from chronic alcoholic and control rats were studied to determine whether alterations in the receptor contribute to the decreased responsiveness of isolated working alcoholic rat hearts to beta-adrenergic stimulation. The receptors, assessed in crude membrane fractions by the binding of (-)[3H]dihydroalprenolol, did not differ significantly in either number or affinity in alcoholic rats (22.5 +/- 1.9 fmol . mg protein-1; Kd = 0.49 +/- 0.03 nmol . litre-1; n = 7) compared with control rats (25.9 +/- 1.3 fmol . mg protein-1; Kd = 0.55 +/-0.04 nmol . litre-1; n = 7). Competition experiments indicated that there was no difference in the binding affinity of (-)isoprenaline for the alcoholic and control rat heart receptors, nor in the affinity of (-)propranolol for he alcoholic and control rat heart receptors. In the presence of 5' -guanylylimidodiphosphate, the affinity of (-)isoprenaline for the receptors was decreased the same amount in the alcoholic and control rat hearts. These results suggest that the beta-adrenergic subsensitivity of chronic alcoholic rat hearts is mediated by a biochemical mechanism other than a direct alteration of the beta-adrenergic receptor or coupling between the receptor and adenylate cyclase.
Cardiovasc Res 1982 Jan
PMID:Beta-adrenergic receptors in chronic alcoholic rat hearts. 627 88

We examined beta-adrenergic receptor density, basal, maximal isoproterenol and fluoride-stimulated adenylate cyclase activities, and morphologic characteristics of rabbit and rat native and heterotopic isograft cardiac tissue. Four weeks after graft placement there were only subtle histologic differences between native and graft tissue. Membrane preparations from isografts of rabbits demonstrated increases in beta-receptor density (maximum [3H]DHA binding = 111 +/- 19.3 fmol/mg versus 52.4 +/- 4.9 in native hearts, p less than 0.05). In a small number of experiments, rat isografts also demonstrated a suggestive increase in beta-receptor density (69.8 +/- 7.1 fmol/mg versus 40.2 +/- 7.3 in native hearts). Isoproterenol-stimulated adenylate cyclase activity was greater in rabbit graft hearts (3.98 +/- 0.20 X basal activity) than in native tissue 2.67 +/- 0.16 X basal activity, p less than 0.05). We conclude that cardiac denervation may lead to a postsynaptic form of beta-adrenergic supersensitivity that is due to an increase in beta-receptor density.
J Thorac Cardiovasc Surg 1983 Aug
PMID:Increased beta-adrenergic receptor density in an experimental model of cardiac transplantation. 630 58

Microtubules have been demonstrated in intact heart muscle as well as in cultured myocytes. To better understand what role these filaments may be playing in the regulation of cardiac function we have used the microtubule disrupting agent colchicine and examined its effect upon the rate of beating of rat heart cells. Colchicine, but not the inactive stereoisomer lumicolchicine, increased the myocyte rate of spontaneous contraction in a dose dependent manner. This effect was clearly distinguishable from the positive chronotropic effect of isoprenaline and unlike isoprenaline was not blocked by propranolol. Colchicine was without effect on the in vitro activity of adenylate cyclase assayed in a myocyte homogenate. The binding of 3H-colchicine to cultured heart cells increased with a time course consistent with the increase in heart rate. Subcellular distribution and sephadex gel chromatography demonstrated that approximately 30% of the cell associated colchicine comigrated with tubulin. Measurements of total myocyte tubulin by 3H-colchicine binding indicated that tubulin represents about 0.04% of the total heart cell protein.
Cardiovasc Res 1983 Aug
PMID:Colchicine stimulates the rate of contraction of heart cells in culture. 661 18

Chronic therapy with the beta 1-selective adrenoceptor partial agonist xamoterol is not associated with the tolerance observed with other beta-adrenoceptor agonists. A possible explanation is that xamoterol therapy does not desensitise human cardiac beta-adrenoceptors in vivo. beta-Adrenoceptor density and adenylate cyclase activities were determined in right atrial appendages obtained from 40 patients randomised in a double-blind fashion to receive either xamoterol or atenolol for at least 5 weeks before coronary artery bypass surgery. There was no significant difference in total or subtype beta-adrenoceptor densities, but basal and isoproterenol stimulated adenylate cyclase activity were significantly greater in the atenolol-treated group, as was the intrinsic activity of the beta 2-adrenoceptor partial agonist procaterol, suggesting that chronic therapy with xamoterol does not downregulate human cardiac beta-adrenoceptors in vivo. Coupling of beta-adrenoceptors to adenylate cyclase, predominantly mediated by the beta 2 subtype, is enhanced, however, after therapy with atenolol relative to therapy with xamoterol.
J Cardiovasc Pharmacol 1993 Sep
PMID:In vivo regulation of human cardiac beta-adrenoceptors by a partial agonist as compared with a full antagonist: selective differences in coupling to adenylate cyclase. 750 42

The objective of this study was to examine the effect of indapamide on cAMP generation in cardiomyocytes. Viable ventricular myocytes were isolated from adult rat hearts which included normal hearts from Wistar rats and hypertrophic hearts from Dahl S rats. cAMP content was measured by competitive binding assay. In normal heart, indapamide did not alter cAMP concentration; however, indapamide pretreatment markedly accentuated forskolin-stimulated cAMP production. In contrast to the response with forskolin, indapamide did not alter isoproterenol-stimulated cAMP generation, suggesting an interaction of indapamide with adenyl cyclase rather than through the guanine stimulatory pathway affected by beta-adrenergic stimulation by isoproterenol. Male inbred Dahl SS/Jr fed a diet supplemented with an additional 6% NaCl from the age of 3 weeks were randomly allocated to receive either indapamide 2 mg/kg s.c. per day or the diluent (ethanol/sterile water) in the same volume. Indapamide or diluent injections were begun 1 week after commencing the high-salt diet. Cardiac hypertrophy is known to be associated with reductions in cellular cAMP. Indapamide-treated animals had significantly greater myocardial cAMP concentrations than control animals. Hypertrophic Dahl S myocytes from untreated animals were less responsive to forskolin compared to myocytes from animals that had been treated with indapamide. Angiotensin II (Ang)-receptor stimulation with Ang II and muscarinic-receptor stimulation with carbachol, accentuate cAMP stimulation in cardiac hypertrophy, whereas the reverse or inhibition was noted in normal myocardium. In cardiomyocytes from rats that had been treated with indapamide, the usual inhibitory effects of Ang II and carbachol were noted.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1993
PMID:Effect of indapamide on cyclic adenosine 3',5'-monophosphate signal transduction system in isolated adult rat cardiomyocytes from normal myocardium and cardiac hypertrophy. 750 59


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