Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The results of the present study show that the reduction of the total number of beta adrenoceptors affected the beta 1-adrenoceptor subpopulation, whereas the beta 2 adrenoceptors were not detectably altered in the failing heart. Dopexamine had a 9.8-fold greater affinity to beta 2 adrenoceptors than to beta 1 adrenoceptors. In nonfailing myocardium, dopexamine increased force of contraction concentration-dependently. However, dopexamine alone had no effect in papillary muscle strips from moderately (NYHA II-III) and severely (NYHA IV) failing myocardium. However, in the presence of milrinone, it concentration-dependently increased force of contraction. Under this condition, the effectiveness was slightly less pronounced in NYHA IV than in NYHA II-III. Dopexamine concentration-dependently stimulated adenylate cyclase activity. Experiments with the beta 1-selective antagonist CGP 207.12 A and the beta 2-selective antagonist ICI 118.551 showed that both stimulation of adenylate cyclase and the increase of force of contraction are mediated by beta 2 adrenoceptors. It is concluded that although the number of beta 2 adrenoceptors is preserved in the failing myocardium, dopexamine alone does not increase force of contraction. However, the positive inotropic effect of dopexamine, which is observed in the presence of milrinone and the stimulation of adenylate cyclase activity by dopexamine are mediated by beta 2 adrenoceptors. Therefore, beta 2 adrenoceptors exist in the human myocardium, are coupled to adenylate cyclase, and are capable of increasing force of contraction. These results provide evidence for an impaired coupling of beta 2 adrenoceptors to mechanisms beyond receptor occupation in terminal heart failure.
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PMID:Reduced effects of dopexamine on force of contraction in the failing human heart despite preserved beta 2-adrenoceptor subpopulation. 247 68

The inotropic effects of sympathetic stimulation on the heart are mainly ascribed to the activation of beta-adrenoceptors. However, several findings suggest that alpha-adrenoceptors also may help mediate the inotropic response to catecholamines under certain conditions. The onset of the positive inotropic effect mediated by beta-adrenoceptors occurs within seconds and is associated with a faster rate of relaxation. Both beta 1- and beta 2-adrenoceptors are stimulatorily coupled to the enzyme adenylate cyclase, thereby leading to the generation of cyclic AMP. Cyclic AMP increases the slow inward calcium current and enhances the uptake of calcium into the sarcoplasmic reticulum. GTP-binding protein Gs is important for the transmembrane signal transduction. Muscarine and adenosine receptors are inhibitorily coupled to adenylate cyclase, thereby decreasing the inotropic response to catecholamines. Another GTP-binding protein, Gi, is involved in this pathway. The stimulation of the myocardium through the activation of alpha-adrenoceptors seems to differ both qualitatively and quantitatively. Myocardial alpha-adrenoceptors of most species are, if existent, predominantly of the alpha 1-subtype; the functional role of these receptors obviously considerably varies among species.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adrenoceptor-mediated changes of excitation and contraction in isolated heart muscle preparations. 247 96

The impaired inotropic responsiveness of myocardial tissue to catecholamines in congestive heart failure has been ascribed to downregulation of beta-adrenergic receptors. It has been reported recently that resistance to catecholamines is related to a defect in the guanine nucleotide binding protein that couples the beta-adrenergic receptor to adenylate cyclase. Studies of beta-adrenergic receptors were carried out using three different experimental protocols: (a) the interactions of the atypical agonists pindolol and celiprolol with beta-adrenergic receptors from C6 glioma cells (40% beta 1, 60% beta 2) were compared with those of the full agonist isoproterenol; (b) the ability of pindolol, celiprolol, and isoproterenol to induce downregulation and sequestration of beta-adrenergic receptors in wild-type S49 lymphoma cells was compared with the responses observed with a mutant line of S49 cells (cyc-, which lack Gs activity); and (c) the differential response of patients with heart failure and age-matched control subjects to exercise-induced changes in the density of beta-adrenergic receptors and isoproterenol-stimulated adenylate cyclase activity on circulating lymphocytes was investigated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of downregulation of beta-adrenergic receptors: perspective on the role of beta-adrenergic receptors in congestive heart failure. 247 5

Sudden cessation of prolonged treatment with clonidine in conscious rats evokes a cardiovascular withdrawal syndrome, characterized by severe tachycardia and brief blood pressure (BP) increases, so-called "upswings." Previously, adenylate cyclase-coupled alpha 2-adrenoceptors were shown to be involved in this phenomenon. In the present study, the effect on the intensity of clonidine withdrawal symptoms of concomitant treatment with various beta-adrenoceptor antagonists during clonidine infusion (100 micrograms/kg/24 h, 7 days) was investigated. Propranolol (18 mg/kg/24 h, beta 1 and beta 2 blocker) and ICI 118.551 (12 mg/kg/24 h, beta 2 blocker) clearly aggravated the withdrawal symptoms, whereas metoprolol (18 mg/kg/24 h, beta 1 blocker) did not affect the severity of the withdrawal syndrome. Accordingly, intensification of the withdrawal syndrome appears to be mediated by beta 2- rather than by beta 1-adrenoceptors. These results point to an interaction at the level of the second-messenger adenylate cyclase (AC) system in development of clonidine withdrawal syndrome.
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PMID:Beta 2-adrenoceptor antagonists intensify clonidine withdrawal syndrome in conscious rats. 248 78

We investigated the effects of adenosine on the positive chronotropic and inotropic responses to an endogenous catecholamine (norepinephrine), a beta 1-adrenoceptor agonist (dobutamine), an adenylate cyclase activator (forskolin), a phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine, IBMX) and a calcium channel agonist (Bay k 8644) in the isolated, blood-perfused dog atrium. Each drug was injected into the sinus node artery of the isolated atrium. Adenosine infusions at low (45 or 90 nmol/min) and high (184 or 450 nmol/min) doses induced a dose-dependent decrease of sinus rate and atrial contractile force. The positive chronotropic and inotropic responses to norepinephrine, dobutamine and forskolin were dose-dependently depressed by adenosine. IBMX- and Bay k 8644-induced positive cardiac responses were also inhibited by adenosine at high doses but not at low doses. These results suggest that adenosine attenuates calcium channel-dependent as well as cyclic AMP-dependent positive chronotropic and inotropic responses to cardiostimulants in the isolated dog atrium.
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PMID:Adenosine inhibits the positive chronotropic and inotropic responses to norepinephrine and Bay k 8644 in the isolated, blood-perfused dog atrium. 248 9

Thyroid hormones exert "permissive effects" on the hormone-sensitive adenylate cyclase. Regulation of the expression of Gi (Gi alpha 2) and Gs by thyroid hormones in vivo was investigated at the level of mRNA. Steady-state levels of the mRNA for Gi alpha 2 and Gs alpha, as well as the G beta-subunits, were quantified using DNA excess solution hybridization analysis. Regulation of protein and mRNA expression in adipose tissue was investigated in hypothyroid, euthyroid, and hyperthyroid rats. In euthyroid animals, steady-state levels of mRNA (amol/microgram RNA) were 13.8, 5.9, and 5.7 for Gs alpha, Gi alpha 2, and G beta 1,2, respectively. Activation of adenylate cyclase by Gs is unaffected by thyroid status. Both Gs alpha and Gs alpha mRNA levels in hypothyroid rats were the same as those of controls (euthyroid). The inhibitory control of adenylate cyclase, in contrast, is markedly potentiated in hypothyroid rats. The expression of G1 alpha s and G beta-subunits was increased in hypothyroidism. Whereas Gi alpha 2 mRNA levels remained essentially unchanged, G beta 1,2 mRNA levels were observed to increase 45% in the hypothyroid state. In the hyperthyroid state G beta 1,2 mRNA levels were observed to decline by 35%. Regulation of G-protein subunit expression, at the level of mRNA, appears to be one component of permissive hormone action on transmembrane signalling.
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PMID:Thyroid hormones regulate G-protein beta-subunit mRNA expression in vivo. 250 75

Although it is recognized that the number of cardiac beta-adrenoceptors is reduced in human dilated cardiomyopathy, the mechanisms involved have not been defined. We examined the possible role of altered humoral immunity by comparing the effect of sera from patients with idiopathic dilated cardiomyopathy (n = 20), ischemic or valvular heart disease (n = 28), or controls with no known cardiac disease (n = 18) on the binding of radioligands to cardiac beta-receptors. The ability of sera from cardiomyopathic patients to inhibit the binding of [3H]dihydroalprenolol to rat cardiac membranes was significantly higher than that of the other two patient groups (40 +/- 5% at 50-fold serum dilution compared to 14 +/- 3% for the ischemic/valvular heart disease group, and 14 +/- 4% for the normal control group, p less than 0.001). A similar inhibition was exerted by IgG from cardiomyopathic patients. Only the number, not the affinity, of the beta-receptors was decreased by cardiomyopathic sera. This decrease could be prevented by preincubating the sera with anti-human IgG, indicating the presence of autoantibodies. Furthermore, the sera were ineffective against cardiac alpha 1-adrenoceptors and considerably less effective against lung beta 2-receptors. In addition to ligand binding inhibition, sera from cardiomyopathic patients could immunoprecipitate beta-adrenoceptors quantitatively from solubilized cardiac membranes. Positive sera inhibited significantly isoproterenol-stimulated adenylate cyclase with no effect on basal or NaF-stimulated activities. These results document the presence in sera from patients with idiopathic dilated cardiomyopathy of autoantibodies directed against the cardiac beta 1-adrenoceptor which may play an important role in the regulation of inotropic responsiveness to beta-agonists.
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PMID:Autoantibodies against beta-adrenoceptors in human idiopathic dilated cardiomyopathy. 253 98

Chronic ethanol ingestion by mice resulted in the loss of high-affinity beta-adrenergic agonist binding sites and a significant decrease in activation of adenylate cyclase by guanine nucleotides and beta-adrenergic agonists in the hippocampus, although no significant change was noted in the total number of beta-adrenergic receptors, as defined by the binding of the antagonist [125]iodocyanopindolol. In cerebellum, chronic ethanol ingestion resulted in a 16% decrease in the total concentration of beta-adrenergic receptors and in a decrease in the affinity for agonist of the high-affinity beta-adrenergic agonist binding sites. However, neither the amount of the high-affinity agonist binding sites nor the activation of adenylate cyclase by agonist was affected. The different responses to ethanol in hippocampus and cerebellum may result from quantitative differences in distribution of beta 1- and beta 2-adrenergic receptors in the tested brain areas and/or differential effects of ethanol on stimulatory guanine nucleotide binding protein in these brain areas.
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PMID:Hippocampal and cerebellar beta-adrenergic receptors and adenylate cyclase are differentially altered by chronic ethanol ingestion. 253 73

The beta 1- and beta 2-adrenergic receptor subtypes are biochemically and functionally similar, because both receptors mediate the catecholamine-dependent activation of adenylate cyclase through the GTP-binding protein, Gs. Pharmacologically, the two receptors can be distinguished on the basis of their relative affinities for the agonists epinephrine and norepinephrine as well as their affinities for several selective antagonists. The primary structures of the human beta 1- and beta 2-adrenergic receptors have recently been deduced from the cloning of their genes and (or) cDNAs, revealing high sequence homology and a membrane topography of seven putative transmembrane regions similar to that of rhodopsin. Chimeric beta 1/beta 2-adrenergic receptor cDNAs have been constructed by site-directed mutagenesis and the chimeric RNA transcripts expressed in Xenopus laevis oocytes. The pharmacological properties of the expressed chimeric receptor proteins were assessed by radioligand binding utilizing subtype-selective agonists and antagonists. Apparently, several of the putative transmembrane regions contribute significantly to the determination of subtype selectivity, presumably by formation of a ligand-binding pocket, with determinants for agonist and antagonist binding being distinguishable.
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PMID:Properties of the beta 1- and beta 2-adrenergic receptor subtypes revealed by molecular cloning. 254 47

The function of beta-adrenoceptors was investigated in ventricular myocardium obtained from patients undergoing open heart surgery. 1. Dopamine increased contractile force up to 1/2 and 1/4 of the maximum increase caused by (-)-noradrenaline or (-)-adrenaline in right and left ventricular preparations, respectively. 2. beta-Adrenoceptors were labelled with 3H-(-)-bupranolol. For 3/4 of the receptors (beta 1) the affinity of (-)-noradrenaline was 20 times higher than for the remaining 1/4 (beta 2). (-)-Adrenaline and dopamine appeared to be non-selective for beta 1 and beta 2. 3. Dopamine was able to stimulate the adenylate cyclase only up to 1/3 of the maximum stimulation caused by (-)-noradrenaline and (-)-adrenaline. 4. Increases in contractile force by (-)-noradrenaline were closely associated with small increases of cyclase activity through beta 1-adrenoceptors, consistent with a common link. 5. The experiments on human myocardium were compared with similar experiments on feline myocardium. Feline ventricle exhibited a 20- to 30-fold higher sensitivity to catecholamines as activators of contractile force than did human ventricle. However, the binding affinities for catecholamines were similar in cat and man. 6. A 3 h exposure of human and feline ventricular myocardium to (-)-isoprenaline caused desensitization by uncoupling beta-adrenoceptors from the adenylate cyclase. Desensitization reduced the maximum contractile response to (-)-isoprenaline in human but not in feline ventricle. 7. The more efficient activation of contractile force by (-)-noradrenaline in cat, compared to man, appears to be related to a 2-fold higher density of beta 1-adrenoceptors, a 6-fold higher production of cyclic AMP per beta 1-adrenoceptor and possibly to a more effective use of cyclic AMP for contraction.
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PMID:Relations between beta-adrenoceptor occupancy and increases of contractile force and adenylate cyclase activity induced by catecholamines in human ventricular myocardium. Acute desensitization and comparison with feline ventricle. 254 8


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