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)

Possible correlation between sympathetic innervation and sensitivity to adrenergic agonists was examined with developing rat hearts. Chronotropic responses of right atria to tyramine (TYR) was absent until the 15th day of gestation. After the 17th day of gestation, the maximum chronotropism by TYR was equal to that by norepinephrine (NE), indicating the development of functional sympathetic innervation to sinus node during this period. In ventricle, TYR responsiveness was low at birth and increased with age, indicating an increased sympathetic innervation during early postnatal period. Both in atria and ventricle, sensitivity to NE was high in early fetal ages followed by a 10-fold decrease after the onset of sympathetic innervation. Similar changes were observed in the sensitivity to isoproterenol, suggesting the postjunctional nature of this sensitivity change. There was no difference in sensitivities to dibutyryl cyclic AMP and forskolin between ventricles from 1-day- and 1-week-old neonates, suggesting changes in beta-receptor-adenylate cyclase system as a cause of this sensitivity change. The observed parallelism between functional sympathetic innervation and postjunctional sensitivity changes supports the hypothesis that sympathetic nerve exerts trophic influence upon cardiac muscle development to regulate the sensitivity to agonists.
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PMID:Changes in sensitivity of rat heart to norepinephrine and isoproterenol during pre- and postnatal development and its relation to sympathetic innervation. 322 36

Prior biochemical studies have shown that the ciliary process epithelium, which is involved in the secretion of aqueous humour, is rich in beta-adrenoceptors with pharmacological characteristics similar to those of the beta 2 subclass. The present experiments demonstrate that the beta-adrenoceptor antagonist, ICI 118,551, is a potent inhibitor of isoprenaline-stimulated adenylate cyclase activity measured in broken cell preparations of rabbit ciliary process. In rabbit cardiac muscle, however, ICI 118,551 is a relatively weak antagonist of isoprenaline-stimulated adenylate cyclase, being approximately 100 fold less potent than the non-selective beta-adrenoceptor antagonist, timolol. ICI 118,551 is also less potent than timolol in inhibiting isoprenaline-sensitive adenylate cyclase of rabbit lung. ICI 118,551 applied topically to eyes of unanaesthetized rabbits causes a dose-dependent decrease in intraocular pressure. Furthermore, in a blind crossover study in rabbits, topically applied ICI 118,551 decreased intraocular pressure for more than 6 h and was more effective than an identical dose of the clinically effective anti-glaucoma agent, timolol. Systemic absorption from topically-applied timolol, but not ICI 118,551, is sufficient to alter cardiac response to subcutaneous administration of isoprenaline. Furthermore, dose-response studies, using direct systemic administration of the two beta-adrenoceptor antagonists, revealed that ICI 118,551 is about 60 times less potent than timolol in blocking isoprenaline-induced cardio-acceleration. ICI 118,551, applied to one eye, causes a decrease in intraocular pressure in the contralateral eye, and systemic administration of ICI 118,551 results in decreased intraocular pressure in both eyes, data indicating that at least part of the ocular hypotensive effect of topical ICI 118,551 is mediated through systemic absorption. 8 These findings provide biochemical and physiological evidence that selective beta 2-adrenoceptor blockers such as ICI 118,551, used topically or systemically, may be useful as ocular hypotensive agents with decreased cardiac side-effects.
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PMID:ICI 118,551: an effective ocular hypotensive agent with selectivity for the ciliary process beta 2-adrenoceptor and with minimal cardiac side effects. 615 Jul 44

Oxidation of several exogenous substrates by cultured adult rat ventricular cardiac muscle cells has been assessed. Unlike freshly isolated cardiac muscle cells which oxidize glucose preferentially, the cultured cells more closely resemble metabolically the in situ heart and the isolated perfused heart, in that their preference for exogenous substrates is in the order of fatty acid greater than glucose. This switch in metabolic preference from glucose to fatty acid is complete within 12 h after placing freshly isolated cells in culture. Glucose oxidation is stimulated by insulin and isoproterenol and inhibited by beta-hydroxybutyrate and octanoate. The adenylate cyclase system has also been examined in these cultured cells. Isoproterenol, norepinephrine and epinephrine stimulate the accumulation of cyclic adenosine 3':5'-monophosphate (cyclic AMP) in a concentration-dependent manner. The order of potency is isoproterenol greater than norepinephrine approximately equal to epinephrine. This stimulation is potentiated by 1-isobutyl-3-methylxanthine and inhibited by 1-propranolol.
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PMID:Culture of the terminally differentiated ventricular cardiac muscle cell. Characterization of exogenous substrate oxidation and the adenylate cyclase system. 620 98

The contractile system of rat cardiac muscle that has been made hyperpermeable by soaking the tissue in EGTA (McClellan and Winegrad. 1978. J. Gen. Physiol. 72:737-764) can be probed directly with Ca buffer from the bathing solution without significant interference from either sarcoplasmic reticulum or mitochondria on the Ca concentration. Changes in Ca-activated force are due therefore to changes in the properties of the contractile system itself and not to regulation of Ca concentration. The addition of cAMP, cGMP, and GTP, guanylyl imidodiphosphate (GMP-PNP), or epinephrine to the bath does not alter maximum Ca-activated force, but when these drugs are added with 1% nonionic detergent to the bath, contractility increases by as much as 180%. An inhibitor of phosphodiesterase must be present for the inotropic effect of cAMP but not cGMP, GTP, GMP-PNP, or epinephrine. The inotropic response to cAMP is independent of the Ca sensitivity of the contractile system, but guanine nucleotides enhance contractility only when Ca sensitivity is not high. The inotropic effect of epinephrine is inhibited to a large extent by cGMP but not by GMP-PNP. These data can be explained by a model in which contractility is enhanced by a cAMP-regulated phosphorylation that can be controlled through the beta-receptor adenylate cyclase complex in the sarcolemma. The regulation involves two reactions, one a phosphorylation and a second that occurs in the presence of detergent. Phosphorylation of neither the myosin light chain nor the inhibitory subunit of troponin appears to be involved in this mechanism for regulating contractility.
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PMID:Cyclic nucleotide regulation of the contractile proteins in mammalian cardiac muscle. 624 20

The very close interdependence of Ca2+ and hormones in the overall metabolism of cyclic nucleotides has recently been emphasized by Cheung. Clearly the results presented here show that [Ca2+] in the physiological range (less than 10(-7) M to greater than 10(-6) M) has profound effects on the activity of adenylate cyclase from both brain and cardiac muscle. Whereas both brain and cardiac cyclase exhibit a Ca2+ dependent inhibition (perhaps mediated by calmodulin), only the brain cyclase is activated by Ca2+ via calmodulin. With both cyclases there is an inverse relationship between the inhibition of cyclase and the activation of calmodulin dependent (cAMP and cGMP) phosphodiesterase as a function of Ca2+ concentration. Because the IC50's for Ca2+ are the same in both heart and brain, the possibility exists that the Ca2+ inhibitory site of both cyclases is similar and perhaps identical. Considering the ability of Ca2+ to both stimulate and inhibit cyclase, one could imagine that in different species, tissues, or regions of the same tissue, there could exist multiple populations of cyclase, that is a cyclase which would only show Ca2+ dependent inhibition, Ca2+ dependent stimulation, or the biphasic response to Ca2+ (FIGURE 7). The fact that Ca2+ still regulates adenylate cyclase after various stimuli (histamine, NaF, etc.) suggests that Ca2+ may function to regulate the cyclase over shorter time periods (regardless of its state of stimulation) and that other affectors of cyclase (e.g., hormones) would serve to regulate the cyclase over longer time periods.
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PMID:Calcium dependent regulation of brain and cardiac muscle adenylate cyclase. 626 49

Experimental cardiomyopathy was produced by isoprenaline (2 x 80 mg/kg sc daily for 2 days). The degree of myocardial damage was evaluated histopathologically. In the damaged cardiac muscle the incorporation of 14C-adenine was impaired, the adenylate cyclase activity was diminished and the total contents of cAMP and 14C-cAMP formed from intracellular 14C-adenine metabolism were reduced. No significant changes in the activity of phosphodiesterase were found. This indicates that cAMP synthesis is impaired as a result of decreased utilization of the ATP pool formed from exogenous adenine in the cardiac muscle damaged by isoprenaline.
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PMID:Incorporation of 14C-adenine to cyclic 3',5'-AMP of cardiac muscle in isoprenaline-induced experimental cardiomyopathy. 626 91

Conversion of phosphorylase b to a which is catalyzed by the enzyme phosphorylase kinase is known to require Ca++. Trifluoperazine, an inhibitor of calmodulin-dependent enzymes, was utilized in the present study to clarify the role in vivo of calcium-calmodulin regulation of phosphorylase kinase. Twenty-minute preperfusion of isolated rat ventricles with 10(-5) M trifluoperazine had no effect on basal levels of phosphorylase a but significantly attenuated phosphorylase activation induced by either calcium (3.75 mM) or isoproterenol (3 x 10(-9) M, 3 x 10(-8) M). The positive inotropic effect of both agents and cyclic adenosine 3',5'-monophosphate (cAMP) levels were not altered by trifluoperazine in the perfused hearts. In addition, no effects of 10(-5) M trifluoperazine were noted on beta-adrenergic receptor binding of [3H](+/-)carazolol or on adenylate cyclase activity. In vitro studies with partially purified rat cardiac phosphorylase kinase demonstrated 1.5- to 3-fold stimulation by exogenous calmodulin. The addition of 10(-5) M trifluoperazine prevented calmodulin stimulation but had little effect on activity in the absence of exogenous calmodulin. The present results suggest that reversible binding of calcium-calmodulin may represent a physiological means for regulating phosphorylase kinase activity in rat cardiac muscle.
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PMID:Regulation of phosphorylase kinase in rat ventricular myocardium. Role of calmodulin. 629 96

Studies on the rats with genetically-controlled hypertension (spontaneously hypertensive rats, SHR) in which myocardiopathy had been produced by isoproterenol (ISP) administration (2 X 80 mg/kg sc daily for two days) have shown that the myocardiopathy results in a fall of the activity of adenylate cyclase (AC) lasting from the second to the fourth day after administration of ISP, while the activity of phosphodiesterase (PDE) remained unchanged. In vitro, ISP (10(-7)-10(-4)M), Mg2+ (4-25nM), GTP (10(-6)-10(-5)M) and GTP (10(-5)M) given in combination with ISP (10(-6)-10(-5)M) elevated the AC activity in the cardiac muscle of SHR similarly in controls and the rats with ISP-induced myocardiopathy. The results indicate that the depression of AC activity in the cardiac muscle of SHR following ISP-induced myocardiopathy is a result of reduction of the number of AC molecules rather than a consequence of the structural damage of AC.
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PMID:The activity of adenylate cyclase and phosphodiesterase in the isoproterenol-damaged cardiac muscle of spontaneously hypertensive rats. 631 39

The presence of receptors, recognized by Vasoactive Intestinal Peptide (VIP) and Peptide having N-terminal Histidine and C-terminal Isoleucine amide (PHI), was documented in membranes from human right auricle and left ventricular cardiac muscle by the ability of these peptides to stimulate adenylate cyclase. The capacity of VIP and PHI to activate the enzyme was comparable, in auricle as well as ventricle membranes, the affinity of the system being moderately higher for VIP than for PHI. In auricles, dose-effect curves appeared compatible with the coexistence of high-affinity and low-affinity VIP receptors. PHI could not, however, discriminate these subclasses of VIP receptors.
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PMID:Vasoactive intestinal peptide (VIP) and peptide having N-terminal histidine and C-terminal isoleucine amide (PHI) stimulate adenylate cyclase activity in human heart membranes. 689 44

Mg2+ and Mn2+ stimulation of basal, F-, and guanyl-5'-yl imidodiphosphate (GPP(NH)P) stimulated adenylate cyclase in particulate and detergent-solubilized preparations of skeletal muscle, cardiac muscle, and erythrocytes was examined. Solubilization decreased the concentrations of Mg2+ required for half-maximal velocity and for saturation. Concentrations of Mn2+ required for saturation and for half-maximal velocity of particulate preparations was much lower than for Mg2+ and these values were not markedly reduced by solubilization. Particulate and soluble preparations were similarly stimulated by NaF and GPP(NH)P. Activation of the heart and skeletal muscle enzyme by NaF and GPP(NH)P greatly reduced the Mg2+ requirement; this was seen with both particulate and solubilized preparations. It is suggested that solubilization removes Mg2+ action at a regulatory site; MgATP and MnATP are both effective at the catalytic site, the latter producing higher Vmax.
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PMID:Mg2+ and Mn2+ effects on membrane-bound and detergent-solubilized adenylate cyclase. 731 21


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