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)

Phenoxybenzamine at a concentration of 2 X 10(-6 M) produced half-maximal inhibition of dopamine-stimulated adenylate cyclase activity in homogenates of rat striatum. Inhibition was sharply dependent on time and temperature of preincubation with the inhibitor. When included in the preincubation medium, dopamine was nearly 8 times more effective than norepinephrine at protecting against this inhibition, whereas neither isoproterenol nor methoxamine appeared to protect at all. These results suggest a direct, and possibly irreversible, interaction of phenoxybenzamine with the dopamine-binding component of the adenylate cyclase.
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PMID:Inhibition of dopamine-stimulated adenylate cyclase activity by phenoxybenzamine. 72 35

An appraisal of the affinity of (-)-propranolol was made for beta-adrenoceptors of isolated heart preparations and myocardial membrane particles from patients undergoing open heart surgery. In order to eliminate possible distorting influences of neuronal and extraneuronal uptakes of catecholamines on the affinity estimates for (-)-propranolol, isolated tissues were pretreated once with 5 or 10 mumol/l phenoxybenzamine for 2 h. Phenoxybenzamine caused potentiation of the positive inotropic effects of (-)-noradrenaline and (-)-adrenaline but not of (-)-isoprenaline; potentiation was more pronounced in atrial than in ventricular preparations. Potentiation was greater for (-)-noradrenaline than for (-)-adrenaline. It is concluded that the concentration of physiological catecholamines at the human heart beta-adrenoceptors is limited by neuronal capture but not by extraneuronal uptake. The antagonism of the positive inotropic effects of (-)-adrenaline and (-)-noradrenaline by (-)-propranolol was simple competitive in left ventricular myocardium of patients with mitral lesion. The effects of (-)-adrenaline and (-)-noradrenaline were antagonized to similar extent by (-)-propranolol. An equilibrium dissociation constant KB (-log mol/l) of 8.6 was estimated for (-)-propranolol. In atrial preparations the inotropic effects of (-)-adrenaline were antagonized significantly more by (-)-propranolol than those of (-)-noradrenaline. KB-Values (-log mol/l) of 8.9 [against (-)-adrenaline] and 8.5 [against (-)-noradrenaline] were estimated for (-)-propranolol. Concentration-effect curves for the stimulation of adenylate cyclase of both atrium and ventricle were biphasic for (-)-noradrenaline and monophasic for (-)-adrenaline. The high-sensitivity and low-sensitivity components of (-)-noradrenaline comprised 1/3 and 2/3, respectively, of maximum cyclase stimulation. As expected from beta 1-adrenoceptors, the high-sensitivity component of the curve for (-)-noradrenaline was selectively antagonized by (-)-bisoprolol; as expected from beta 2-adrenoceptors, the low-sensitivity component was selectively antagonized by ICI 118,551. (-)-Propranolol antagonized the effects of (-)-noradrenaline mediated by beta 2-adrenoceptors 2 to 3 times more potently than the effects mediated by beta 1-adrenoceptors. (-)-Propranolol competed with 3H-(-)-bupranolol for binding to left ventricular beta-adrenoceptors. An equilibrium dissociation constant (-log mol/l) of 8.6 was estimated for (-)-propranolol.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The affinity of (-)-propranolol for beta 1- and beta 2-adrenoceptors of human heart. Differential antagonism of the positive inotropic effects and adenylate cyclase stimulation by (-)-noradrenaline and (-)-adrenaline. 299 16

1. The mechanism of stimulation of cyclic adenosine 3',5'-monophosphate (cyclic AMP) accumulation by adrenaline and ouabain and the effect of Mn(++) substitution for Mg(++) as the metal ion requirement of this system was studied in cell-free preparations of adenyl cyclase from rat brain.2. In the rat cerebral cortex preparation, substitution of Mn(++) for Mg(++) significantly increased cyclic AMP accumulation while significantly inhibiting adenosine triphosphate (ATP) and adenosine diphosphate (ADP) hydrolysis and adenosine 5'-monophosphate (AMP) accumulation. In the synaptic membrane preparation, in the absence of NaF, the highest amount of ATP hydrolysis was obtained in tissue prepared with Mn(++) and incubated with Mg(++); under these conditions cyclic AMP accumulation was equal to that produced under any other condition and significantly higher than that observed in the presence of Mg(++) prepared and Mg(++) incubated tissue.3. Preparation and/or incubation of tissue with Mn(++) significantly reduced phosphodiesterase (PDE) activity compared to that observed in Mg(++) prepared tissue.4. Adrenaline and ouabain both significantly increased cyclic AMP accumulation in the rat cerebral cortex preparation but did not inhibit ATP or ADP hydrolysis. In the synaptic membrane preparation, in the presence of 0.01 mM Ca(++), adrenaline but not ouabain significantly increased cyclic AMP accumulation. Phenoxybenzamine (0.1 mM) and pronethalol (0.1 mM) significantly inhibited adrenaline-induced cyclic AMP accumulation in both these preparations.5. Ouabain and adrenaline both failed to stimulate cyclic AMP accumulation in the presence of Mn(++) prepared and/or incubated tissue.6. Ouabain and adrenaline had no effect on PDE activity in either of these preparations.7. It was concluded that Mn(++) increased cyclic AMP accumulation in part by indirect inhibition of ATP and ADP hydrolysis which provides inhibitors of cyclic AMP destruction, by direct stimulation of adenyl cyclase and by inhibition of cyclic AMP destruction in a way unrelated to nucleotide inhibition of PDE. Adrenaline and ouabain appeared tp stimulate cyclic AMP accumulation in a more direct manner.
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PMID:The relation of adenyl cyclase to the activity of other ATP utilizing enzymes and phosphodiesterase in preparations of rat brain; mechanism of stimulation of cyclic AMP accumulation by adrenaline, ouabain and Mn++. 414 40

1 At higher temperatures, near the physiological range for mammals and nonhibernating frogs, the adrenoceptors for both inotropic responses to adrenaline and noradrenaline and for cyclic 3',5'-adenosine monophosphate (cyclic AMP) production in rat and frog isolated heart preparations, had typical beta characteristics. Phenoxybenzamine potentiated the inotropic response and the accumulation of cyclic AMP; conversely, propranolol inhibited the two responses.2 When the ambient temperature was reduced, the adrenoceptors mediating cyclic AMP production changed very little; they were blocked as effectively as at the higher temperature by propranolol and were not blocked by phenoxybenzamine. However, the adrenoceptors mediating the inotropic response were markedly changed by the decrease in temperature; phenoxybenzamine now inhibited this response and the inhibitory activity of propranolol was reduced about tenfold.3 These results indicate that the adrenoceptors that mediate cardiac inotropic responses at physiological temperatures are distinct from those that mediate the production of cyclic AMP, and that the activation of adenylate cyclase and the accumulation of cyclic AMP are probably not intermediate steps in cardiac inotropic responses to catecholamines.
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PMID:Dissociation of cardiac inotropic and adenylate cyclast activating adrenoceptors. 437 24

Effects of alpha adrenergic agents on intestinal secretion induced by prostaglandin E1 (PGE1), vasoactive intestinal peptide (VIP) and dibutyryl cyclic AMP (Bt2cAMP) were investigated in rat jejunum in vivo. Oxymetazoline and clonidine were more potent than epinephrine in inhibiting the PGE1-induced secretion. Methoxamine failed to inhibit the PGE1-induced secretion even with a 100-fold higher dose than that of clonidine. A high dose (1 mumol/kg) of oxymetazoline not only inhibited the PGE1- induced secretion but also enhanced net fluid absorption. Yohimbine reversed the inhibitory effect of clonidine, whereas phenoxybenzamine did not. These antagonists per se did not produce any effects on PGE1-induced secretion. Clonidine inhibited the intestinal secretion induced by VIP or Bt2cAMP, whereas methoxamine did not. The inhibitory effect of clonidine was reversed by yohimbine. Phenoxybenzamine per se inhibited intestinal secretion induced by either VIP or Bt2cAMP. Clonidine did not produce any significant effects on PGE1- augmented cAMP levels in jejunal mucosa in vivo. These results suggest that stimulation of alpha-2 adrenoceptors in rat jejunal mucosa inhibits some mechanisms distal to cAMP generation and in turn results in the inhibition of net water intestinal secretion. These findings also raise the question of general validity of a hypothesis that alpha-2 adrenoceptors regulate cellular functions through the inhibition of adenylate cyclase activity.
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PMID:Alpha-2 adrenergic inhibition of intestinal secretion induced by prostaglandin E1, vasoactive intestinal peptide and dibutyryl cyclic AMP in rat jejunum. 612 Oct 49

alpha 2-Adrenergic receptors are members of an important class of membrane-bound receptors which appear to mediate physiologic responses by decreasing the activity of the regulatory enzyme adenylate cyclase. This report describes the first direct indentification of the subunit-binding site of alpha 2-adrenergic receptors. alpha 2-Adrenergic receptors from human platelets were solubilized with 1% digitonin and were purified approximately 600-fold by repetitive affinity chromatography. In saturation and competition binding studies using [3H]yohimbine the original alpha 2-adrenergic characteristics were retained by the partially purified receptor, i.e. the following potency series (based on Ki values) was obtained: phentolamine approximately equal to yohimbine much greater than prazosin and (-)epinephrine greater than (+)epinephrine. Phenoxybenzamine was found to have a Ki for the partially purified alpha 2-adrenergic receptor of 108 nM. As judged by the loss of specific [3H]yohimbine binding, phenoxybenzamine (a known alkylating agent) was found to bind irreversibly to the partially purified alpha 2-adrenergic receptor. Using [3H]phenoxybenzamine, covalent labeling of proteins in the partially purified receptor preparation was obtained. Following sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography, a specifically labeled peptide with a relative molecular mass of 61,000 was visualized. Irreversible labeling of this peptide by [3H]phenoxybenzamine could be prevented with either phentolamine or (-)epinephrine, but not with prazosin or (+)epinephrine, suggesting that this peptide of Mr = 61,000 represents the major subunit binding site of the human platelet alpha 2-adrenergic receptor.
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PMID:Identification of the subunit-binding site of alpha 2-adrenergic receptors using [3H]phenoxybenzamine. 633 87