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

The interaction of the renin-angiotensin system and the sympathetic nervous system in patients with congestive heart failure is not well understood. We tested the hypothesis that angiotensin-converting enzyme inhibitors can resensitize the beta-adrenergic receptor system. Guinea pigs were given captopril, isoproterenol, or both for 2 weeks. At death, cardiac sarcolemmal and light vesicle fractions and intact mononuclear leukocytes were prepared. Captopril treatment led to an up-regulation of cardiac beta 1- but not mononuclear leukocyte beta 2-adrenergic receptors and an increase in isoproterenol-stimulated adenylate cyclase activity in the heart. Animals treated with isoproterenol developed cardiac hypertrophy, had increased plasma norepinephrine levels, and had a decreased number and responsiveness of both cardiac and mononuclear leukocyte beta-adrenergic receptors. Concomitant treatment with captopril attenuated alterations of heart weight, plasma norepinephrine levels, and cardiac beta-receptor density and function. In contrast to its cardiac effects, captopril treatment did not diminish the down-regulation of mononuclear leukocyte beta 2-adrenergic receptors by isoproterenol. Our data suggest that captopril may resensitize the cardiac but not the mononuclear leukocyte beta-adrenergic receptor-adenylate cyclase system after long-term catecholamine exposure.
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PMID:Regulation of cardiac beta-adrenergic receptors by captopril. Implications for congestive heart failure. 254 69

Adenylate cyclase activation through adrenergic receptors in rat ascites hepatoma (AH) 130 cells in response to adrenergic drugs was studied, and receptor binding and displacement were compared with those of normal rat hepatocytes. Epinephrine (Epi) and norepinephrine (NE) activated AH130 adenylate cyclase about half as much as isoproterenol (IPN) but equaled IPN after treatment with the alpha-antagonist phentolamine or islet-activating protein (IAP). The three catecholamines in hepatocytes were similar regardless of phentolamine or IAP. These catecholamines activated adenylate cyclase in order of IPN greater than NE greater than Epi in AH130 cells but IPN greater than Epi greater than NE in hepatocytes. We then used the alpha 1-selective ligand [3H]prazosin, the alpha 2-selective ligand [3H]clonidine, and the beta-ligand [125I]iodocyanopindolol [( 125I]ICYP), and found that AH130 cells had few prazosin-binding sites, about eight times as many clonidine-binding sites with high affinity, and many more ICYP-binding sites than in hepatocytes. The dissociation constant (Ki) of the beta 1-selective drug metoprolol by Hofstee plots for AH130 cells was lower than that for hepatocytes. The inhibition of specific ICYP binding by the beta 2-selective agonist salbutamol for AH130 cells gave only one Ki value which was much higher than both high and low Ki values of the drug for hepatocytes. These findings indicate that the alpha- and beta-adrenergic receptors in hepatocytes are predominantly alpha 1-type and beta 2-type, but that those in AH130 cells are predominantly alpha 2-type and beta 1-type, and the low adrenergic response of AH130 cells is due to the dominant appearance of alpha 2-adrenergic receptors, linked with the inhibitory guanine-nucleotide binding regulatory protein, instead of alpha 1-adrenergic receptors, and beta 1-adrenergic receptors with low affinity for the hormone.
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PMID:Altered adrenergic response and specificity of the receptors in rat ascites hepatoma AH130. 255 51

In heart failure a decrease in cardiac beta-adrenoceptors presumably due to endogenous down-regulation by the elevated catecholamines is a general phenomenon. Thus, attempts have been made to assess beta-adrenoceptor function in patients with chronic heart failure in order to monitor the functional state of cardiac beta-adrenoceptors. The model most widely used is that of circulating lymphocytes that contain a homogeneous population of beta 2-adrenoceptors coupled to the adenylate cyclase/cyclic AMP system. The biochemical and pharmacological properties of beta 2-adrenoceptors present in lymphocytes are quite comparable to those of beta 2-adrenoceptors in the human heart, but clearly different from those of human cardiac beta 1-adrenoceptors. Furthermore, beta-adrenoceptor agonists and antagonists regulate lymphocyte beta 2- and cardiac beta 1- and beta 2-adrenoceptors in a subtype-selective fashion: while non-selective agonists (independent of exogenously applied or endogenously elevated) and antagonists affect both cardiac beta 1- and beta 2- as well as lymphocyte beta 2-adrenoceptors, beta 1-selective agonists and antagonists influence only cardiac beta 1-, but not cardiac and lymphocyte beta 2-adrenoceptors. Finally, direct comparison of lymphocyte and cardiac beta-adrenoceptor densities revealed that changes in lymphocyte beta 2-adrenoceptors are significantly correlated with changes in cardiac beta 2-adrenoceptors, but not related to changes in cardiac beta 1-adrenoceptors. Since beta 1-adrenoceptors predominate in all parts of the human heart, the use of lymphocyte beta 2-adrenoceptors as a tool for predicting the status of cardiac beta-adrenoceptors is, therefore, quite limited.
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PMID:Beta-adrenoceptor regulation in the human heart: can it be monitored in circulating lymphocytes? 255 8

Prenalterol (beta 1-agonist), denopamine (beta 1-agonist), and zinterol (beta 2-agonist) were partial agonists of adenylate cyclase (AC) stimulation in human ventricular myocardium obtained from nonfailing chambers whose beta 1/beta 2 receptor subtype ratio was approximately 80/20. At a concentration less than its low affinity (beta 2) Kl, betaxolol, a highly selective beta 1-antagonist, inhibited isoproterenol (non-selective agonist), denopamine, and prenalterol stimulation of AC, indicating that isoproterenol, denopamine, and prenalterol are all capable of stimulating AC through beta 1-receptor activation. At a concentration less than its low affinity (beta 1) Kl, ICI 118,551, a highly selective beta 2-agonist, inhibited both isoproterenol and zinterol stimulation of AC, indicating that isoproterenol and zinterol stimulate AC through beta 2-receptors. Zinterol stimulation of AC was mediated entirely by beta 2-receptors, inasmuch as 10(-7) M betaxolol had no effect on the zinterol dose-response curve and ICI 118,551 produced a degree of blockade (KB = 5.2 +/- 1.6 X 10(-9) M), consistent with the beta 2-receptor Kl of the latter (2.0 +/- .4 X 10(-9) M, p, not significant). In nonfailing myocardium, analysis of beta 1 versus beta 2 stimulation by the nonselective agonist isoproterenol revealed that the numerically small (19% of the total) beta 2 fraction accounted for the majority of the total adenylate cyclase stimulation. In failing ventricular chambers with a beta 1/beta 2 receptor subtype ratio reduced from 82/19 (nonfailing) to 64/36 (p less than 0.001) and a beta 1-receptor density reduced by 61% (p less than 0.001), maximal denopamine stimulation was reduced by 49% (p less than 0.001). Moreover, in preparations from failing heart, the component of denopamine stimulation that was inhibited by 10(-7) M betaxolol (beta 1 component) was reduced by 77% (p less than 0.05). Finally, in preparations derived from failing ventricular myocardium, beta 2-receptor density was not significantly decreased, but zinterol stimulation of AC was reduced by 32% (p less than 0.05). We conclude that heart failure results in subsensitivity to both selective beta 1 and beta 2 stimulation of adenylate cyclase, with beta 1 subsensitivity due to selective beta 1 receptor down-regulation and beta 2 subsensitivity due to partial uncoupling of beta 2 receptors from subsequent events in the beta 2-adrenergic pathway.
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PMID:Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. 256 29

The adrenergic nervous system profoundly alters water excretion by both renal and extrarenal pathways. The effects of catecholamines on cultured rat inner medullary collecting tubule cells were studied. The beta-adrenergic agonist, isoproterenol, increases cAMP from 19.5 +/- 2.3 to 79.4 +/- 14.4 fm/micrograms protein, P less than 0.001. The response to arginine vasopressin (AVP) is also greater in the presence of isoproterenol, but the increment is unchanged when compared to that seen in the absence of AVP. The agonist effect of isoproterenol is blocked by propranolol but not by the specific beta 1 antagonist, atenolol. The effect of alpha-adrenergic stimulation was studied by the use of norepinephrine (NE) in the background of the beta blocker, propranolol. NE decreases AVP-stimulated cAMP generation from 190 +/- 11 to 117 +/- 10 fm/micrograms, P less than 0.001, N = 6. The specific alpha 2 antagonist, yohimbine, but not the alpha 1 antagonist, prazosin, prevents the NE-induced decrease as AVP-stimulated cAMP is restored to 187 +/- 19 fm/micrograms. Similarly the selective alpha 2 agonist, clonidine, significantly inhibits both AVP- and isoproterenol-mediated cAMP generation. To define the site of alpha 2 inhibition in the adenylate cyclase (AC) complex the effect of pertussis toxin (PT) was investigated. After pretreatment with PT (1-1000 ng/ml), AVP-stimulated cAMP was not inhibited by NE. The alpha 1 agonist, phenylephrine, fails to inhibit AC or to increase cytosolic Ca in these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adrenergic control of cAMP generation in rat inner medullary collecting tubule cells. 256 11

The agonist (-)-denopamine was used as a tool to study relationships between pharmacological effects and adenylate cyclase stimulation mediated through beta 1-adrenoceptors. 1. (-)-Denopamine was a full agonist in kitten papillary muscles (force), kitten left atria (force) and kitten and guinea-pig atria (sinoatrial frequency). (-)-Denopamine was a strong partial agonist in guinea-pig tracheae (relaxation). None of these effects was influenced by blockade of beta 2-adrenoceptors. beta 1-Adrenoceptors mediated all effects of (-)-denopamine in atria and effects of low (-)-denopamine concentrations in papillary muscles and tracheae, as assessed with beta 1-selective antagonists. 2. High (-)-denopamine concentrations caused positive inotropic effects in papillary muscles and tracheorelaxant effects that were resistant to blockade by beta 1-, beta 2- and alpha-adrenoceptor antagonists (non-adrenergic effects). 3. (-)-Denopamine stimulated the adenylate cyclase of membranes derived from kitten ventricle and calf tracheal cells with an intrinsic activity of 0.3 and 0.2, respectively, compared to catecholamines. The contribution of beta 1- and beta 2-adrenoceptors to cyclase stimulation was assessed by selective blockade. Cyclase stimulation through beta 2-adrenoceptors by (-)-denopamine was 12% in ventricle and 82% in trachea but is not associated with positive inotropic effects and tracheal relaxation. 4. (-)-Denopamine exhibited only a 2- to 5-fold selectivity for beta 1-adrenoceptors compared to beta 2-adrenoceptors, as estimated consistently from binding assays and blockade of cyclase stimulation in myocardial and tracheal cell membranes. 5. Desensitization of kitten ventricular tissues, caused by a 3 h exposure to 30 mumol/l (-)-isoprenaline followed by 5 h washout, reduced the inotropic sensitivity of papillary muscles without decreasing the maximum inotropic effects of (-)-denopamine. In desensitized tissues, the nonadrenergic effect contributed by 30% to the maximum inotropic effect of (-)-denopamine. 6. In membranes, derived from desensitized tissues, the maximum adenylate cyclase stimulation induced by (-)-isoprenaline, (-)-denopamine and xamoterol was reduced to 1/2 of the corresponding stimulations observed in membranes from sham desensitized tissues. The density of beta-adrenoceptors, assessed with 3H-(-)-CGP 12,177, was not changed by the desensitization procedure suggesting that part of the receptors was uncoupled from the adenylate cyclase. The partial inotropic agonist xamoterol, which has an intrinsic activity of 0.5 in non-desensitized tissues, failed to cause positive inotropic effects in desensitized papillary muscles suggesting that not all cyclic AMP possesses inotropic relevance.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:On minimum cyclic AMP formation rates associated with positive inotropic effects mediated through beta 1-adrenoceptors in kitten myocardium. Beta 1-specific and non-adrenergic stimulant effects of denopamine. 256 21

The nature of the receptors that mediate the relaxation of smooth muscle by field stimulation, (-)-noradrenaline and (-)-adrenaline was investigated in calf tracheal smooth muscle. The relation between relaxation, stimulation of the adenylate cyclase and density of beta-adrenoceptor subtypes was studied with the help of antagonists of beta 1- and beta 2-adrenoceptors. The question of the existence of catecholamine-containing nerves was also investigated. (1) Nerves with varicosities exhibiting catecholaminergic fluorescence were observed between bundles of smooth muscle cells. (2) Consistent with the existence of adrenergic nerves (-)-noradrenaline was also found. The content of (-)-noradrenaline (1 microgram.g-1 w.w.) was the same in smooth muscle strips from the sublaryngeal region and from the region close to the bifurcation of the calf trachea. (-)-Adrenaline was not detected. (3) Smooth muscle relaxation by low (-)-noradrenaline concentration (0.6-2 nmol/l) was mediated through beta 1-adrenoceptors. Low concentrations of (-)-adrenaline (0.06-1 nmol/l) relaxed through beta 2-adrenoceptors. High concentrations of (-)-noradrenaline and (-)-adrenaline also caused relaxation through beta 2- and beta 1-adrenoceptors respectively. (4) Field stimulation caused relaxation which was half maximal at 0.2-0.8 Hz. Blockade of beta 1-adrenoceptors strongly attenuated the relaxant response to field stimulation and shifted the frequency-relaxation curves to 4 times higher frequencies. These results are consistent with a beta 1-adrenoceptor-mediated relaxation caused by (-)-noradrenaline released from sympathetic nerve endings at low stimulation frequencies. (5) Blockade of beta 2-adrenoceptors failed to reduce smooth muscle relaxation caused by field stimulation at low stimulation frequencies (0.1-1 Hz). However, after beta 1-adrenoceptor blockade, additional blockade of beta 2-adrenoceptors reduced the relaxant effects observed at high frequencies (2-400 Hz). The results suggest that high concentrations of endogenous (-)-noradrenaline cause relaxation through beta 2-adrenoceptors. (6) Binding experiments with 3H-(-)-bupranolol and 3H-ICI 118,551 revealed between 10,000 and 20,000 beta-adrenoceptors per smooth muscle cell of which 3/4 were beta 2 and 1/4 beta 1. The equilibrium dissociation constant of (-)-adrenaline for both beta 1- and beta 2-adrenoceptors and of (-)-noradrenaline for beta 1-adrenoceptors was 1 mumol/l. The affinity of (-)-noradrenaline for beta 2-adrenoceptors was 10 to 20 times lower than for beta 1-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neuronally released (-)-noradrenaline relaxes smooth muscle of calf trachea mainly through beta 1-adrenoceptors: comparison with (-)-adrenaline and relation to adenylate cyclase stimulation. 256 29

Two cell cultures, NEP2 and NEM2, isolated from human foetal brain have been maintained through several passages and found to express some properties of astrocytes. Both cell cultures contain adenylate cyclase stimulated by catecholamines with a potency order of isoprenaline greater than adrenaline greater than salbutamol much greater than noradrenaline, which is consistent with the presence of beta 2-adrenergic receptors. This study reports that the beta 2-adrenergic-selective antagonist ICI 118,551 is approximately 1,000 times more potent at inhibiting isoprenaline stimulation of cyclic AMP (cAMP) formation in both NEP2 and NEM2 than the beta 1-adrenergic-selective antagonist practolol. This observation confirms the presence of beta 2-adrenergic receptors in these cell cultures. The formation of cAMP in NEP2 is also stimulated by 5'-(N-ethylcarboxamido)adenosine (NECA) more potently than by either adenosine or N6-(L-phenylisopropyl)adenosine (L-PIA), which suggests that this foetal astrocyte expresses adenosine A2 receptors. Furthermore, L-PIA and NECA inhibit isoprenaline stimulation of cAMP formation, a result suggesting the presence of adenosine A1 receptors on NEP2. The presence of A1 receptors is confirmed by the observation that the A1-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine reverses the inhibition of isoprenaline stimulation of cAMP formation by L-PIA and NECA. Additional evidence that NEP2 expresses adenosine receptors linked to the adenylate cyclase-inhibitory GTP-binding protein is provided by the finding that pretreatment of these cells with pertussis toxin reverses the adenosine inhibition of cAMP formation stimulated by either isoprenaline or forskolin.
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PMID:Regulation of cyclic AMP formation in cultures of human foetal astrocytes by beta 2-adrenergic and adenosine receptors. 256 6

The effects of some beta-adrenergic agonists were studied in the parotid gland of the rat by electrophysiological techniques. In the unoperated gland, isoprenaline caused depolarizations which were slowly developing, long-lasting and of low amplitude. The same response was seen when noradrenaline was combined with alpha-adrenoceptor blocking drugs. A greater number of cells responded to this combination than to isoprenaline. After either parasympathetic or sympathetic denervation 1-3 weeks in advance, to induce supersensitivity, the number of cells responding to beta-adrenoceptor stimulating drugs was significantly increased. In the latter case the threshold dose required to evoke a response was also significantly lowered. Atropine did not have any effect on the isoprenaline-evoked response. The combined parasympathetic and sympathetic denervation did not further increase the responsiveness. It is concluded that beta-adrenoceptor stimulation in the parotid gland of the rat may cause membrane depolarizations. The response is mediated by beta 1-adrenoceptors. The responsiveness is increased in the denervated gland. Secretory studies have demonstrated a supersensitivity to beta-adrenergic agonists as a result of denervation. On the other hand, beta-adrenoceptor stimulation is believed mainly to activate the adenylate cyclase/cyclic AMP system independent of membrane potential changes. It is thus not known if the present 'supersensitivity' is correlated to the increased secretory response earlier demonstrated in this gland.
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PMID:Effects of beta-adrenergic agonists in the parotid gland of the rat--an electrophysiological study. 257 Dec 34

The stimulant effects of adrenaline and noradrenaline on contractile force and adenylate cyclase, mediated through beta 1 and beta 2-adrenoceptors, are analysed in isolated atrial and ventricular myocardium of man. The tissues were obtained from patients without advanced heart failure undergoing heart surgery. Usually, both adrenaline and noradrenaline stimulated adenylate cyclase predominantly through ventricular and atrial beta 2-adrenoceptors. Because the relative density of beta 2-adrenoceptors is usually smaller than that of beta 1-adrenoceptors, stimulation of one beta 2-adrenoceptor leads to the production of up to 10 times more cyclic AMP molecules than does stimulation of one beta 1-adrenoceptor. Adrenaline and noradrenaline maximally enhance contractile force through both atrial and ventricular beta 1-adrenoceptors. Adrenaline can also maximally enhance contractile force through atrial beta 2-adrenoceptors. In the ventricle, adrenaline increases force via beta 2-adrenoceptors by up to 60% of its maximal beta 1 response. Noradrenaline can increase atrial and ventricular contractile force through beta 2-adrenoceptors but only at high concentrations. Unexpectedly, in atria from patients treated with the beta 1-selective antagonist atenolol, contractile responses to adrenaline are markedly and selectively augmented through activation of beta 2-adrenoceptors. In atria from atenolol-treated patients equi-inotropic concentrations of adrenaline and noradrenaline acting through beta 2 and beta 1-adrenoceptors, respectively, cause similar increases of cyclic AMP and of cyclic AMP-dependent protein kinase activity.
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PMID:A comparison of the effects of adrenaline and noradrenaline on human heart: the role of beta 1- and beta 2-adrenoceptors in the stimulation of adenylate cyclase and contractile force. 257 19


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