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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of cGMP as a second messenger for renin secretion is contentious. This was investigated using a superfused collagenase-dispersed rat kidney cortex cell preparation devoid of indirect influences on renin secretion. Nitroprusside, atriopeptin II and 8-Br-cGMP all increased renin release but the dose-response relationships were biphasic. At low dose ranges there was a positive correlation between increasing drug concentration and renin secretion, but at high drug concentrations, a negative correlation was apparent. Methylene blue, a guanylate cyclase inhibitor, also suppressed baseline renin release at 10(-5) and 10(-6) M, but stimulated release at 10(-3) M. Using mid-range drug concentrations, the cGMP specific phosphodiesterase inhibitor MB22948 potentiated renin release in response to nitroprusside and 8-Br-cGMP. Inhibition of guanylate cyclase with either methylene blue or LY83583 attenuated renin release in response to nitroprusside, but, as expected, had no effect on 8-Br-cGMP induced release. We conclude that, under physiological conditions, cGMP is a stimulatory second messenger for renin release. This activity is mimicked at low dose ranges by 8-Br-cGMP, nitroprusside and atriopeptin II. In response to high doses of these drugs an unknown inhibitory pathway is activated and this opposes, in a dose-related manner, the stimulatory actions of cGMP for renin release.
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PMID:Cyclic GMP-linked pathway for renin secretion. 770 14

The principle functions of the heart are to accept blood from the systemic and the pulmonary circulatory system, pump and deliver it to the whole body tissues and lungs. The term "heart failure" is used to describe the pathophysiological state in which an abnormality of cardiac function is responsible for failure of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues, or to do so only from an elevated filling pressure. Thus, for a long period, heart failure has been thought of as a mechanical disorder of the heart and vessels, and its treatment has been based on improving impaired cardiac function and hemodynamic disorder. Recently multi-center, randomized placebo-controlled survival trials revealed that pure inotropic agents such as phosphodiesterase inhibitors succeeded in mechanical improvement, yet not only failed to prolong the patient's life, but also increased mortality. A number of neurohumoral mechanisms, which are activated in heart failure, were thought to be compensatory ones. However, survival trials demonstrated that two types of drug interfering with the renin-angiotensin system and the sympathetic nervous system reduced mortality. Those drugs are angiotensin-converting enzyme (ACE) inhibitors and beta blockers. ACE inhibitors reduce the direct effects of angiotensin II on myocardial cells, which may lead to cell necrosis, imbalanced remodeling through fibrosis, and attenuate the progressive ventricular dilatation. Local tissue renin-angiotensin system may be potentially important in regulating the angiotensin II production in both heart and vessels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Pathophysiology and treatment of congestive heart failure--recently advanced strategy for heart failure]. 774 73

Experiments were performed on juxtaglomerular granular cells (JGC) in short-term primary culture to determine the direct immediate effect of NO on renin secretion and to test whether JGC are able to generate NO. Renin secretion was measured repeatedly over short time intervals in a cell superfusion system. Renin release did not significantly decrease over a 40-min observation period in untreated JGC. Addition of sodium nitroprusside (SNP) caused a reduction in renin release (measured in nano-Goldblatt hog units vs. time, i.e., nGU/min) from 479 +/- 25, 423 +/- 70, and 388 +/- 54 nGU/min to 295 +/- 19 (n = 5), 102 +/- 21 (n = 7), and 71 +/- 9 nGU/min (n = 6) with 10(-5), 10(-4), and 10(-3) M SNP, respectively. In the presence of the guanylate cyclase inhibitor methylene blue at 10(-4) M, SNP at 10(-4) M had no significant effect on renin secretion. 8-Bromoguanosine 3',5'-cyclic monophosphate at 10(-4) M in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (10(-3) M) caused a reduction of renin secretion to 50.1 +/- 3.6% of control. To examine the possibility that renin secretion is affected by NO release from JGC, we assessed the effect of the NO synthase (NOS) substrate L-arginine (10(-3) M) and the NOS blocker N omega-nitro-L-arginine (10(-4) M) on renin secretion. Renin release was not significantly altered by either stimulation or inhibition of NOS activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of nitric oxide on renin secretion. I. Studies in isolated juxtaglomerular granular cells. 777 23

This study evaluated activation of beta-adrenoceptors and the cAMP pathway on prorenin secretion from human placental explants. For comparative purposes, hCG secretion was also measured. Treatment with selective beta-adrenergic agonists (beta 1-dobutamine and beta 2-terbutaline) produced dose-dependent increases in prorenin secretion, with dobutamine yielding a greater response (10- vs. 6-fold). In contrast, hCG secretion was stimulated only by terbutaline (5-fold). Prorenin and hCG secretory responses were inhibited by corresponding selective receptor antagonists (beta 1-metoprolol and beta 2-ICI 118,551). Selective phosphodiesterase inhibitors were used to evaluate the role of cAMP in mediating these responses. Marked potentiation of beta-adrenoceptor-dependent prorenin secretion was observed with the type III inhibitor, cilostamide (63-76%), and the type IV inhibitor, Ro-201724 (32-43%). Type I (8-methoxymethyl-3-isobutylmethylxanthine) and type V inhibitors (dipyridamole and M&B 22,948) showed no potentiation. These studies demonstrate that activation of both beta 1- and beta 2-receptors stimulates placental prorenin release. The potentiation of beta-adrenergically activated prorenin release by selective inhibitors of phosphodiesterase indicates a coupling of beta-adrenoceptor and adenylate cyclase. The contrast in secretion of prorenin and hCG by selective beta-adrenergic agonists suggests differences in cellular localization. The results indicate that clinically used adrenergic agonists can affect the placental renin-angiotensin system. The role of endogenous activators of beta-adrenoceptors in this system remains to be determined.
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PMID:Beta-adrenoceptor activation stimulates, and phosphodiesterase inhibition potentiates, placental prorenin synthesis and release. 790 14

Although prevention of heart failure recently has become a realistic issue, management of heart failure once the syndrome has developed, is mainly supportive, based on the various cardiac and peripheral changes which occur in the course of heart failure. Of these, abnormal neurohormonal activation is of major pathophysiologic and prognostic significance. Consequently, modulation of neuroendocrine activation is now recognized a prime target in the treatment of heart failure, besides diuretic therapy. In this respect, the value of converting enzyme inhibition is well established. Future developments in this area include dopaminergic agents, vasopressin antagonists, angiotensin II receptor antagonists, renin inhibitors, spironolactone and, possibly, ANF peptidase inhibitors. Besides diuretics, necessary when signs of fluid retention are present, the approach to heart failure management involves other pharmacologic issues. In view of abnormal vascular control with vasoconstriction prevailing during progressive heart failure, it clearly makes sense to vasodilate. However, of available vasodilators, only the combination of relatively high dose nitrates and hydralazine has proven to be of clinical significance, in terms of hemodynamics, exercise capacity and survival. It is possible, though, that novel generation dihydropyridine derivatives may prove beneficial as well. Thus far, there has been much debate concerning the usefulness and particularly the safety of positive inotrope therapy and inodilator treatment. Taken together, this concern relates to presence and predominance of cAMP-dependent mechanisms to induce these effects. Thus, sympathomimetic agents and phosphodiesterase inhibitors, such as milrinone or enoximone, are without beneficial effects, but instead shorten survival during long-term therapy. This may be different where compounds which act through cAMP-independent mechanisms, i.e., calcium sensitization or sodium channel stimulation, are concerned, but needs to be confirmed yet.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Congestive heart failure. Drug therapy: central or peripheral approach? 791 52

Renin synthesis and secretion from human chorion and decidua have previously been shown to be stimulated by agents which increase cellular cyclic adenosine monophosphate (cAMP). We have now used organ culture of villous placenta, incubated for periods up to 72 h, to investigate the cellular regulation of renin in this tissue. The placental tissues release renin (92-96% in the form of prorenin) and human chorionic gonadotrophin (hCG), but not prolactin. We found that cholera toxin and forskolin markedly stimulate the synthesis and release of renin in a time-dependent manner. This stimulation was potentiated by phosphodiesterase inhibitors and inhibited by an angiotensin II agonist, sar-1-angiotensin II. The inhibitory action of the angiotensin agonist on renin release was blocked by sar-1-leu-8-angiotensin II, a selective angiotensin receptor antagonist. The potential for stimulation of renin expression by cyclic AMP-regulated elements is supported by the dramatic (two-orders of magnitude) increase in renin release observed with cholera and forskolin at 72 h. There are several possible candidates for primary signals for adenylyl cyclase-coupled renin secretion from the placenta, including relaxin and epinephrine. The extremely low concentration of renin in term villous placenta may be related to activation of negative regulatory elements on the renin gene. We propose that angiotensin II is one negative regulator of this system.
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PMID:Prorenin secretion from villous placenta: regulation by cyclic AMP and angiotensin. 799 49

Previous studies in experimental diabetes have demonstrated cardiovascular abnormalities of the beta-adrenergic system and reduced adrenergically stimulated renal renin secretion. To examine the defect in the beta-adrenergic signal, glomerular cyclic adenosine monophosphate (cAMP) levels were measured in response to isoproterenol and other humoral agonists (coincubated with the phosphodiesterase inhibitor isomethylxanthine) in nondiabetic and diabetic BB/Wor rats. Basal (unstimulated) levels of glomerular cAMP did not differ between control and diabetic BB/Wor rats, nor did cAMP accumulation differ on incubation with the humoral agonists PGE2 and histamine. However, on incubation with varied concentrations of the nonselective beta-adrenergic agonist isoproterenol, control glomeruli demonstrated a twofold increase in cAMP while a negligible response was observed in diabetic glomeruli. Peak levels of cAMP were higher in control (192 +/- 24 pmol/mg protein) than in diabetic (141 +/- 8 pmol/mg protein) glomeruli (p < 0.01). No differences were observed on incubation with the adenylate cyclase stimulator forskolin. Measurement of glomerular beta-adrenoreceptors by coincubation with iodine 125-labeled cyanopindolol demonstrated no differences in either receptor number (Bmax) or affinity (KD). These data indicate that a specific defect in beta-adrenergic signalling exists in glomerular tissue from spontaneously diabetic rats. Because no decrease in forskolin-stimulated adenylate cyclase was observed, defective coupling of the receptor to its effector, perhaps through the guanine nucleotide stimulatory protein, may account for these observations.
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PMID:Defective glomerular beta-adrenergic signal transmission in spontaneously diabetic rats. 805 89

We investigated the effect of high physiological plasma levels of human varies; is directly proportional to atrial natriuretic factor (ANF) on renin and aldosterone secretion in normal sodium deplete men. In short term infusion studies (2 or 8 h duration), ANF plasma levels as observed after sodium loading (50-70 pg/ml) lowered basal renin (PRA) and aldosterone, but had only a marginal effect on angiotensin II-stimulated aldosterone secretion. Preliminary results of a study with long term infusion (6 days) of ANF during a period of dietary sodium depletion argue against a significant tonic inhibitory effect of ANF on the renin-aldosterone system in the preceding period of sodium repletion: the plasma aldosterone response to sodium depletion was similar with and without ANF infusion. The second messenger of ANF for the direct inhibition of aldosterone secretion from zona glomerulosa cells is still unknown. To test the hypothesis, that cGMP is the second messenger of ANF, we produced a rise in intracellular cGMP in rat and rabbit zona glomerulosa cells using the unspecific phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the more cGMP specific phosphodiesterase specific inhibitor M + B2948 (Zaprinast). Both inhibitors simulated the action of ANF in suppressing steroid secretion and elevating cGMP levels. The results are compatible with the view that cGMP is of importance as a second messenger for ANF in adrenal zona glomerulosa cells. Selective inhibition of phosphodiesterases in combination with endopeptidase inhibition may be an interesting principle to enhance the action of endogenous and exogenous ANF.
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PMID:Effects of atrial natriuretic factor on the renin-aldosterone system: in vivo and in vitro studies. 838 32

Congestive heart failure is a clinical syndrome producing symptomatic deterioration, functional impairment, and shortened life span. The syndrome is complex in that it includes both peripheral and cardiac effects which contribute to the progression of heart failure. In the periphery, elevations in the sympathetic nervous system and renin-angiotensin system increase afterload and contribute to further salt and water retention. The central cardiac abnormalities include remodeling of the heart and downregulation of beta receptors. Traditional heart failure therapy has included treatment of fluid retention with diuretics, although their effect on mortality has never been addressed. The most proven therapy in heart failure is treatment with vasodilators, particularly angiotensin-converting enzyme (ACE) inhibitors. Improved survival with ACE-inhibitor therapy has been demonstrated in patients with severe heart failure (CONSENSUS), mild to moderate heart failure (SOLVD), and in comparison with vasodilator therapy with hydralazine isosorbide dinitrate (VHeFT II). Improved survival has also been noted in postmyocardial infarction when the ejection fraction is decreased (SAVE). The ACE inhibitors have now become standard therapy for heart failure regardless of severity. Additive vasodilator therapy with calcium-channel antagonists is under investigation. Inotropic therapy is controversial at present because of disappointing mortality results. The clinical mainstay digitalis remains without convincing mortality reduction data. Other inotropic agents, particularly phosphodiesterase inhibitors, have shown uniformly negative survival results. However, the new mixed action agents vesnarinone and pimobenden have shown favorable data, with vesnarinone demonstrating a mortality reduction effect. Beta-blocker therapy in heart failure has also found renewed interest, particularly with the new agents carvedolol and bucindolol which also have vasodilating properties.
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PMID:Pharmacologic treatment of congestive heart failure. 870 66

We have reported that inhibition of nitric oxide synthesis with N(G)-nitro-L-arginine methyl ester (L-NAME) attenuates the renin secretory response to beta adrenoceptor stimulation. We proposed that the attenuation results from disinhibition of the cyclic GMP-inhibitable isoform of phosphodiesterase (PDE III) with a resultant increase in cyclic AMP hydrolysis in the juxtaglomerular cells. In our investigation, experiments were performed in conscious rabbits to test the effects of the specific PDE III inhibitor milrinone on resting renin secretion and on the renin responses to isoproterenol and L-NAME. In the first series of experiments, infusion of milrinone increased plasma renin activity from 5.4 +/- 0.6 to 10.2 +/- 1.4 ng/ml/2 hr (P < .01). Heart rate increased markedly, but arterial pressure did not change. In the second series, infusion of isoproterenol increased plasma renin activity from 6.3 +/- 1.1 to 15.0 +/- 1.0 ng/ml/2 hr (P < .01). The renin response to isoproterenol was increased (P < .01) in the presence of milrinone (15.3 +/- 3.7 to 38.4 +/- 6.2 ng/ml/2 hr, P < .01). In the third series, L-NAME alone decreased plasma renin activity from 5.0 +/- 1.0 to 3.3 +/- 1.0 ng/ml/2 hr (P < .01). Milrinone again increased plasma renin activity and prevented the suppression of plasma renin activity by L-NAME. By contrast, milrinone did not alter the suppression of plasma renin activity produced by infusion of phenylephrine. In addition, a PDE IV inhibitor failed to prevent the suppression of PRA by L-NAME. Finally, administration of milrinone completely reversed the L-NAME-induced suppression of the renin response to isoproterenol. These results provide evidence that PDE III participates in the regulation of renin secretion, and support the proposal that the L-NAME-induced reductions in renin secretion and in the renin response to beta adrenoceptor stimulation result from disinhibition of PDE III and increased hydrolysis of cyclic AMP in the juxtaglomerular cells.
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PMID:Role of cyclic GMP-inhibitable phosphodiesterase and nitric oxide in the beta adrenoceptor control of renin secretion. 876 33


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