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)

Recently an inhibitory effect of atrial natriuretic factor (ANF) on the adenylate cyclase system has been reported in vascular tissue. In seeking similar affects in renal tissue, we studied the effect of ANF on cyclic AMP levels in single nephron segments and in glomeruli from the rat. Individual nephron segments or glomeruli were incubated in the presence of a phosphodiesterase inhibitor, with or without parathyroid hormone (PTH) or arginine vasopressin (AVP) and varying concentrations of ANF at 37 degrees C for 2 min. The capacity for alpha 2-adrenoceptor inhibition of adenylate cyclase was demonstrated in the proximal convoluted tubule, cortical collecting tubule and in glomeruli. Nevertheless, ANF could not inhibit cAMP formation in any of these nephron segments nor in the glomerulus. Thus, unlike the vasculature, ANF has no inhibitory effect on cAMP formation in these renal tissues.
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PMID:Lack of inhibition by atrial natriuretic factor on cyclic AMP levels in single nephron segments and the glomerulus. 298 66

A functional role for the numerically predominant renal alpha2-adrenoceptors, which in other tissues inhibit adenylate cyclase, remains undefined. We therefore examined the effect of alpha2-adrenoceptor stimulation with (-)-epinephrine (E) on cell cAMP content in the isolated proximal convoluted tubule (PCT), medullary and cortical thick ascending limb of Henle, and collecting tubule (MTAL, CTAL, MCT, and CCT, respectively). Parathyroid hormone (1-34 PTH), in PCT or CTAL, or arginine vasopressin (AVP), in MTAL, CTAL, MCT, or CCT, was used to activate adenylate cyclase in intact cells from these microdissected nephron segments in the presence of 3-isobutyl-1-methylxanthine (phosphodiesterase inhibitor) and propranolol. Alpha2-Adrenoceptors were activated using varying concentrations of E (37 degrees C, 2 min). Alpha2-Adrenoceptor activation with E (5 X 10(-7) to 5 X 10(-6) M) suppressed cellular cAMP stimulation by PTH by 35% in PCT and stimulation by AVP in CCT by 50%. This suppression by E in PCT and CCT was inhibited by 5 X 10(-6) M yohimbine or 5 X 10(-7) M phentolamine but not by 5 X 10(-6) M prazosin. E also suppressed cAMP stimulated by AVP in MCT, but it did not suppress the PTH-or AVP-stimulated increase in cellular cAMP in CTAL and MTAL. These studies show that there are alpha2-adrenoceptors in the rat nephron. Activation of these alpha 2-adrenoceptors can inhibit cAMP formation stimulated by PTH in PCT and by AVP in the CCT and MCT but not in the CTAL and MTAL. A pathophysiological role of altered regulation of these receptors is yet to be described.
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PMID:Alpha2-adrenoceptors and cellular cAMP levels in single nephron segments from the rat. 299 Feb 39

The effect of calmodulin on the stimulation of cyclic AMP production by arginine vasopressin (AVP), prostaglandin E2 (PGE2) and forskolin was examined in cultured renal papillary collecting tubule cells of the rat. In the presence of the phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine submaximal concentrations of AVP (1 nmol/l), PGE2 (20 nmol/l) and forskolin (240 nmol/l) significantly increased cellular cyclic AMP accumulation by 2.3-, 6.0- and 8.4-fold respectively. Two chemically dissimilar inhibitors of calmodulin, namely trifluoperazine and N-(6-amino-hexyl)-5-chloro-1-naphthalenesulphonamide (W-7), attenuated the AVP-, PGE2- and forskolin-stimulated cellular production of cyclic AMP in a dose-related manner. Cellular production of cyclic AMP was inhibited by 50% (ID50) by doses ranging from 16 to 28 mumol trifluoperazine/l and 35 to 44 mumol W-7/1. Basal accumulation of cellular cyclic AMP was also decreased by treatment with either trifluoperazine or W-7, but the effective dose was higher than that which inhibited cellular cyclic AMP production stimulated by AVP, PGE2 and forskolin. Since forskolin directly activates adenylate cyclase at a site of the catalytic unit and the cellular action of AVP to activate adenylate cyclase is mediated through receptor-guanine nucleotide regulatory-catalytic units, the present study indicates calmodulin regulation of basal, AVP-, PGE2- and forskolin-activated adenylate cyclase in the papillary collecting tubule cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calmodulin regulation of cellular cyclic AMP production in response to arginine vasopressin, prostaglandin E2 and forskolin in rat renal papillary collecting tubule cells in culture. 299 30

In the present study, the role of calmodulin in the cellular action of arginine vasopressin (AVP), prostaglandin (PG) E2 and forskolin on adenosine-3', 5'-monophosphate (cAMP) production was examined in cultured rat renal papillary collecting tubule cells. In the presence of the phosphodiesterase inhibitor, submaximal concentrations of 10(-9) M AVP, 2 X 10(-8) M PGE2 and 2.4 X 10(-7) M forskolin significantly increased cellular cAMP accumulation by 2.3, 6.0 and 8.4-fold, respectively. Two chemically dissimilar inhibitors of calmodulin, namely trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), attenuated the cellular production of cAMP in a dose-related manner in response to all three stimuli. A dose which inhibited the cellular production of cAMP by 50% (ID50) ranged from 1.6 X 10(-5) to 2.8 X 10(-5) M for trifluoperazine and from 3.5 X 10(-5) to 4.4 X 10(-5) M for W-7. Basal accumulation of cellular cAMP was also decreased by treatment with either trifluoperazine or W-7, but an effective dose was relatively higher than that which inhibited agents-stimulated cellular cAMP production. Since forskolin is recognized as activating adenylate cyclase at one step of the catalytic component and the cellular action of AVP to activate adenylate cyclase is mediated through receptor-catalytic component, the present study indicates calmodulin regulation of basal, AVP-, PGE2- and forskolin-activated adenylate cyclase in the papillary collecting tubule cells. Further study demonstrated the inhibition of AVP- or PGE2-induced cellular cAMP production by treatment with either a calcium-free medium or verapamil, a blocker of cellular calcium uptake, before and during the experiment. These findings suggest that an increase in cytosolic calcium, which interacts with calmodulin to form an active complex, is, at least in part, due to the increased cellular influx of calcium from the extracellular space.
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PMID:[Evidence for a role of calmodulin in cellular cAMP production in response to vasopressin, prostaglandin E2 and forskolin in cultured rat renal papillary collecting tubule cells]. 300 Aug 38

The phosphodiesterase inhibitor CI-930 hydrochloride exerts a positive inotropic and vasodilator effect in experimental animals. The acute hemodynamic and hormonal effects of intravenous CI-930 were studied in 9 patients with severe congestive heart failure. At 60 minutes of drug infusion, there was an increase in cardiac index (2.7 +/- 0.9 vs 2.0 +/- 0.7 liters/min/m2, p less than 0.01) and positive dP/dt (1,390 +/- 470 vs 1,100 +/- 300 mm Hg/s, p less than 0.02). Additionally, there were decreases in mean systemic arterial (78 +/- 16 vs 86 +/- 15 mm Hg, p less than 0.01), mean right atrial (5 +/- 3 vs 9 +/- 4 mm Hg, p less than 0.02), mean pulmonary arterial (27 +/- 11 vs 37 +/- 9 mm Hg, p less than 0.01) and LV end-diastolic (19 +/- 8 vs 28 +/- 6 mm Hg, p less than 0.01) pressures. Heart rate did not change (97 +/- 17 vs 97 +/- 22 beats/min). The inotropic response correlated significantly (r = 0.70, p less than 0.05) with the dose of CI-930. Plasma renin activity did not change significantly (from 16 +/- 9 to 23 +/- 15 ng/ml/hour), nor did plasma norepinephrine or arginine vasopressin levels. The plasma atrial natriuretic peptide level decreased (from 153 +/- 97 to 83 +/- 35 pg/ml, p less than 0.02). These findings suggest that intravenous CI-930 hydrochloride is a useful therapeutic agent in congestive heart failure and that its use does not appear to further activate potentially deleterious hormonal systems.
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PMID:Acute hemodynamic and hormonal effects of CI-930, a new phosphodiesterase inhibitor, in severe congestive heart failure. 359 91

Enzymatically dispersed testis cells derived from 7-day-old male rats maintained their gonadotropin-stimulated testosterone production for 18 days in culture. Treatment with hCG or LH stimulated androgen production in a dose-dependent manner, with ED50 values of 0.030 +/- 0.007 and 1.0 +/- 0.4 ng/ml for hCG and LH, respectively. Concomitant treatment with a phosphodiesterase inhibitor further enhanced LH action. In contrast, treatment with FSH, GH, or PRL was without effect. Treatment with forskolin, cholera toxin, or 8-bromo-cAMP induced dose-dependent increases in testosterone biosynthesis; this was accompanied by stimulation of 3 beta-hydroxysteroid dehydrogenase activity after treatment with hCG, forskolin, or 8-bromo-cAMP. RIA measurement of different androgens in HPLC-fractionated medium revealed that the main androgen secreted by the neonatal testis cells was testosterone, with lower production of 5 alpha-androstane-3 alpha,17 beta-diol and negligible 5 alpha-dihydrotestosterone, androstenedione, and androsterone. Treatment with epidermal growth factor, GnRH, and arginine vasopressin (AVP) decreased hCG-induced testosterone biosynthesis. Since the inhibitory actions of GnRH and AVP were blocked by concomitant addition of specific hormone antagonists, their inhibitory actions were probably mediated by specific testis receptors. In contrast, treatment with several potent synthetic steroid hormone analogs [diethylstilbestrol (an estrogen), dexamethasone (a glucocorticoid), R5020 (a progestin; 17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione), R1881 (an androgen; 17 beta-hydroxy-17 alpha-methyl-4,9,11-estratrien-3-one), or cyproterone acetate (an antiandrogen; 17 alpha-acetyloxy-6-chloro-1,2-dihydro-(1 beta,2 beta)3'-H-cyclopropa-(1,2) pregna-1,4,6-trien-3,20-dione)] did not affect testosterone biosynthesis in hCG-treated cells. These results demonstrate that testosterone production by neonatal testis cells is maintained by gonadotropins during prolonged culture; the ability of cAMP-generating drugs and a cAMP analog to mimic gonadotropin actions on testosterone biosynthesis and 3 beta-hydroxysteroid dehydrogenase activity suggests a mediatory role of cAMP in gonadotropin action; and AVP, epidermal growth factor, and GnRH, through their putative testis receptors, directly inhibit gonadotropin-stimulated testosterone synthesis, while various steroids (androgens, estrogens, progestins, and glucocorticoids) do not affect Leydig cell function in the neonatal testis. The present culture system offers a unique model for elucidating the hormonal control of Leydig cell androgen biosynthesis during neonatal development.
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PMID:Hormonal regulation of androgen biosynthesis by primary cultures of testis cells from neonatal rats. 388 12

Studies to identify the physiological role of glomerular mesangial cells were undertaken using homogeneous cultures of rat glomerular cells of apparent mesangial origin (MS). Cultured MS cells were treated with arginine vasopressin (AVP), angiotensin II (AGII), prostaglandin E(2), and parathyroid hormone. AVP (0.1 nM) and AGII (1 nM) stimulated contraction of MS cells in vitro that was complete by 2 min at 37 degrees C or 10 min at 23 degrees C as observed by phase contrast and electron microscopy. Relaxation recurred 15 min after hormonal addition at 23 degrees C. Similar experiments in cloned rat glomerular epithelial cells or "renin"-producing cells did not demonstrate a contractile response. The contraction of MS cells was independent of cyclic AMP (cAMP) and cyclic 3',5'-guanosine monophosphate (cGMP) production, even when cyclic nucleotides were measured as early as 30 s after hormonal stimulation. To demonstrate that contraction was a function of hormone-receptor interaction, binding of [(3)H](8-lysine)vasopressin was studied. Specific binding for 1.6 and 5 nM hormone was both time- and dose-dependent. The estimated apparent affinity was 10 nM. In late MS cell passages (>16th) that no longer demonstrated hormone-stimulated contraction, no specific binding of [(3)H](8-lysine)vasopressin was observed. Incubations were modified to optimize the conditions for detecting the effect of hormones on cell cyclic nucleotide content. A supramaximal concentration of AVP (200 nM) increased the cAMP content of MS cells twofold in the presence of a phosphodiesterase inhibitor. Similar experiments with prostaglandin E(2) (1 mug/ml) led to a 1.5-6-fold increase in MS cell cAMP content, but no effect on contraction was observed. Neither hormone altered cGMP content. These data are further support for the independence of contraction and cyclic nucleotide production. Our studies suggest that MS cells are the equivalent of smooth muscle cells in the glomerulus and that their contraction may be important in control of glomerular filtration.
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PMID:Contraction of cultured rat glomerular cells of apparent mesangial origin after stimulation with angiotensin II and arginine vasopressin. 615 93

The effect of chlorpropamide was determined in Brattleboro diabetes insipidus (DI) rats that were injected with 1-deamino-8-D-arginine vasopressin (dDAVP). Chlorpropamide augmented the antidiuretic responses to 0.78 and 1.56 ng dDAVP but not to larger doses. In an effort to explain this observation we investigated the effect of chlorpropamide on renal medullary adenylate cyclase activation by dDAVP and on phosphodiesterase activity. We found that the injection of chlorpropamide increased adenylate cyclase activation by dDAVP added in vitro to renal medullary cell membrane preparations from Brattleboro DI rats but had no effect on phosphodiesterase activity. When kidneys from Brattleboro DI rats, treated and not treated with chlorpropamide, were perfused in vitro, we found that 10(-4) M dDAVP increased the concentration of cAMP in comparison to untreated and chlorpropamide-treated groups, and that chlorpropamide plus dDAVP resulted in a greater concentration of renal cAMP than was found with dDAVP alone. We believe that treatment with chlorpropamide increases dDAVP-stimulated renal medullary adenylate cyclase activity without altering phosphodiesterase activity and that this leads to increased renal cAMP concentrations. This, in turn, causes an augmented antidiuresis in response to dDAVP.
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PMID:Augmentation by chlorpropamide of 1-deamino-8-D-arginine vasopressin-induced antidiuresis and stimulation of renal medullary adenylate cyclase and accumulation of adenosine 3',5'-monophosphate. 624 58

Among other defects in water metabolism, adrenal insufficiency is associated with an inability to concentrate urine maximally in both man and experimental animals. Recent studies in the rabbit cortical collecting tubule have suggested indirectly that this defect may result from impaired cyclic AMP (cAMP) formation in response to antidiuretic hormone stimulation. In the present study, we examined key elements of arginine vasopressin (AVP)-dependent cAMP metabolism in the papillary collecting duct (PCD), microdissected from 8-d adrenalectomized (ADX) and sham-operated control rats. AVP-sensitive adenylate cyclase (ADC) activity in PCD did not differ between control and ADX rats. cAMP-phosphodiesterase activity (cAMP-PDIE), measured at 10(-6) M cAMP substrate concentration, was significantly higher (delta + 31.6%) in PCD of ADX rats compared with controls. Incubation of intact PCD from ADX rats with AVP resulted in an accumulation of cAMP (delta - 48.5%) significantly lower than observed in control PCD. Chronic administration of dexamethasone reduced cAMP-PDIE activity in PCD of ADX rats to levels close to or below those observed in control rat PCD, and also resulted in a restoration of AVP-stimulated cAMP accumulation to levels approaching control values. Results indicate that the impaired maximal urinary concentrating ability associated with adrenal insufficiency may be due, at least in part, to a reduced accumulation of cAMP in response to AVP in the PCD. This decreased cAMP accumulation results from increased cAMP-PDIE activity in the PCD of ADX rats and can be corrected by administration of glucocorticoid.
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PMID:Concentrating defect in the adrenalectomized rat. Abnormal vasopressin-sensitive cyclic adenosine monophosphate metabolism in the papillary collecting duct. 630 13

The pathophysiology of heart failure is closely associated with neuroendocrine changes. Activation of these humoral systems apparently serves as a compensatory mechanism for the failing circulation. However, overshoot of such mechanisms may further depress cardiac function by increasing afterload, resulting in a vicious cycle of reflex neuroendocrine activation. Corollary decreases in renal function activate the renin-angiotensin-aldosterone system as well, which further contributes to the cycle of downward-spiralling cardiac function. Many hormonal factors are increased in congestive heart failure. While some influences are vasodilatory, the net effect is marked vasoconstriction. The level of activation of these systems apparently corresponds to the severity of heart failure. Furthermore, elevated levels of these hormones, including norepinephrine, atrial natriuretic factor, plasma renin, and plasma arginine vasopressin, may play a more direct role in worsening heart failure. In fact, elevated catecholamine levels are directly related to prognosis. Catecholamines increase myocardial oxygen demand and are also arrhythmogenic. Oral catecholamines and phosphodiesterase inhibitors, which work by similar mechanisms, have yielded increased mortality rates in heart failure trials. In contrast, mortality rates are reduced in patients treated with angiotensin-converting enzyme inhibitors. Thus, it is clear that neuroendocrine changes are not only a marker of the severity of heart failure, but also directly worsen it. Interventions that antagonize or diminish these neuroendocrine changes apparently benefit patients with heart failure.
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PMID:Neuroendocrine changes in heart failure and their clinical relevance. 758 61


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