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)

Neurohypophysial hormones stimulate gonadotrophin release from dispersed rat anterior pituitary cells in vitro, acting through receptors distinct from those which mediate the secretory response to gonadotrophin-releasing hormone (GnRH). The LH response to oxytocin was not affected by the presence of the phosphodiesterase inhibitor, methyl isobutylxanthine, but was diminished in the absence of extracellular calcium and was progressively increased as the calcium concentration in the medium was raised to normal. In addition, the calcium channel antagonist, nifedipine, suppressed oxytocin-stimulated secretion of LH. It is likely that the mechanisms of LH release induced by GnRH and neurohypophysial hormones are similar, although stimulation of gonadotrophin secretion is mediated by separate receptor systems. Oxytocin was more active than vasopressin in releasing LH, but less active in releasing ACTH. The highly selective oxytocin agonist, [Thr4,Gly7]oxytocin, elicited concentration-dependent secretion of LH but had little effect on corticotrophin secretion. The neurohypophysial hormone antagonist analogues, [d(CH2)5Tyr(Me)2]vasopressin, [d(CH2)5Tyr(Me)2,Orn8]vasotocin and [d(CH2)5D-Tyr(Et)2Val4,Cit8]vasopressin, inhibited the LH response to both oxytocin and vasopressin. However, [d(CH2)5Tyr(Me)2]vasopressin was much less effective in inhibiting the ACTH response to the neurohypophysial hormones, and [d(CH2)5Tyr-(Me)2,Orn8]vasotocin and [d(CH2)5D-Tyr(Et)2,Val4,Cit8]vasopressin exhibited no inhibitory activity against ACTH release. Thus, agonist and antagonist analogues of neurohypophysial hormones display divergent activities with regard to LH and ACTH responses, and the neuropeptide receptor mediating gonadotroph activation is clearly different from that on the corticotroph. Whereas the corticotroph receptor is a vasopressin-type receptor an oxytocin-type receptor is responsible for gonadotrophin release by neurohypophysial hormones.
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PMID:Gonadotrophin-releasing activity of neurohypophysial hormones: II. The pituitary oxytocin receptor mediating gonadotrophin release differs from that of corticotrophs. 247 64

We investigated the effects of adenosine on the positive chronotropic and inotropic responses to an endogenous catecholamine (norepinephrine), a beta 1-adrenoceptor agonist (dobutamine), an adenylate cyclase activator (forskolin), a phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine, IBMX) and a calcium channel agonist (Bay k 8644) in the isolated, blood-perfused dog atrium. Each drug was injected into the sinus node artery of the isolated atrium. Adenosine infusions at low (45 or 90 nmol/min) and high (184 or 450 nmol/min) doses induced a dose-dependent decrease of sinus rate and atrial contractile force. The positive chronotropic and inotropic responses to norepinephrine, dobutamine and forskolin were dose-dependently depressed by adenosine. IBMX- and Bay k 8644-induced positive cardiac responses were also inhibited by adenosine at high doses but not at low doses. These results suggest that adenosine attenuates calcium channel-dependent as well as cyclic AMP-dependent positive chronotropic and inotropic responses to cardiostimulants in the isolated dog atrium.
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PMID:Adenosine inhibits the positive chronotropic and inotropic responses to norepinephrine and Bay k 8644 in the isolated, blood-perfused dog atrium. 248 9

The direct negative inotropic actions of calcium channel blockers limit the use of these otherwise effective systemic and coronary vasodilators in patients with heart failure. We studied the effects of amrinone pretreatment on the dose--hemodynamic response curve of diltiazem in order to test the hypothesis that amrinone might potentiate diltiazem's positive effects in anesthetized dogs. The control group (no pretreatment, n = 6) had a typical dose-related response to diltiazem (50, 100, and 150 micrograms/kg): coronary and systemic vasodilation, increased stroke volume, and no change in myocardial work and power. Amrinone pretreatment of the study group (n = 7) altered the hemodynamic response, thus maximal systemic vasodilation and stroke volume increase at a lower diltiazem dose, a 15 to 35% increase in myocardial work and power, and more profound coronary vasodilation. We propose that amrinone, by inhibiting phosphodiesterase, potentiates diltiazem vasodilation and reflexly secreted catecholamines' actions on the heart. This positive interaction may permit effective use of lower doses of diltiazem, thus circumventing its dose-limiting direct negative effects while still profitting from beneficial peripheral, reflex, and coronary actions.
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PMID:Positive hemodynamic interaction between amrinone and diltiazem in anesthetized dogs. 259 32

Nitrendipine, nifedipine and verapamil inhibit the in vitro formation of irreversibly sickled cells. Using a method of forming both dehydrated cells and irreversibly sickled cells in vitro by repeated cycles of sickling and unsickling, the effects of several drugs in inhibiting the formation of these cells were studied. Drugs known as Ca2+ channel antagonists, such as nitrendipine, nifedipine and verapamil were found to inhibit these reactions. Other types of calcium channel blockers, such as lanthanum and zinc, did not inhibit the formation of these cells. The potency of drugs to inhibit irreversibly sickled cell formation was related to the potency of inhibition of calmodulin-activated phosphodiesterase.
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PMID:Nitrendipine, nifedipine and verapamil inhibit the in vitro formation of irreversibly sickled cells. 294 Jun 6

Insulin (INS) stimulates, and diabetes inhibits, low Km cAMP phosphodiesterase (PDE). This mechanism, at least in part, accounts for the lowering of cyclic AMP levels in plasma and tissue of diabetic patients and animals. Phorbol, a tumor-promoting agent known to act through protein kinase C and calcium translocation, exhibits a powerful effect stimulating PDE in rat adipose tissue. Nifedipine, a calcium channel blocker, inhibits insulin, but not phorbol stimulated PDE. These data demonstrate new effects of inositide diacylglycerol-Ca++ pathway components on PDE and suggest some common pathways of activation of low Km cAMP PDE through insulin and phorbol esters.
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PMID:Activation of cyclic AMP phosphodiesterase by phorbol and protein kinase C pathway. 301 37

Fendiline is an anti-anginal agent for the treatment of coronary heart disease. Together with other diphenylalkylamines it is sub-classified in the group of lipophilic calcium antagonists. It binds to the calcium channel and to calmodulin with rather similar affinities. Pharmaco-dynamically, it exerts the typical calcium as well as calmodulin antagonistic actions: inhibition of the transmembrane calcium current, smooth muscle relaxation, negative inotropism, cardioprotection, inhibition of calmodulin-activated myosin light-chain kinase and phosphodiesterase. Pharmacokinetics reveal slow onset of action and a long half-life. The anti-anginal and anti-ischaemic efficacy of fendiline has been proven in several placebo-controlled, double-blind trials. It does not interfere with digoxin therapy. Direct comparison with other calcium antagonists by means of controlled studies revealed that its potency is at least equal to that of nifedipine but, in contrast to nifedipine, verapamil, and diltiazem, its anti-anginal action increases during chronic therapy, reaching a steady state of action after 2 to 3 weeks. In addition, the anti-ischaemic and anti-anginal potency is about equal to that of isosorbide dinitrate but fendiline has the advantage of lacking tolerance development. Nevertheless, the data presented indicate that a combination of fendiline with low doses of ISDN may be beneficial. Adverse cardiac and haemodynamic actions, such as increase or decrease in heart rate, disturbance of AV nodal conduction, impairment of cardiac contractile performance or considerable decrease in arterial pressure in hypotensives and normotensives, are lacking.
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PMID:Fendiline: a review of its basic pharmacological and clinical properties. 331 16

This study examined the platelet-aggregating and procoagulant activities of two hematogenously disseminating tumors, a mouse lymphoblastic leukemia (L5178Y) and a mouse renal adenocarcinoma (RAG). Tumor-induced human platelet aggregation was inhibited by addition of the following agents to platelet-rich plasma (PRP): a calcium channel blocker (verapamil), a chelator of divalent cations (EDTA), stimulators of adenylate cyclase (2-fluoroadenosine and forskolin), and inhibitors of cAMP phosphodiesterase (oxagrelate and papaverine). The platelet-aggregating activities of both cell lines were completely blocked by treatment of the cells with heat, sonication, phospholipase A2, and Triton X-100. These data suggest that L5178Y and RAG cell-induced human platelet aggregation are dependent on a heat-labile phospholipid component of the tumor cell membrane. L5178Y cells had greater platelet-aggregating activity in human plasma than in rat or mouse plasma, whereas RAG cells had greater procoagulant activity in rat or mouse plasma than in human plasma. The procoagulant activity of RAG cells in rat and mouse plasma was demonstrated by three lines of evidence: RAG cells induced heparinized PRP to clot; the thrombin inhibitor DAPA lengthened of the clotting time and the lag time before aggregation; and RAG cells shortened of the recalcification time of the plasma. The above data indicate that RAG cell-induced murine platelet aggregation and coagulation is dependent on thrombin generation.
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PMID:Murine tumor-induced platelet aggregation and coagulation: mechanisms, inhibitors, and species differences. 359 Jan 14

Serotonin release from rabbit enterochromaffin cells located in the mucosal epithelium of the small intestine was studied in vitro. Serotonin release from both the serosal and mucosal sides of the small intestine was measured. The addition of muscarinic but not nicotinic cholinergic agonists to the serosal medium resulted in a large but transient increase in serotonin release from the serosal but not the mucosal side of the intestine. Mucosal addition of these agents was ineffective. Serotonin release stimulated by the cholinergic agonist carbachol appeared to be dependent upon influx of extracellular Ca++ for the following reasons: 1) depletion of serosal Ca++ inhibited carbachol-stimulated release; 2) carbachol-stimulated serotonin release was blocked by the inorganic calcium channel blockers Co++, Ni++, Cd++, La and Gd; and 3) serosal serotonin release was increased by the Ca++ ionophore, ionomycin, and by Ba++. The addition of 8-bromoadenosine cyclic AMP or the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, to the serosal medium produced a sustained elevation of serosal serotonin release. 8-bromoadenosine-cyclic AMP-stimulated release was not blocked by depleting extracellular Ca++. Forskolin, a compound which stimulates adenylate cyclase, also stimulated serosal serotonin release. 8-bromoadenosine-cGMP had no effect on serotonin release. Somatostatin (10(-8)-10(-6) M) caused a dose-dependent inhibition of carbachol-stimulated serotonin release. Somatostatin (10(-6) M) only partially inhibited serotonin release stimulated by 8-bromoadenosine-cyclic AMP, 3-isobutyl-1-methylxanthine and forskolin and had no effect on release stimulated by Ba++. The results suggest potential roles for both calcium and cyclic nucleotides in the regulation of serotonin release.
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PMID:Regulation of serotonin release from rabbit intestinal enterochromaffin cells. 614 Mar 9

The possible role of calcium as a primary mediator in the control of prolactin secretion from normal pituitary cells was examined. Basal prolactin secretion, and secretion stimulated by thyrotrophin releasing hormone (TRH), raised K+ or the calcium ionophore, A23187, were all dependent on the presence of extracellular Ca2+. The calcium channel antagonists, methoxyverapamil, cobalt and manganese, inhibited basal, TRH- and K+-stimulated prolactin secretion. In addition, prolactin secretion stimulated by a phosphodiesterase inhibitor, isobutylmethylxanthine, which increases cellular cyclic AMP, was inhibited by these Ca2+ antagonists. These observations indicate that Ca2+ may be the primary intracellular mediator in the control of prolactin secretion, with cyclic AMP having a secondary modulatory role on Ca2+ influx, probably on voltage-dependent Ca2+ channels.
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PMID:An investigation of the involvement of calcium in the control of prolactin secretion: studies with low calcium, methoxyverapamil, cobalt and manganese. 672 8

The effects of two calcium channel blockers, nifedipine and nicardipine, on glucagon-stimulated glycogenolysis in primary cultures of rat hepatocytes were examined in vitro. When nifedipine and nicardipine (10(-7)-10(-6) M) were added to the incubation mixture with various concentrations of glucagon (10(-10)-10(-6) M), these dihydropyridine calcium channel blockers significantly potentiated the glycogenolytic action of glucagon by increasing intracellular cAMP levels. 1-Methyl-3-isobutylxanthine (IBMX), caffeine and papaverine, which is known to inhibit cAMP phosphodiesterase, also potentiated the stimulatory effect of glucagon on the glycogenolysis in a dose-dependent manner. Parallel to the potentiation of glycogenolysis, IBMX also increased the glucagon-stimulated intracellular cAMP levels in a dose-dependent manner. These results suggest that the mechanism of potentiation of the glucagon-stimulated glycogenolysis by nifedipine and nicardipine is related to the known inhibition of cAMP phosphodiesterase by these agents.
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PMID:Nifedipine and nicardipine potentiate glucagon-stimulated glycogenolysis in primary cultures of rat hepatocytes. 750 85


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