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)

Congestive heart failure is an increasingly common patient problem. It is a multisystem disease that involves not only the heart but also the kidneys and neurohormonal systems. Any treatment for heart failure should address depressed contractility and exercise intolerance, as well as control compensatory mechanisms. There are many different approaches to the treatment of congestive heart failure: among the drugs used are diuretics, digitalis compounds, nitrates, calcium channel blockers, beta-blockers, beta-agonists, vasodilators, angiotensin-converting enzyme (ACE) inhibitors and the new phosphodiesterase inhibitors. The therapy usually involves a multiple drug treatment plan to achieve the maximum effect for the patient with the lowest incidence of side effects. Heart failure involves a large spectrum of patients with left ventricular dysfunction, and success at achieving treatment goals with these patients will vary with the severity of that symptom. A major concern is that increasing contractility may further damage the myocardium and shorten the survival of these patients, although there is as yet no evidence of such shortening. The new phosphodiesterase inhibitor drugs are an exciting development in the treatment of heart failure, because they add a dimension to the treatment for patients who are not sufficiently improved by a regimen of digoxin, diuretics and ACE inhibitors. Any new heart failure medication should be able to improve rest and exercise haemodynamics, maintain its benefits when given orally and result in an improved exercise capacity and quality of life, and prolonged survival.
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PMID:Risks and benefits of the treatment of heart failure. Current status. 188 43

The possible involvement of calcium in the regulation of steroidogenesis in the goldfish was investigated using preovulatory ovarian follicles incubated in vitro. Incubation of follicles in media deficient in calcium impaired testosterone production in response to human chorionic gonadotropin (hCG) in both the presence and the absence of the phosphodiesterase inhibitor IBMX. Similarly, addition of calcium channel antagonists (verapamil, nifedipine, nicardipine, and CoCl2) caused a dose-dependent inhibition of hCG-stimulated testosterone production. TMB-8, an inhibitor of intracellular calcium mobilization, also suppressed hCG-stimulated testosterone production. Basal testosterone production was not affected by incubation in calcium-deficient media or with drugs which reduce intracellular calcium availability. In other studies, nifedipine blocked forskolin and dibutyryl cyclic AMP-stimulated testosterone production suggesting that one of the major sites of calcium action is distal to cyclic AMP generation. Two inhibitors of calmodulin, W5 and W7, significantly inhibited hCG-stimulated testosterone production. These findings suggest that calcium derived from intracellular and extracellular pools participate in the expression of gonadotropin effects on steroid production in goldfish ovarian follicles and that these effects are mediated intracellularly by interaction with calmodulin.
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PMID:Role of calcium in the control of steroidogenesis in preovulatory ovarian follicles of the goldfish. 201

Venodilatation may be an important property in drugs used to treat heart failure. Deductions about venous tone from standard hemodynamic studies may be misleading since filling pressures may be reduced by improved left ventricular function. To study the venodilator properties of drugs, we have modified a radionuclide blood pool method and shown that venous volume is increased by 10% after glyceryl trinitrate but is unchanged after the arteriolar dilator hydralazine. In patients with congestive cardiac failure, the calcium channel blocker, felodipine, causes a marked reduction in systemic vascular resistance and left ventricular filling pressures, but venous volume remains unchanged. In a similar group of patients comparable arterial and central effects are seen after the administration of captopril, but venous volume increases by 16%, and this increased venous volume is sustained after 3 months of long-term treatment. Milrinone has been used to treat both acute and chronic heart failure. As expected of a phosphodiesterase inhibitor, it exhibits inotropic properties in animals and humans and also causes arterial vasodilatation. We have studied its effects on venous tone in 10 patients with severe heart failure (New York Heart Association classes III to IV). Milrinone was given intravenously at a loading dose of 50 micrograms/kg followed by an infusion of 0.5 micrograms/kg/min. After treatment, cardiac index, which was measured by thermodilution, increased from 1.8 +/- 0.48 to 2.3 +/- 0.65 L/min/m2 (p less than 0.001); pulmonary artery wedge pressure fell from 23 +/- 6 to 11 +/- 5 mm Hg (p less than 0.001); and systemic vascular resistance index decreased from 4296 to 3168 dynes.sec.cm-5/m2 (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of venous tone in heart failure. 203 25

The calcium channel-blocking activity and associated cardiovascular effects of diproteverine, a novel compound derived from papaverine, were investigated. Electrophysiological measurements in sheep Purkinje fibres showed diproteverine to reduce the amplitude of the slow action potential (IC30 = 2 microM) and to shorten the duration of the fast action potential at 50% repolarisation (IC30 = 2.5 microM). Higher concentrations (4-5 times) were required to block block the sodium channel, as assessed by a reduction in Vmax of the fast action potential. Papaverine was found to possess marginal membrane channel-blocking activity and to be much more potent than diproteverine as a cAMP-phosphodiesterase inhibitor. The most significant haemodynamic property of diproteverine, seen in anaesthetised dogs and conscious dogs pretreated with atropine, was to cause a reduction in heart rate. This appeared to be a particular feature of diproteverine as the other calcium antagonists studied produced either a smaller decrease in heart rate or tachycardia as a reflex response to hypotension. In a chronic myocardial infarct model in dogs, diproteverine caused a redistribution of the available coronary blood flow, to the benefit of an ischaemic area of the myocardium. Diproteverine resembled diltiazem in its effects on coronary blood flow, with both these agents being preferable to nifedipine and verapamil, which caused coronary steal in this model. The combination of the reduction in heart rate, to lower cardiac oxygen demand, with the beneficial action on coronary blood flow should result in diproteverine being particularly beneficial for the treatment of angina pectoris.
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PMID:Diproteverine (BRL 40015): a new type of calcium antagonist with potential antianginal properties. 205 33

Infusion of forskolin, an adenylate cyclase activator, in concentrations (2 microM) that do not alter basal prostaglandin (PG) synthesis inhibit synthesis of PG elicited by isoproterenol in rabbit heart. This inhibitory action of forskolin appears to be dependent on cyclic AMP (cAMP). Bolus injection of forskolin (75 nmol), however, was found to stimulate PG synthesis in rabbit heart. The purpose of this study was to elucidate the mechanism of the stimulatory action of forskolin on PG synthesis (prostaglandin I2 measured as 6-ketoprostaglandin F1 alpha [6-keto-PGF1 alpha]) in isolated perfused rabbit heart. Forskolin enhanced PG production in a dose-dependent manner. 1,9-Dideoxyforskolin, a forskolin analogue devoid of adenylate cyclase-stimulating activity, also enhanced PG synthesis. The cAMP analogue chlorophenylthio-cAMP failed to stimulate output of 6-keto-PGF1 alpha, although this agent produced dose-related changes in mechanical function in rabbit heart. Furthermore, the adenylate cyclase inhibitor (-)-N6-(R-phenylisopropyl)adenosine potentiated, whereas the phosphodiesterase inhibitor cilostamide attenuated, forskolin-stimulated PG production. (-)-N6-(R-Phenylisopropyl)adenosine and cilostamide had no effect on the mechanical actions of chlorophenylthio-cAMP, suggesting selectivity of these agents for adenylate cyclase and phosphodiesterase, respectively. 6-Keto-PGF1 alpha output elicited by forskolin was abolished by reduction of calcium in the perfusion fluid as well as by the calcium channel blocker diltiazem. The intracellular calcium antagonists TMB-8 and ryanodine also abolished forskolin-stimulated PG synthesis in rabbit heart. PG synthesis stimulated by 1,9-dideoxyforskolin was also prevented by reduced extracellular calcium, diltiazem, and ryanodine. The calmodulin antagonists trifluoperazine, W-7, and calmidazolium failed to significantly alter PG production in response to forskolin. These results indicate that forskolin-stimulated PG synthesis in rabbit heart is independent of cAMP and requires calcium from both extracellular and intracellular sources.
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PMID:Forskolin stimulates prostaglandin synthesis in rabbit heart by a mechanism that requires calcium and is independent of cyclic AMP. 217 6

Pharmacologic inhibition of uterine contractions remains the mainstay of treatment for preterm labor despite the ongoing controversy regarding its effectiveness. A diverse variety of tocolytic medications have been proposed for clinical use, with betamimetics and magnesium sulfate being the common therapeutic agents of choice in the United States today. The clinician using these agents should be aware of the significant maternal and fetal side-effects associated with these particular medications. New classes of pharmacologic agents, including prostaglandin synthetase inhibitors, calcium channel blockers and phosphodiesterase inhibitors, have been proposed as tocolytic agents and are currently undergoing critical clinical evaluation. The purpose of this review is to provide a compilation of the available clinical studies that document the safety and efficacy of these various tocolytic agents.
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PMID:The safety and efficacy of tocolytic agents for the treatment of preterm labor. 219 9

Calcium ion has been shown to have a negative regulatory effect on the secretion of human placental lactogen (hPL). We report an inhibitory effect of cyclic AMP on hPL secretion in a model system of cultured human term trophoblast. Similar results were obtained by modulation of cyclic AMP-phosphodiesterase. The effects of ionophore A23187 and cyclic AMP were non-additive. In searching for the sequence of the common pathway, we found that the ionophore A23187 reduced cyclic AMP concentration and that the inhibitory effect of cyclic AMP was abolished by verapamil, a calcium channel blocker, and by trifluoperazine, a calcium-calmodulin inhibitor. Cyclic AMP seems to mobilize intracellular calcium, and the latter, by way of a calcium-calmodulin complex, modulates the secretion of hPL.
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PMID:Interrelated calcium ion and cyclic AMP inhibition of placental lactogen secretion by cultured human term trophoblast. 243 81

Milrinone, a potent positive inotropic and vasodilating agent, has shown promise in the clinical treatment of congestive heart failure, but significant controversy about its mechanism of action exists. To approach these mechanistic problems in a non-innervated, non-diffusion-limited system, the effects of milrinone on cultured embryonic chick ventricular cells were examined. At 37 degrees C in physiologic buffer, milrinone produced a rapid, concentration-dependent increase in amplitude of contraction that was 45% of the maximum increment in contraction produced by elevated extracellular calcium; the EC50 was 8 microM. This peak response was quantitatively similar to the contractile response produced by isobutyl methylxanthine, a potent phosphodiesterase inhibitor. Milrinone inhibited 70% of total phosphodiesterase activity of cultured ventricular cells with an EC50 of 11 microM. Exposure to 1 X 10(-4) M milrinone resulted in rapid increase in cyclic AMP content to levels greater than 100% above control within 4 min. The same concentration also produced a 43% increase in the rate of transsarcolemmal 45Ca uptake. The stimulation of 45Ca uptake rate was similar to the response produced by 1 microM isoproterenol and could be completely abolished by 10 microM verapamil. Thus, in cultured embryonic chick myocardial cells, the positive inotropic effect of milrinone is largely, if not entirely, attributable to phosphodiesterase inhibition, leading to intracellular cyclic AMP accumulation and stimulation of transsarcolemmal calcium influx via the slow calcium channel.
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PMID:Mechanism of the positive inotropic effect of milrinone in cultured embryonic chick ventricular cells. 243 20

The firing rate of locus coeruleus (LC) neurons in rat brain slices was increased reversibly by agents that either elevate intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) or mimic its actions (e.g., forskolin, and activator of adenylate cyclase, 8-Br-cAMP, a membrane permeable analog of cAMP, and Ro20-1724, a preferential inhibitor of cAMP-phosphodiesterase). Intracellular recordings showed that 8-Br-cAMP and forskolin induce a depolarization of LC neurons, accompanied by a decrease in input resistance. The 8-Br-cAMP- and forskolin-elicited depolarization persisted in the presence of cobalt, a calcium channel blocker. Steady-state current-voltage curves revealed that in the voltage range of -50 to -120 mV, 8-Br-cAMP and forskolin induced an inward current, which did not reverse at the potassium equilibrium potential and could not be blocked by tetrodotoxin. Partial replacement of sodium with Tris or choline markedly reduced the depolarization elicited by 8-Br-cAMP. We conclude that 8-Br-cAMP and forskolin act through a common mechanism to increase the firing rate of locus coeruleus neurons by inducing a cAMP-activated inward current, carried out at least in part by sodium ions.
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PMID:Excitation of locus coeruleus neurons by an adenosine 3',5'-cyclic monophosphate-activated inward current: extracellular and intracellular studies in rat brain slices. 246 88

To define the cellular mechanism of action of a dihydropyridine Ca channel antagonist in an experimental model system devoid of neural influences and reflex effects, we studied the actions of RS93522 on cultured vascular smooth muscle cells and on cultured chick embryo ventricular cells. 45Ca uptake by monolayer cultures of vascular smooth muscle cells was inhibited in a concentration-dependent manner. The IC50 for this effect was 10 nM, similar to that for nifedipine (7 nM) in the same system. 10(-6) M RS93522 inhibited 45Ca uptake more fully than 10(-6) M nifedipine (P less than 0.05). Using an optical-video system, the effect of RS93522 on amplitude of contraction of spontaneously beating cultured ventricular cells was studied. Amplitude of contraction was inhibited with IC50 = 7.9 x 10(-8)M. 45Ca uptake in myocytes was depressed by 15% at 5 min. RS93522 had the additional property of inhibiting phosphodiesterase activity in myocardial homogenates with IC50 = 1.6 x 10(-5)M; the potency and efficacy of phosphodiesterase inhibition was similar to that for milrinone in the same system. As expected of Ca channel antagonists, it has a negative inotropic effect on cultured myocardial cells. The compound also has phosphodiesterase inhibitory activity that possibly may potentiate vasodilatation and ameliorate, in part, negative inotropic effects. Thus, RS93522 has two distinct pharmacodynamic effects in myocytes and is a potent calcium channel blocker.
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PMID:A dihydropyridine calcium channel blocker with phosphodiesterase inhibitory activity: effects on cultured vascular smooth muscle and cultured heart cells. 247 Sep 9


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