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)

Intravenous inotropic agents promote increased myocardial contractility via elevation of myocyte calcium concentrations, a mechanism that is also known to promote the development of cardiac arrhythmias. The purpose of this article is to review the electrophysiologic effects and relative potential for proarrhythmia associated with dobutamine, dopamine, and the phosphodiesterase inhibitors amrinone and milrinone. Dobutamine increases sinoatrial node automaticity and decreases atrial and atrioventricular (AV) node refractoriness and AV nodal conduction time. The drug also decreases ventricular refractoriness in both healthy and ischemic myocardium. Dobutamine has been shown to increase heart rate in a dose-related fashion in animals and in humans. In humans, dobutamine has been reported to induce ventricular ectopic activity (VEA) in 3% to 15% of patients, although VEAs are often asymptomatic, requiring no intervention. Ventricular tachycardia (VT) associated with dobutamine appears to occur rarely. Patients with underlying arrhythmias or heart failure or those receiving excessive doses of dobutamine are at greatest risk for proarrhythmia. Dopamine increases automaticity in Purkinje fibers and has a biphasic effect on action potential duration. Dopamine has been reported to induce atrial or ventricular arrhythmias in animals. In humans, dopamine may be associated with dose-related sinus tachycardia but has also been reported to cause VEA, which is usually asymptomatic. Dopamine-associated VT appears to occur rarely. Dopamine produces greater elevations in heart rate or frequency of ventricular premature beats at a given value of cardiac index than does dobutamine. The phosphodiesterase inhibitors amrinone and milrinone increase conduction through the AV node and decrease atrial refractoriness. Intravenous administration of these drugs may result in sinus tachycardia in some patients and has been reported to cause VEA, which is often asymptomatic, in up to 17% of patients. VT has also been reported in association with short-term use of intravenous phosphodiesterase inhibitors. In summary, intravenous inotropic agents may be associated with proarrhythmic effects in some patients. The primary arrhythmias reported are sinus tachycardia and VEA, although other supraventricular or ventricular arrhythmias have been reported less commonly. However, clinically significant proarrhythmic effects associated with these agents appear to occur rarely, and, at conventional doses, intravenous inotropic agents are relatively safe with respect to proarrhythmic effects.
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PMID:Electrophysiologic and proarrhythmic effects of intravenous inotropic agents. 756 5

1. Mesenteric artery vascular smooth muscle cells derived from male Wistar rats and grown in culture were prelabelled with [3H]-adenine and exposed to a range of dopamine receptor agonists and antagonists. Resultant [3H]-cyclic AMP formation was determined and concentration-effect curves constructed, in the presence of propranolol (10-6) M) and the phosphodiesterase inhibitor IBMX (5 x 10(-4) M). 2. Ka apparent values for D1/DA1 dopamine receptor agonists SKF 38393, fenoldopam, 6,7-ADTN, and dopamine were 0.06, 0.59, 4.06 and 5.77 x 10(-6) M respectively. Although fenoldopam and SKF 38393 were more potent than dopamine, they were partial agonists with efficacies, relative to dopamine of approximately 48% and 24% respectively. 6,7-ADTN, in contrast, behaved as a full agonist. 3. Dopamine-stimulated cyclic AMP formation was inhibited in a concentration-dependent manner by the D1/DA1 dopamine receptor selective antagonists, SCH 23390 and cis-flupenthixol (Ki values 0.53 and 36.1 x 10(-1) M respectively). In contrast, the D2/DA2 dopamine receptor selective antagonists, domperidone and (-)-sulpiride, were less potent (Ki values 2.06 and 5.82 x 10(-6) M respectively). Furthermore, the stereoisomers of SCH 23390 and cis-flupenthixol, SCH 23388 and trans-flupenthixol, were at least two orders of magnitude less potent (Ki values 0.14 and 13.2 x 10(-6) M respectively) indicating the stereoselective nature of this receptor. 4. Our results indicate that rat mesenteric artery vascular smooth muscle cells in culture express a dopamine receptor coupled to cyclic AMP formation, which has the pharmacological profile, characteristic of the D1 dopamine receptor subfamily.
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PMID:Pharmacological characterization of the dopamine receptor coupled to cyclic AMP formation expressed by rat mesenteric artery vascular smooth muscle cells in culture. 790 78

When fluid administration is not sufficient to restore hemodynamic stability, inotropic agents may be given to restore the tissue perfusion pressure and to increase oxygen delivery (DO2) to the cells. Dopamine remains the drug of choice in the resuscitation of septic shock but norepinephrine can also have a place in the treatment of profound cardiovascular collapse or severe right ventricular failure. Dobutamine has become the inotropic agent of choice to increase DO2 to the tissues. Unfortunately, the beneficial effects of these agents on the extraction capabilities of the tissues are questionable. The potential of other adrenergic agents (such as dopexamine) or nonadrenergic agents (such as phosphodiesterase inhibitors) is also discussed in this article. Inotropic therapy should be guided not only by measurements of systemic BP but also by repeated assessments of the metabolic function of organs.
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PMID:Inotropic agents. 792 87

D1 dopamine receptors stimulate cAMP accumulation in opossum kidney (OK) cells, but this response is attenuated by pretreatment with dopamine. Dopamine pretreatment also causes a reduction in D1 dopamine receptor number. We transfected OK cells with a rat cAMP phosphodiesterase cDNA (rPDE3) in order to determine the contribution of elevations of cAMP to those two phenomena. Wild-type (WT) OK cells were compared to three clones (C, H, and N) which demonstrated stable expression of the rPDE3 phenotype and genotype, rPDE3 RNA expression was confirmed in clones C, H, and N (but not in WT-OK cells) by reverse transcriptase-polymerase chain reaction. A functional rPDE3 phenotype was demonstrated in that dopamine-responsive cAMP accumulation was absent in clones C, H, and N in intact cells, but could be restored by preincubation with cAMP phosphodiesterase inhibitors, or by using washed membranes from those clones. All three clones had increased cAMP phosphodiesterase activity when compared to WT-OK cells (approximately 100% increase), and blunted or absent dopamine (1 microM)-induced protein kinase A activation. After pretreatment with dopamine (1 microM) for 1 h, clones C, H, and N desensitized equally well as WT-OK cells (approximately 40-50% reduction in maximal increase in cAMP). In contrast, down-regulation of D1 dopamine receptors was blunted for clone C (20% receptor loss) and absent for clones H and N, when compared to a 45% loss of receptors for WT-OK cells. These findings suggest that in OK cells pretreated with 1 microM dopamine (i) cAMP accumulation is not necessary for dopamine-induced desensitization, but (ii) is necessary for down-regulation of D1 dopamine receptors, and (iii) that the down-regulation and desensitization processes may be differentially regulated.
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PMID:Elevation of cAMP is required for down-regulation, but not agonist-induced desensitization, of endogenous dopamine D1 receptors in opossum kidney cells. Studies in cells that stably express a rat cAMP phosphodiesterase (rPDE3) cDNA. 839 59

OPC-18790, (+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-quin olinone, is a novel positive inotropic agent, and its mechanism of positive inotropic action involves not only phosphodiesterase inhibition, but also a prolongation of action potential duration in ventricular muscle. Prolongation of action potential duration is also a property of class III antiarrhythmic agents; therefore, we examined the cardiohemodynamic effects and arrhythmogenicity of a combination of OPC-18790 and dopamine in halothane-anesthetized dogs. Dopamine (5 micrograms/kg/min) alone increased the peak of the first derivative of left ventricular pressure (LVdP/dtmax) and cardiac output (CO) by 43-48% and 16-20%, respectively, while OPC-18790 (10 micrograms/kg/min) increased these parameters by 56% and 22%, respectively. The combination of OPC-18790 (10 micrograms/kg/min) and dopamine (5 micrograms/kg/min) and dopamine alone at an increased dose of 10 micrograms/kg/min further increased LVdP/dtmax and CO by 104-113% and 29-30%, respectively. Thus, positive inotropic effects were equally observed in both groups, and the effects of OPC-18790 and dopamine seemed to be additive. The other hemodynamic effects were similar among all groups. Arrhythmias such as premature ventricular contraction developed in 5 out of 7 dogs (71.4%) in the 10-micrograms/kg/min dopamine group, while only one premature ventricular contraction was observed in 1 of 7 dogs (14.3%) in the OPC-18790 (10 micrograms/kg/min) and dopamine (5 micrograms/kg/min) combination group. These results suggest that the combination of OPC-18790 and dopamine may provide new therapeutic options for the treatment of heart failure.
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PMID:Cardiovascular effects of the combination of OPC-18790 and dopamine in halothane-anesthetized dogs. 869 31

The anterior pituitary gland is a site of nitric oxide (NO) production and action, suggesting a local regulatory function. We recently reported that NO inhibits in vitro prolactin release. The aim of the present study was to establish the mechanism of action of NO on prolactin release and to determine whether NO is involved in the inhibitory effect of GABA on prolactin release. Since NO exerts its action through cGMP by activating guanylate cyclase in different tissues, we examined the effect of sodium nitroprusside (NP), a NO releaser, on intrapituitary cGMP levels. Incubation of anterior pituitary glands with 0.5 mM NP 4-fold increased intrapituitary cGMP content, but decreased intrapituitary cAMP levels. In addition, we studied the effect of NP on prolactin release in the presence of LY 83583, an inhibitor of guanylate cyclase activity and 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of phosphodiesterase activity. 10 microM LY 83583 and 0.5 mM IBMX blocked the inhibitory effect of NP on prolactin release. (10(-3) M) 8Br-cGMP, an analogue of cGMP, mimicked the effect of NP on prolactin release. On the other hand, NO seems to be involved in the inhibitory effect of GABA on prolactin release since hemoglobin, a scavenger of NO, and Nw-nitro-L-arginine methyl ester, an inhibitor of NO synthase (NOS), blocked the pituitary response to GABA. Moreover, GABA (10(-6) M) stimulated NOS activity by almost 50%. GABA increased intrapituitary cGMP levels and decreased cAMP. Dopamine stimulated NOS activity weakly. These observations suggest that NO, acting through the guanylate cyclase-cGMP pathway, inhibits prolactin secretion. In addition, NO may be involved in the inhibitory effect of GABA and dopamine on prolactin release.
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PMID:Role of nitric oxide/cyclic GMP pathway in the inhibitory effect of GABA and dopamine on prolactin release. 895 68

The purpose of this study was to determine the mechanisms of dopamine regulation of phosphate uptake in opossum kidney (OK) cells, a model of proximal renal tubules. Dopamine stimulated cAMP generation and inhibited radiolabeled phosphate uptake into OK cell monolayers by 14.4 +/- 1.8%. The effect of dopamine was transient, as phosphate uptake returned toward control level by 3 h despite the continued presence of dopamine. Pretreatment with pertussis toxin increased dopamine inhibition of phosphate uptake to 25 +/- 3%, increased the duration of the dopamine effect to at least 3 h, and enhanced cAMP generation. In an OK cell clone that overexpressed cAMP phosphodiesterase, dopamine did not inhibit phosphate uptake, but pharmacologic inhibition of protein kinase A activation did not prevent dopamine inhibition of phosphate uptake. A DA1 receptor agonist inhibited phosphate uptake more potently than dopamine (29.5 +/- 1.1%) or a DA2 receptor agonist (7.9 +/- 2%). However, both DA1 and DA2 receptor antagonists completely blocked dopamine inhibition of phosphate uptake. DA1, but not the DA2, antagonists blocked dopamine-stimulated cAMP generation. Treatment with alpha-adrenergic receptor antagonists potentiated dopamine inhibition of phosphate uptake to the same extent as pertussis toxin and was not additive with pertussis toxin. It is concluded that dopamine inhibits phosphate uptake through DA1 and DA2 receptor stimulation by cAMP-dependent and -independent pathways and activates a pertussis toxin-sensitive counter-regulatory pathway that attenuates this response through alpha-adrenergic receptor stimulation.
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PMID:Dopamine regulates phosphate uptake by opossum kidney cells through multiple counter-regulatory receptors. 962 Dec 80

Phototransduction in Drosophila is mediated by a G-protein-coupled phospholipase C transduction cascade in which each absorbed photon generates a discrete electrical event, the quantum bump. In whole-cell voltage-clamp recordings, cAMP, as well as its nonhydrolyzable and membrane-permeant analogs 8-bromo-cAMP (8-Br-cAMP) and dibutyryl-cAMP, slowed down the macroscopic light response by increasing quantum bump latency, without changes in bump amplitude or duration. In contrast, cGMP or 8-Br-cGMP had no effect on light response amplitude or kinetics. None of the cyclic nucleotides activated any channels in the plasma membrane. The effects of cAMP were mimicked by application of the non-specific phosphodiesterase inhibitor IBMX and the adenylyl cyclase activator forskolin; zaprinast, a specific cGMP-phosphodiesterase inhibitor, was ineffective. Bump latency was also increased by targeted expression of either an activated G(s) alpha subunit, which increased endogenous adenylyl cyclase activity, or an activated catalytic protein kinase A (PKA) subunit. The action of IBMX was blocked by pretreatment with the PKA inhibitor H-89. The effects of cAMP were abolished in mutants of the ninaC gene, suggesting this nonconventional myosin as a possible target for PKA-mediated phosphorylation. Dopamine (10 microM) and octopamine (100 microM) mimicked the effects of cAMP. These results indicate the existence of a G-protein-coupled adenylyl cyclase pathway in Drosophila photoreceptors, which modulates the phospholipase C-based phototransduction cascade.
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PMID:Modulation of the light response by cAMP in Drosophila photoreceptors. 1051 99

Maintenance of adequate oxygen balance to all tissues is one of the primary objectives when dealing with patients undergoing cardiac surgery. Cardiac output is one of the major components of oxygen delivery so that its maintenance is an important consideration. Due to pre-operative cardiac lesion and myocardial dysfunction secondary to the events related to cardiac surgery and cardiopulmonary by-pass, circulatory support by pharmacological or mechanical means is frequently required after surgery. Therefore, inotropes and vasodilators are used to improve the myocardial performance after cardiac surgery. Epinephrine, dopamine and dobutamine are commonly used inotropes. Dopexamine and phosphodiesterase inhibitors such as amrinone, milrinone and enoximone are some of the newer agents that have been introduced in clinical practice. Amongst the vasodilators, sodium nitroprusside and nitroglycerin are commonly used. Alpha adrenergic blockers such as phentolamine and phenoxybenzamine and calcium channel blockers such as diltiazem are some other vasodilators that can be used. Many units still regard epinephrine as an inotrope of choice and use its predominant beta agonist effect in the dose range of 0.02 to 0.04 mg/kg/minute. Some prefer dobutamine and others a combination of inotrope and vasodilator or an inodilator. Phosphodiesterase inhibitors can be useful in certain situations such as pre-existing ventricular dysfunction or when stunning of the myocardium is suspected with down regulation of beta receptors. Dopamine is useful in the renal vasodilating dose to improve renal perfusion and improve output. There is no ideal inotrope at present and each one has its own drawbacks. The clinician must learn to use the inotropes (especially the newer ones) based on his own clinical experience.
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PMID:Pharmacologic support of circulation in patients undergoing cardiac surgery. 1063 2

All involuntary innervated structures of the body are controlled by the sympathetic and parasympathetic nervous system. Adrenaline, noradrenaline and dopamine are endogenous catecholamines binding to adrenergic and dopaminergic receptors, respectively, to mediate their clinical effects. Adrenoceptors are classified as alpha 1, alpha 2, beta 1 and beta 2 subtypes which were even further subcharacterized the recent years. Adrenoceptors are membrane proteins interacting with the agonist and, thus, inducing G-protein mediated intracellular effects. Adrenaline induces an extensive increase of heart rate and stroke volume mediated by beta-adrenoceptors and significantly enhances peripheral vascular resistance by alpha-adrenoceptor stimulation, when administered beyond 0.1 microgram/kg.min. In contrast, the clinical effects of noradrenaline are predominantly characterized by alpha-adrenoceptor stimulation resulting in a less pronounced increase of heart rate. Dopamine, less potent on adrenoceptors, shows additional effects on renal as well as on splanchnic circulation mediated by dopaminergic receptors. Dobutamine, primarily acting on beta-adrenoceptors, results in positive inotropic effects without an increase in vascular resistance. Dopexamine, a synthetic catecholamine, induces vasodilation via beta 2-adrenoceptor stimulation and potentially increases splanchnic blood flow by additional effects on dopaminergic receptors. Isoproterenol, the classical beta-adrenoceptor agonist, mediates positive inotropic effects and causes a major increase in heart rate and a significant decrease of systemic vascular resistance. Independent on adrenoceptors, phosphodiesterase-III-inhibitors exert positive inotropic and vasodilating activity by an increase in intracellular cAMP concentration induced by inhibition of cAMP hydrolysis.
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PMID:[Principles of catecholamine therapy. 1. Characterization of clinically relevant sympathomimetics]. 1071 95


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