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)

5-Hydroxytryptamine (5-HT) stimulates corticosteroid secretion from adrenal cells through activation of 5-HT4 receptors positively coupled to adenylyl-cyclase. In the present study, we investigated in frog adrenocortical cells the effect of 5-HT4 receptor agonists on cytosolic calcium concentration ([Ca2+]i) and determined the sequence of events associated with 5-HT4 receptor agonist zacopride (10[-8] to 10[-5]M each in the vicinity of cultured adrenocortical cells caused a dose-dependent increase in [Ca2+]i. Preincubation of the cells with the selective 5-HT4 receptor antagonist [1-[2-(methylsulfonylamino)ethyl]-4- piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate maleate totally blocked the 5-HT-induced stimulation of [Ca2+]i. Chelation of extracellular calcium with ethylene glycol bis (beta-aminoethyl ether)-N,N,N', N'-tetraacetic acid (10 MM) suppressed the stimulatory effect of 5-HT on [Ca2+]i. Conversely, thapsigargin, an inhibitor of calcium ATPase activity, had no effect on the [Ca2+]i rise. The calcium influx induced by 5-HT4 receptor agonists was not affected by nifedipine and omega-conotoxin GVIA but was totally blocked by pimozide, a T-type calcium channel antagonist. The [Ca2+]i response to zacopride was potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine and markedly reduced by the protein kinase A inhibitor adenosine-3',5'-cyclic monophosphorothioate. We studied in perifused frog adrenal slices the involvement of [Ca2+]i rise and cAMP formation in the mechanism of action of 5-HT4 receptor agonists. Zacopride-induced steroidogenesis was significantly reduced in the presence of adenosine-3'5'-cyclic monophosphorothioate or after suppression of calcium in the perifusion medium. The stimulatory effect of zacopride on corticosteroid secretion was not affected by nifedipine and omega-conotoxin GVIA but was significantly inhibited by pimozide. Taken together, these data indicate that activation of 5-HT4 receptors in adrenocortical cells causes stimulation of adenylyl cyclase and subsequently increases calcium influx through a T-type calcium channel. Both the increased in cAMP formation and the calcium rise are involved in the stimulatory effect of 5-HT on corticosteroid secretion.
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PMID:Activation of 5-hydroxytryptamine4 receptors causes calcium influx in adrenocortical cells: involvement of calcium in 5-hydroxytryptamine-induced steroid secretion. 864 88

A phosphodiesterase (PDE) III inhibitor, amrinone, inhibited both the negative inotropic actions of verapamil and nicardipine in guinea pig ventricular papillary muscle; this effect was canceled by the protein kinase A inhibitor H-89. The PDE IV inhibitor 1,3-di-n-butyl-7-(2'-oxopropyl)xanthine (denbufylline), which elicited a negative inotropic action by itself, attenuated the action of verapamil up to 10 microM, without any interaction with nicardipine. The attenuation by denbufylline was not influenced by H-89. This suggests that in the ventricular papillary muscle, denbufylline acts on some verapamil-sensitive site(s) in the membrane and interferes with the calcium channel function without involvement of its PDE inhibitory activity.
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PMID:A xanthine derivative denbufylline inhibits negative inotropic response to verapamil in guinea pig ventricular papillary muscles, independent of its phosphodiesterase inhibitory activity. 869 37

This study explores the mechanisms by which free arachidonic acid (AA) affects ovarian steroidogenesis by full-grown prematurational follicles of the goldfish in vitro. AA (6-400 microM) stimulated testosterone production and this action was mediated by prostaglandin E2 (PGE2). The steroidogenic actions of AA and the corresponding increase in the production of PGE2 were blocked by inhibitors of the cyclooxygenase pathway (indomethacin, ETYA). Exogenous PGE2 (20-2000 ng/ml) also stimulated steroid production. In the presence of human chorionic gonadotropin (hCG), AA had differential effects. AA potentiated the steroidogenic actions of low dosages of hCG (0.1 IU/ml), while with maximal gonadotropin (1-10 IU/ml) stimulation a high concentration of AA (400 microM) attenuated steroid production in spite of elevated PGE2 synthesis, nor did it affect the PGE2 production obtained with AA-treated follicles. The steroidogenic induction by AA via PGE2 was mediated in part by Ca2+ since the calcium channel blocker nifedipine (25 microM) inhibited stimulated steroid production by both AA and PGE2. The conversion of AA to PGE2 does not require Ca2+ since PGE2 production by AA-treated follicles was not affected by nifedipine. However, treatment with the calcium ionophore A23187 (1 microM) potentiated the stimulatory actions of AA on steroid and prostaglandin production. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (1 mM) potentiated the stimulatory actions of AA on testosterone production but had no effect on the conversion of AA to PGE2. The steroidogenic actions of AA and PGE2 involve both transcription and translation since stimulated steroidogenesis was inhibited by actinomycin D and and cycloheximide (1-10 micrograms/ml). The conversion of AA to PGE2 was also blocked by these inhibitors. These results underscore the importance of AA and PGE2 in the regulation of ovarian steroidogenesis in the goldfish.
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PMID:Mechanisms of action of free arachidonic acid on ovarian steroid production in the goldfish. 886 Mar 17

It has been shown previously that the interaction between uroepithelial cells (UEC) from healthy donors and adherent. Escherichia coli suppresses bacterial growth in vitro. The following study was performed to investigate the nature of membrane signal transduction mechanisms involved in this process. UEC/E. coli cocultures were established in the presence of substances known to modulate transmembranous signals. Inhibition of calcium flux, either by calcium channel-blocking substances or by a calmodulin antagonist, depressed the antibacterial UEC function of "healthy" UEC. In contrast, receptor/ligand-induced stimulation of G-proteins, activation of the adenylate cyclase, and the increase of intracellular cyclic AMP levels by cytoplasmatic phosphodiesterase did not increase the antibacterial capacity of healthy UEC. However, the antibacterial function of defense-deficient UEC from patients with recurrent idiopathic urinary tract infection could be reconstituted by this treatment to almost normal levels. In conclusion, the antibacterial UEC defense function is activated by transmembranous signals from bacteria attached to the host cell surface. Activation involves the adenylate cyclase pathway. Activation of the phosphoinositol pathway may contribute to intracellular calcium fluxes.
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PMID:Host defense within the urinary tract. II. Signal transducing events activate the uroepithelial defense. 889 58

A number of new positive inotropic agents with diverse mechanisms of action have been discovered over the past 20 years. Most of these cardiotonic drugs exhibit characteristic electrophysiologic profiles. This prompted us to propose a classification scheme based on electrophysiologic principles, modifying the categories recently suggested by another author. Class I actions designate positive inotropic mechanisms that enhance the transmembrane calcium current by various means, such as beta-receptor stimulation (dobutamine, class I/A), phosphodiesterase inhibition (milrinone, class I/B), direct stimulation of adenylate cyclase (forskolin, class I/C), or direct modulation of calcium channel gating (BAY K 8644, class I/D). Class II action includes mechanisms that lead to elevation of intracellular sodium activity either by inhibiting the Na,K pump (digitalis, class II/A) or by increasing transmembrane sodium influx (DPI 201-106, class II/B). Class III action involves a mechanism by which sensitivity of the myofilaments to calcium increases (EMD 53998, levosimendan). This mechanism is not associated with apparent electrophysiologic manifestations. Positive inotropism due to lengthening of the cardiac repolarization (almokalant) is considered as class IV action. The possible clinical implications of the various positive inotropic mechanisms are also discussed.
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PMID:Classification of positive inotropic actions based on electrophysiologic characteristics: where should calcium sensitizers be placed? 890 29

Positive inotropic compounds may be harmful in the long-term treatment of chronic congestive heart failure because they may induce a calcium overload, unwanted changes in cross-bridge kinetics and an acceleration in heart rate. As a result of all three alterations, energy consumption would be increased. Different pharmacological modes of action may have different effects on the molecular mechanisms underlying the positive inotropic effect, and hence on myocardial energy consumption. Therefore, we studied the effects of a variety of cardiotonic agents on the heat released from small guinea pig papillary muscles contracting isometrically at an experimental temperature of 21 degrees C and a stimulation frequency of 12 per minute using rapid antimony-bismuth thermopiles. We were able to define the economy of muscle contraction, which was lowest with phosphodiesterase inhibitors and highest with calcium sensitizers. Compared with an increase in extracellular calcium concentration, beta 1-adrenoceptor stimulators and phosphodiesterase inhibitors profoundly decrease the economy of myocardial contraction, and calcium-sensitizers (pimobendan and EMD-53998) slightly increase myocardial economy, whereas ouabain and the calcium channel agonist BAY K 8644 have no effect on this parameter. In addition, we provide evidence that acceleration of heart rate may be harmful not only from an energetic point of view: an increase in heart rate may also decrease the contractility of the failing human myocardium (inverse force-frequency relationship). Taking these observations into consideration, an "optimal' positive inotropic compound should have no, or even negative, chronotropic effects, should not be mediated by increases in calcium transients, and should decelerate, rather than accelerate, cross-bridge kinetics.
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PMID:New inotropic concepts: rationale for and differences between calcium sensitizers and phosphodiesterase inhibitors. 914 31

Improved understanding of the pathophysiologic course of heart failure has led to many advances in pharmacologic therapy. Angiotensin-converting enzyme inhibitors represent the first effort at targeting neurohormonal activation in chronic heart failure. More recently, beta-adrenergic receptor antagonists have been shown effective in blocking chronic sympathetic nervous system activation. The roles of digoxin and the newer, vasoselective calcium channel blockers in heart failure have been better defined. Other agents targeting the neurohormonal system are under investigation. These include angiotensin-receptor antagonists, aldosterone inhibitors, and endothelin antagonists. Experience with phosphodiesterase inhibitors and adrenergic agents has confirmed the importance of neurohormonal activation in progression of heart failure. Despite angiotensin-converting enzyme inhibitor, diuretic, and digoxin therapy, mortality in heart failure remains high. Careful manipulation of the neurohormonal response to heart failure holds promise for altering the course of the disease.
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PMID:Innovations in the pharmacologic management of heart failure. 963 71

Stimulating cardiac beta 1-adrenoceptors with oxyfedrine causes dilatation of coronary vessels and positive inotropic effects on the myocardium. beta 1-adrenergic agonists increase coronary blood flow in nonstenotic and stenotic vessels. The main indication for the use of the phosphodiesterase inhibitors pamrinone, mirinone, enoximone and piroximone is acute treatment of severe congestive heart failure. Theophylline is indicated for the treatment of asthma, chronic obstructive pulmonary disease, apnea in preterm infants ans sleep apnea syndrome. Severe arterial occlusive disease associated with atherosclerosis can be beneficially affected by elcosanoids. These drugs must be administered parenterally and have a half-life of only a few minutes. Sublingual or buccal preparations of nitrates are the only prompt method (within 1 or 2 min) of terminating anginal pain, except for biting nifedipine capsules. The short half-life (about 2.5 min) of nitroglycerin (glyceryl trinitrate) makes long term therapy impossible. Tolerance is a problem encountered with longer-acting nitric oxide donors. Knowledge of the pharmacokinetic properties of vasodilating drugs can prevent a too sudden and severe blood pressure decrease in patients with chronic hypertension. In considering the administration of a second dose, or another drug, the time necessary for the initially administered drug to reach maximal efficacy should be taken into account. In hypertensive emergencies urapidil, sodium nitroprusside, nitroglycerin, hydralazine and phentolamine are the drugs of choice, with the addition of beta-blockers during catecholamine crisis or dissecting aortic aneurysm. Childhood hypertension is most often treated with angiotensin-converting enzyme (ACE) inhibitors or calcium antagonists, primarily nifedipine. Because of the teratogenic risk involved with ACE inhibitors, extreme caution must be exercised when prescribing for adolescent females. The propagation of health benefits to breast-fed infants, combined with more women delaying pregnancy until their fourth decade, has entailed an increase in the need for hypertension management during lactation. Low dose hydrochlorothiazide, propranolol, nifedipine and enalapril or captopril do not pose enough of a risk of preclude breastfeeding in this group. The most frequently used antihypertensive agents during pregnancy are methyldopa, labetalol and calcium channel antagonists. Methyldopa and beta-blockers are the drugs of choice for treating mild to moderate hypertension. Prazosin and hydralazine are used to treat moderate to severe hypertension and hydralazine, urapidil or labetalol are used to treat hypertensive emergencies. The use of overly aggressive antihypertensive therapy during pregnancy should be avoided so that adequate uteroplacental blood flow is maintained. Methyldopa is the only drug accepted for use during the first trimester of pregnancy.
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PMID:Clinical pharmacokinetics of vasodilators. Part II. 967 32

The authors studied the pharmacotherapeutic activity of drugs belonging to various pharmacological groups which are inhibitors of cAMP phosphodiesterase in the hypoxic syndrome. The increase in the level of the secondary intermediate of the adenylate cyclase path in transmission of the intracellular signal from the outer surface of the cell to the nucleus, the hypoxia protector cAMP, under the effect of the drugs under study favorably influenced survival and the course of hypoxic hypoxia in overheating. A combination of quercetin bioflavonoid with acetylsalicylic acid demonstrated stronger antihypoxic and thermoprotector properties. The results were less marked with the use of the calcium channel blocker cinnarizine and an agent of the xanthine pentoxyfelline group. The possible mechanisms of the antihypoxic activity of the drugs under study are discussed.
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PMID:[The role of cAMP phosphodiesterase inhibitors in the pharmacotherapy of the hypoxic syndrome]. 992 14

In the coronary circulation, endothelin-1 (ET-1) evokes spasms which are difficult to treat when the endothelial integrity is compromised. This study compares several classes of relaxing agents on already established contractions to ET-1 in an in vitro model using ring segments of the porcine left descending coronary artery (pLAD). All segments were precontracted with 10 nmol/L ET-1. The calcium channel blocker isradipine was 300 times more potent than verapamil, but was only a partial relaxant; the maximal relaxation obtained was 52 +/- 2% (n = 6). Atrial natriuretic peptide (ANP) was an equally potent relaxant of the ET-1 contraction; however, it too was an incomplete relaxant, maximal relaxation being < 60%. A 50% relaxation of the ET-1 contraction was obtained with 0.28 +/- 0.24 mumol/L ANP, n = 4 (IC50). Comparison of cyclic nucleotide analogues revealed a 30 times higher potency for 8-bromo-cyclic guanosine monophosphate (8-Br-cGMP)(IC50 44 +/- 11 mumol/L, n = 6) than for 8-bromo-cyclic adenosine monophosphate (8-Bi-cAMP) (IC50 1600 mumol/L, n = 6). The cyclic nucleotide phosphodiesterase (PDE) inhibitor milrinone, a PDE 3-inhibitor with an IC50 2.4 +/- 1.8 mumol/L, (n = 6) was 10 times more potent than rolipram (PDE 4-inhibitor), zaprinast (PDE 5-inhibitor) and vinpocentine (PDE 1-inhibitor). Withdrawal of these analogues and inhibitors from segments continuously exposed to 10 nmol/l ET-1 revealed that vinpocentine and 8-Br-cGMP were irreversible relaxants, in contrast to milrinone and 8-Br-cAMP. In conclusion, this study has demonstrated that cGMP-enhancing agents, such as the naturally occurring ANP, the calcium channel blocker isradipine, and the synthetic inhibitor of PDE 3, were the most effective relaxants of ET-1 evoked contractions in pLAD in vitro.
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PMID:Relaxing effects of cyclic GMP and cyclic AMP-enhancing agents on the long-lasting contraction to endothelin-1 in the porcine coronary artery. 1008 99


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