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)

Indolidan (IN) experimentally inhibits type IV phosphodiesterase. It was administered to twelve patients (age 64 +/- 15 years) with New York Heart Association (NYHA) class 2-3 congestive heart failure in which digoxin and diuretic therapy were continued. IN was administered i.v. at 1,180 +/- 340 micrograms (15 micrograms/kg) over two hours. After 24 hours, IN was given p.o. at 231 +/- 44 micrograms. The time course effect of IN i.v. revealed an increase in cardiac index and a decrease in pulmonary capillary wedge pressure and blood pressure. Daily oral administration of IN or placebo was carried out for up to 3 months. There were no significant hemodynamic changes of chronically administered IN. The maximum oxygen uptake increased in placebo relative to IN therapy. IN tended to be arrhythmogenic as evidenced by a general increased frequency of ventricular premature contractions of both single and paired type. Therefore, IN had some hemodynamic efficacy on acute i.v. and p.o. administration but not during chronic therapy, and there was negative safety features of arrhythmias.
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PMID:Clinical effect of indolidan in congestive heart failure. 144 58

LY186126 was found to be a potent inhibitor of type IV cyclic AMP phosphodiesterase located in the sarcoplasmic reticulum of canine cardiac muscle. This compound, a close structural analogue of indolidan (LY195115), was prepared in high specific activity, tritiated form to study the positive inotropic receptor(s) for cardiotonic phosphodiesterase inhibitors such as indolidan and milrinone. A high-affinity binding site for [3H]LY186126 was observed (Kd = 4 nM) in purified preparations of canine cardiac sarcoplasmic reticulum vesicles. Binding was proportional to vesicle protein, was inactivated by subjecting membranes to proteolysis or boiling, and was dependent on added Mg2+. Scatchard analysis suggested the presence of a single class of binding sites in the membrane preparation. Indolidan, milrinone, and LY186126 (all at 1 microM) produced essentially complete displacement of bound [3H]LY186126, while nifedipine, propranolol, and prazosin had little or no effect at this concentration. This represents the first reported use of a radioactive analogue to label the inotropic receptor for cardiotonic phosphodiesterase inhibitors. The results suggest that [3H]LY186126 is a useful radioligand for examining the subcellular site(s) responsible for positive inotropic effects of these drugs.
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PMID:Specific binding of [3H]LY186126, an analogue of indolidan (LY195115), to cardiac membranes enriched in sarcoplasmic reticulum vesicles. 253 21

The neurotransmitter, pituitary adenylate cyclase-activating polypeptide (PACAP), is present in the rat adrenal medulla and is a potent stimulus for catecholamine secretion. Previous studies have suggested that neurally derived signals stimulate proliferation of chromaffin cells in adult rats. To determine whether PACAP might be involved in mitogenic signalling, its effects on bromodeoxyuridine incorporation were studied in adrenal medullary cell cultures from adult female rats. Both PACAP 27 and PACAP 38 are able to stimulate proliferation of adult rat chromaffin cells in vitro, either alone or in conjunction with PMA, an activator of protein kinase C. BrdU-labelled nuclei are observed in both epinephrine and norepinephrine cells, and proliferation of both cell types is stimulated by the same concentrations of PACAP that elicit secretion of catecholamines. The mitogenic effects of PACAP are potentiated by indolidan, a phosphodiesterase inhibitor known to cause pheochromocytomas in rats, and are inhibited by H-89, an inhibitor of protein kinase A. Mitogenic concentrations of PACAP inhibit mitogenic effects of nerve growth factor. These findings support the hypothesis that neurally derived signals regulate chromaffin cell proliferation in adult rats. Indolidan and a variety of nongenotoxic agents that cause pheochromocytomas in rats may do so indirectly by increasing neurally mediated chromaffin cell turnover. The antagonism between PACAP and NGF suggests that neurotransmitters may supersede growth factors in regulating chromaffin cell proliferation during development by suppressing or co-opting portions of growth factor signaling pathways.
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PMID:Mitogenic and antimitogenic effects of pituitary adenylate cyclase-activating polypeptide (PACAP) in adult rat chromaffin cell cultures. 762 29

Previous studies have demonstrated that cGMP and cAMP reduce the endothelial permeability for fluids and macromolecules when the endothelial permeability is increased by thrombin. In this study, we have investigated the mechanism by which cGMP improves the endothelial barrier function and examined whether nitric oxide (NO) can serve as an endogenous modulator of endothelial barrier function. Thrombin increased the passage of macromolecules through human umbilical vein and human aortic endothelial cell monolayers and concomitantly increased [Ca]2+ in vitro. Inhibition of these increases by the intracellular Ca2+ chelator BAPTA indicated that cytoplasmic Ca2+ elevation contributes to the thrombin-induced increase in endothelial permeability. The cGMP-dependent protein kinase activators 8-bromo-cGMP (8-Br-cGMP) and 8-(4-chlorophenylthio)cGMP (8-PCPT-cGMP) decreased the thrombin-induced passage of macromolecules. Two pathways accounted for this observation. Activation of cGMP-dependent protein kinase by 8-PCPT-cGMP decreased the accumulation of cytoplasmic Ca2+ in aortic endothelial cells and hence reduced the thrombin-induced increase in permeability. On the other hand, in umbilical vein endothelial cells, cGMP-inhibited phosphodiesterase (PDE III) activity was mainly responsible for the cGMP-dependent reduction of endothelial permeability. The PDE III inhibitors Indolidan (LY195115) and SKF94120 decreased the thrombin-induced increase in permeability by 50% in these cells. Thrombin treatment increased cGMP formation in the majority of, but not all, cell cultures. Inhibition of NO production by NG-nitro-L-arginine methyl ester (L-NAME) enhanced the thrombin-induced increase in permeability, which was restricted to those cell cultures that displayed an increased cGMP formation after addition of thrombin. Simultaneous elevation of the endothelial cGMP concentration by atrial natriuretic factor, sodium nitroprusside, or 8-Br-cGMP prevented the additional increase in permeability induced by L-NAME. These data indicate that cGMP reduces thrombin-induced endothelial permeability by inhibition of the thrombin-induced Ca2+ accumulation and/or by inhibition of cAMP degradation by PDE III. The relative contribution of these mechanisms differs in aortic and umbilical vein endothelial cells. NO can act in vitro as an endogenous permeability-counteracting agent by raising cGMP in endothelial cells of large vessels.
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PMID:cGMP and nitric oxide modulate thrombin-induced endothelial permeability. Regulation via different pathways in human aortic and umbilical vein endothelial cells. 783 30

The hemodynamic and beta adrenergic blocking effects of GI104313, a chimeric molecule containing a phosphodiesterase-inhibiting pyradazinone and a beta blocking phenoxpropanolamine, were examined in barbiturate-anesthetized, vagotomized dogs. The results of these studies were compared to those of indolidan, a known phosphodiesterase inhibitor, and xamoterol, a partial beta adrenoceptor agonist. The compounds were infused at six increasing dose rates in 10-min intervals. Isoproterenol (0.5 microgram/kg) was administered before each dose increment to determine beta adrenoceptor responsiveness. In a separate set of experiments, the hemodynamic effects of GI104313, indolidan and xamoterol were examined in the presence of complete beta blockade with atenolol. GI104313 elicited dose-dependent increases in heart rate, contractility (+dP/dt) and cardiac output and decreases in arterial blood pressure, left ventricular end diastolic pressure and systemic vascular resistance in unpretreated and atenolol-pretreated dogs. However, GI104313 was less potent hemodynamically in atenolol-pretreated animals. This was evidenced by a 4-fold dextral shift in the dose-response relation for several hemodynamic variables. In unpretreated dogs, GI104313 elicited potent dose-dependent blockade of the heart rate, diastolic blood pressure and +dP/dt responses to isoproterenol. Greater than 95% inhibition of isoproterenol response was attained at 1 mumol/kg GI104313 for all observed variables. Indolidan increased contractility and heart rate and decreased diastolic blood pressure in a dose-related fashion. Indolidan did not modify the stimulatory effects of isoproterenol. Atenolol had modest effects on indolidan's hemodynamic effect, only shifting its inotropic effect 2-fold. Xamoterol produced hemodynamic and beta blocking effects similar to GI104313.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The inotropic and beta blocking effects of a chimeric molecule that putatively inhibits both type III phosphodiesterase and beta adrenoceptors in anesthetized dogs. 809 17