Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serotonin (5-hydroxytryptamine; 5-HT) and its analogs activate adenylate cyclase in membrane particles from neuroblastoma NCB.20 cells. Low concentrations of GTP (EC50 = 60 nM) were required for activation by serotonin. Guanosine 5'-O-(2-thiodiphosphate) inhibited serotonin-activated cyclase in these cells. The nonhydrolyzable GTP analogs guanosine 5'-O-(3-thiotriphosphate) (EC50 = 3 nM) and guanylyl-imidodiphosphate (EC50 = 100 nM) substituted for GTP in potentiating serotonin activation. Pretreatment of the cells with cholera toxin potentiated enzyme activation by serotonin, whereas pertussis toxin was found to have little effect, indicating the involvement of the alpha subunit of a stimulatory GTP-binding protein in enzyme activation. Homologous desensitization of the serotonin-stimulated adenylate cyclase was demonstrated in membranes prepared from intact cells pretreated with serotonin. Cell membrane particles that were desensitized to serotonin were still responsive to beta-adrenergic agonists and to prostaglandin E1. Evidence is presented indicating that serotonin stimulation of adenylate cyclase is mediated by receptors that are distinct from other positively coupled receptors (beta-adrenergic, histamine, and prostacyclin). Equilibrium binding analysis with [3H]serotonin, [3H]lysergic acid diethylamide, and [3H]dihydroergotamine suggested that the site density was below the level of detection of binding of these radioligands. The pharmacological characteristics of the serotonin-activated cyclases were analyzed in order to compare these serotonin receptors with the family of different receptor subtypes. Correlation analysis between the potencies of different agonists and antagonists at the cyclase in these cells and their reported relative potencies for different serotonin receptor subtypes showed no correlation with the 5-HT1A, 5HT1B, 5HT1D, 5-HT2, and 5-HT3 receptors. On the other hand, the analysis showed that the NCB.20 serotonin receptors are similar but not identical to the rat and pig brain 5-HT1C receptors and to the serotonin receptors coupled to adenylate cyclase in the trematodes Schistosoma mansoni and Fasciola hepatica. The results point to a novel serotonin receptor which has a low density in these cells.
Mol Pharmacol 1990 May
PMID:Serotonin receptor-mediated activation of adenylate cyclase in the neuroblastoma NCB.20: a novel 5-hydroxytryptamine receptor. 233 46

Myocardial ischemia leads to the damage of cellular membranes and release of intracellular enzymes. We studied the influence of the prostacyclin analog, iloprost, on alterations in membrane phospholipid content and composition in rat myocardium during ischemia. Infusion of iloprost (100 ng/kg/min) or its vehicle started 20 min after coronary artery ligation, and the hearts were analyzed after 6 h. Myocardial creatine kinase activity was significantly reduced by approximately 25% in the ischemic areas of hearts from rats receiving vehicle. This reduction in myocardial creatine kinase activity was totally abolished by infusion of iloprost. Total phospholipid content was significantly reduced by 10% in ischemic areas of hearts obtained from vehicle infused animals. Iloprost infusion also prevented the loss of total phospholipids in the ischemic areas. The data show that coronary artery ligation is associated with a significant loss of total membrane phospholipids in ischemic regions of rat myocardium, characterized by significant decreases in phosphatidylcholine, phosphatidylethanolamine and cardiolipin. The decrease in cardiac phosphatidylcholine and phosphatidylethanolamine content was prevented by iloprost, whereas the decrease in cardiolipin content was unaltered. Infusion of the prostacyclin analog iloprost almost totally inhibited the ischemia induced loss of phospholipids, suggesting that this may be an important component of its cytoprotective mechanism of action.
J Mol Cell Cardiol 1987 Mar
PMID:Protective actions of a stable prostacyclin analog in ischemia induced membrane damage in rat myocardium. 243 96

To assess whether the administration of the stable prostacyclin-mimetic ZK 36374 (iloprost) protects the myocardium in a dose-dependent manner against ischaemia and reperfusion, isolated rabbit hearts were infused with three different concentrations of iloprost: 2.7, 27 and 270 nM. Diastolic and developed pressures were monitored; coronary effluent was collected and assayed for creatine phosphokinase (CPK) activity and for noradrenaline concentration; mitochondria were harvested and assayed for respiratory activity; ATP production and calcium content and tissue concentration of adenosine triphosphate (ATP) and creatine phosphate (CP) were determined. Treatment with iloprost altered neither developed pressure under normoxic conditions nor the rate and extent of depletion of ATP and CP during ischaemia. The ischaemic-induced deterioration of mitochondrial function, however, was attenuated. On reperfusion, hearts treated with iloprost recovered better than the untreated hearts with respect to left ventricular performance, replenishment of ATP and CP stores and mitochondrial function. The reperfusion-induced mitochondrial calcium overload and release of CPK and of noradrenaline were also significantly reduced. The effect of iloprost was dose-dependent. The lower concentration (2.7 nM) failed to modify ischaemic and reperfusion damage. The best protective effect was found at 27 nM. An increase of the dose to 270 nM did not result in further protection. It is concluded that iloprost infusion provides a dose-dependent protection of the heart against some of the deleterious effects of ischaemia and reperfusion and, in particular, prevents mitochondrial calcium overload and maintains mitochondrial function. Because this protection occurred in the absence of negative inotropic effect during normoxia or of a coronary dilatory effect during ischaemia, it cannot be attributed to an energy sparing effect or to improvement of oxygen delivery. Therefore, alternative mechanisms of action are to be considered.
J Mol Cell Cardiol 1988 Dec
PMID:Protective effect of a prostacyclin-mimetic on the ischaemic-reperfused rabbit myocardium. 247 Sep 8

The secretagogue effects of prolactin (PRL) and of various agents acting on cAMP levels, forskolin, cholera toxin and iloprost (a stable analogue of prostaglandin I2) have been assessed in lactating doe mammary gland fragments in vitro. Forskolin (10 microM), cholera toxin (1 microgram/ml) and iloprost (10 mM) stimulated milk casein secretion. The effects of forskolin (10 microM) and cholera toxin (1 microgram/ml) were potentiated by PRL (10 micrograms/ml). Conversely, the action of iloprost (10 microM) was not amplified by PRL (10 micrograms/ml). Forskolin (10 microM) and cholera toxin (1 microgram/ml) stimulated the intracellular accumulation of cAMP. Neither PRL nor iloprost, at concentrations which stimulated casein secretion, modified the accumulation of cAMP. These results demonstrate that PRL does not act directly by any increase in intracellular cAMP levels. However, stimulating effects of forskolin and cholera toxin on casein secretion and intracellular cAMP levels suggest that various transduction signals are effective in the mammary cells.
Mol Cell Endocrinol 1989 Aug
PMID:The actions of forskolin, cholera toxin and iloprost on casein secretion by lactating doe mammary glands. 247 50

The kinetics of prostaglandin-regulated cyclic AMP formation by intact human platelets were studied in the presence and absence of phosphodiesterase inhibitors. In the case of iloprost, a chemically stable analogue of prostaglandin I2, the shape of the time course varied with prostaglandin concentration. In the presence of phosphodiesterase inhibitors, low concentrations of iloprost gave a linear rate of cyclic AMP formation. At higher concentrations of iloprost, the initial rate increased as a saturable function of prostaglandin concentration but the curves decayed with time to give new linear rates of cyclic AMP formation with a different prostaglandin concentration dependence from the initial rates. Time courses were simulated using KINSIM [Anal. Biochem. 130: 134-145 (1983)], a kinetic simulation program that employs numerical integration, over a wide range of iloprost concentration (3 nM to 30 microM) by use of a simple model involving rapid activation of adenylate cyclase, followed by slow reversible transition of adenylate cyclase to an inactive form (desensitization) through a distinct inhibitory receptor. The model requires that the affinity for prostaglandins of both the stimulatory and inhibitory receptors declines with prostaglandin concentration, which may be related to the existence of high and low affinity receptor forms depending on the activation state of the appropriate GTP-binding protein. The same two-receptor model can be used to describe cyclic AMP metabolism in the absence of phosphodiesterase inhibitors, giving rise to characteristic peak and plateau effects in the time courses. The putative inhibitory receptor has an apparent affinity for prostaglandin lower than the stimulatory receptor in the case of iloprost and a higher affinity than the stimulatory receptor in the case of prostaglandin E1. The contribution of phosphodiesterase activation to the time course of cyclic AMP formation through phosphorylation by cyclic AMP-dependent protein kinase was assessed. It was shown that phosphodiesterase activation must be rapid. A plausible and perhaps complete description of prostaglandin-regulated cyclic AMP metabolism in platelets is presented.
Mol Pharmacol 1989 Dec
PMID:Model of prostaglandin-regulated cyclic AMP metabolism in intact platelets: examination of time-dependent effects on adenylate cyclase and phosphodiesterase activities. 248 Dec 25

Previous studies have suggested the possibility that the non-steroidal antiflammatory drug (NSAID), ibuprofen, may inhibit thromboxane (TX) A2 synthase activity in addition to inhibiting cyclooxygenase activity. Microsomal fractions isolated from the cat lung contain cyclooxygenase as well as prostacyclin (PGI2) synthase, TX synthase, and a GSH-dependent prostaglandin (PG) E2 isomerase activities. When [1-14C] PG endoperoxide H2 (PGH2) was used as substrate, ibuprofen, indomethacin, and meclofenamate exhibited differential effects on terminal enzyme activities. Ibuprofen, at concentrations up to 1 mM, had no effect on the activities of PGI2 synthase, TXA2 synthase of GSH-dependent PGE2 isomerase, whereas indomethacin selectively inhibited PGI2 synthase activity at 5 X 10(-4) M and 10(-3) M. Meclofenamate selectively inhibited TXA2 synthase activity at 5 X 10(-4) M and 10(-3) M. At concentrations of 5 X 10(-3) M, this selectivity was not observed, and indomethacin and meclofenamate decreased the formation of both 6-keto-PGF1 alpha and TXB2. These data indicate that the choice of NSAID and the concentration employed may specifically alter PGH2 metabolism. This action may affect the physiologic consequences of the exchange of PGH2 between cells. The data further indicate that indomethacin has the potential for use as a tool to specifically attenuate PGI2 synthase activity in vitro.
Mol Cell Biochem 1989 May 04
PMID:Differential effects of ibuprofen, indomethacin, and meclofenamate on prostaglandin endoperoxide H2 metabolism. 250 61

Neonatal calves exposed to chronic hypobaric hypoxia develop severe pulmonary hypertension associated with altered vascular reactivity, cellular proliferation, and increased elastin and collagen production. We hypothesized that prostaglandin (PG) production would be decreased in the pulmonary arterial vessel wall of these calves. Further, because of the possibility that the hemodynamic stresses of hypoxic pulmonary hypertension might change along the longitudinal axis of the pulmonary circulation, we measured prostaglandin synthetic capability in tissues isolated from proximal pulmonary artery, distal pulmonary artery, and pulmonary vein. We found that PGI2 production was decreased in both proximal and distal pulmonary artery rings isolated from pulmonary hypertensive calves compared to controls. PGI2 production was greater in distal than in proximal lobar pulmonary artery. In contrast, pulmonary veins from hypertensive calves, which are protected from the hemodynamic stress of pulmonary arterial hypertension, did not demonstrate altered PGI2 production compared to controls. PGE2 production was also decreased in proximal hypertensive pulmonary arterial rings as compared to controls. To determine if this decrease in vessel wall production of prostaglandins was due to changes in cellular prostaglandin production, we studied prostaglandin production by the three major cell types comprising hypertensive and control arteries. Endothelial cells cultured from hypertensive main pulmonary artery produced less PGI2 than did those from control artery, and there appeared to be a shift from PGI2 production to PGE2 production in endothelial cells isolated from hypertensive artery. Explanted advential fibroblasts from hypertensive artery produced less PGE2 than did controls. Smooth muscle cell PGI2 production did not differ between cells isolated from hypertensive and control arteries in these brief 30-min incubations. We conclude that there is a relative deficit in PGI2 and PGE2 production in the pulmonary arteries of calves with hypoxia-induced pulmonary hypertension and speculate that this contributes to altered vascular tone and vessel remodeling.
Am J Respir Cell Mol Biol 1989 Dec
PMID:Decreased arterial wall prostaglandin production in neonatal calves with severe chronic pulmonary hypertension. 251 77

Endothelial cells responses to a variety of agonists include release of endothelium dependent vasodilators, such as endothelium dependent relaxing factor (EDRF) and prostacyclin (PGI2). These substances act on vascular smooth muscle to cause relaxation and also have potent anti-aggregatory effects on platelets. A study of the mechanisms of signal transduction involved in these processes was undertaken. An investigation of intracellular calcium using FURA-2 and INDO-1 loaded endothelial cells shows transient elevation in response to vasodilator agonists. The calcium content of endothelial cells calculated using 45Ca flux techniques is increased in response to bradykinin and thrombin. Receptor activation leads to increased phosphoinositide turnover in endothelial cells and activates protein kinase C, the latter may be involved in feedback regulation. Patch clamp studies have demonstrated receptor-operated ionic channels in the endothelial cell membrane. Thus, intracellular calcium concentration is elevated in response to receptor activation, both as a result of liberation of calcium from intracellular stores and calcium entry from extracellular sources. Endothelial cells also respond to particulate stimuli. They can selectively bind and phagocytize bacteria. Phagocytosis leads to generation of superoxide aionin, a process which also seems to be controlled by elevation of intracellular calcium and activation of protein kinase C. In addition phagocytosis activates endothelial cells resulting in increased migration, division and further phagocytosis. All in all, the plethora of different endothelial responses to a variety of stimuli suggests a complex and multipotent cell type.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1989 Feb
PMID:Endothelium as a transducing surface. 254 30

Lung injury induced in rats by the pyrrolizidine alkaloid monocrotaline is a well-documented model of pulmonary hypertension. To our knowledge, however, monocrotaline-induced cardiopulmonary injury has rarely been described and has never been quantitated in mice. In the present study, adult male mice received 2.4, 4.8, or 24.0 mg monocrotaline/kg body weight/day in the drinking water continuously for 6 weeks. These doses represent 1, 2, and 10 times the severely pneumotoxic regimen in rats. Pulmonary endothelial function was monitored by right lung angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Light and electron microscopy were performed on the left lungs. Cardiac right ventricular hypertrophy was evaluated by the right ventricle to left ventricle plus septum weight ratio (RV/LV + S). Monocrotaline-treated mice exhibited a dose-dependent decrease in lung ACE and PLA activities and an increase in PGI2 and TXA2 production, indicative of endothelial dysfunction. However, these responses were significant only after the highest monocrotaline dose. Light and electron microscopy revealed dose-dependent pulmonary inflammatory and exudative reactions. Unlike previous studies in rats, however, monocrotaline-treated mice developed relatively little lung fibrosis, cardiomegaly, or right ventricular hypertrophy, and no occlusive medial thickening of the pulmonary arteries, even at the highest dose level. These and previous data indicate that there are quantitative biochemical and qualitative morphological differences between mice and rats with respect to monocrotaline pneumotoxicity. Furthermore, in monocrotaline-treated mice (but not in rats) there appears to be a dissociation between lung endothelial dysfunction and inflammation on the one hand, and pulmonary hypertension and fibrosis on the other.
Virchows Arch B Cell Pathol Incl Mol Pathol 1989
PMID:Monocrotaline pneumotoxicity in mice. 257 Apr 81

The objective of this study was to characterize the effect of prostacyclin (PGI2) on ventricular function following total global ischemia in isolated working rat hearts and to investigate the mechanism of its action. Ischemia was initiated for 10, 15, 20 or 25 min with or without treatment with PGI2. Increasing durations of ischemia resulted in a progressive decline in high energy phosphate (HEP) stores, an elevation in tissue lactate, and incomplete recovery of function with reperfusion. Prostacyclin at either 1 or 10 ng/ml had no effect on HEP levels or total adenine nucleotides, and tissue lactate was not significantly affected by PGI2 in hearts made ischemic for 10 to 20 min, but both PGI2 concentrations significantly elevated lactate levels after 25 min ischemia. Reperfusion recovery of left ventricular function was complete following 10 and 15 min ischemia, but incomplete recovery was evident following 20 min ischemia (77% of pre-ischemic function); and although PGI2 had no direct effect on the function of aerobically perfused hearts, recovery of aortic flow with 1 ng/ml PGI2 after 20 min of ischemia was reduced to approximately 20% (P less than 0.01). This depression in recovery was associated with significantly increased lactate levels during reperfusion. At a concentration of 10 ng/ml PGI2 did not depress ventricular recovery or elevate lactate content after 20 min ischemia. When hearts made ischemic for 20 min were analyzed, a significant negative correlation was found between ventricular recovery (aortic flow rate) and lactate concentration; however, no correlation existed between recovery and ATP levels. After 25 min of ischemia, five of eight (62.5%) untreated hearts demonstrated some degree of ventricular recovery, however, only two of ten hearts studied demonstrated any measurable functional recovery with either PGI2 concentration. This effect of PGI2 to reduce or prevent recovery of ventricular function following either 20 or 25 min of ischemia as well as the corresponding elevation in lactate levels was prevented by treatment with the calcium channel blocker verapamil. This study therefore shows that PGI2 at critical low concentrations can depress left ventricular recovery following total ischemia. This effect of PGI2 becomes more pronounced as ischemia duration is prolonged and is associated with elevated tissue lactate levels. The studies with verapamil suggest that PGI2 may be acting via the slow calcium channel to increase lactate levels and depress ventricular recovery following prolonged periods of ischemia.
J Mol Cell Cardiol 1989 Mar
PMID:Inhibition of post-ischemic ventricular recovery by low concentrations of prostacyclin in isolated working rat hearts: dependency on concentration, ischemia duration, calcium and relationship to myocardial energy metabolism. 266 90


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