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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The regulation of cAMP generation in rat myometrium during gestation was investigated comparatively to the stimulations evoked in the estrogen-dominated myometrium. At the onset of gestation, there was a progressive attenuation in both tissue cAMP accumulation and adenylate cyclase activation in response to isoproterenol and prostaglandins (PGs) (PGE2 and prostacyclin, PGI2), as well as to cholera toxin and to forskolin. Minimal responses were observed at midgestation (day 12). The decline in isoproterenol-mediated cAMP accumulation could not be ascribed to alterations in either beta-adrenergic receptor density or coupling properties. Treatment of day 12 myometrium with islet-activating protein (IAP), pertussis toxin, caused a reversal of the attenuated beta-adrenergic--as well as cholera toxin--responses, suggesting that the inhibitory regulatory protein, Gi, was involved. However IAP treatment did not improve the PGE2-mediated stimulatory effect. In membranes from day 12 myometrium, the amount of [32P]NAD incorporated by IAP into the Mr = 41,000 peptides (alpha i, subunit of Gi was markedly increased compared to membranes from day 0 tissue. There was also a consistent decrease (25%) of the label incorporated by cholera toxin into the Mr = 52,000 (major) and 45,000/53,000 (minor) peptides (alpha s, subunit of Gs). The advanced stages of gestation were associated with a progressive restoration of cAMP responses to isoproterenol, cholera toxin, and forskolin with a full responsiveness before parturition (day 22). By contrast, the inability of PGE2 to generate any active Gs (stimulatory regulatory protein)-C complex persisted and coincided with the development of PGE2-induced inhibition of cAMP generation due to isoproterenol. The inhibitory effect, which was similarly evoked by PGE2 as well as by PGI2 and PGF2 alpha, was prevented by IAP. The data suggest that alterations of the stimulatory Gs-mediated pathway, which culminated at midgestation, is due at least in part to an increase in the abundance of Gi relative to Gs. Additional alterations operate at the level of the prostaglandin receptor(s) with a conversion from a stimulatory (Gs-mediated) cAMP response in the estrogen-dominated myometrium to an inhibitory (Gi-mediated) effect, fully expressed in the final stage of gestation.
Mol Pharmacol 1987 Aug
PMID:Heterologous regulations of cAMP responses in pregnant rat myometrium. Evolution from a stimulatory to an inhibitory prostaglandin E2 and prostacyclin effect. 303 39

A kinetic scheme of the prostacyclin-thromboxane system has been evolved on the basis of the authors experimental data and the results described elsewhere. The kinetic behavior of the model has been analysed with the aid of computer technology by varying the following parameters: phospholipase activities, free arachidonic acid exchange rates between platelets and endothelium, PGH-synthetase biosynthesis rates, velocities of arachidonic acid pathways other than the cyclooxygenase ones. It has been demonstrated that the biological system is capable of sustaining prostacyclin and thromboxane concentrations at steady fixed levels within a wide range of kinetic parameters.
Mol Biol (Mosk)
PMID:[Kinetic model of a multienzyme system of blood prostanoid synthesis. I. Mechanism of stabilization of thromboxane and prostacyclin levels]. 309 45

The dynamic replies of the multienzyme system of blood prostanoid synthesis to the introduction of an irreversible inhibitor of prostaglandin H synthetase (PGH synthetase) have been analysed by using kinetic modelling. The alterations of arachidonic acid and PGH synthetase concentrations in platelets and endothelium and the concentrations of thromboxane and prostacyclin have been demonstrated. Particularities of kinetic behaviour of the system probably providing the therapeutic effect of non-steroidal anti-inflammatory drugs have been shown. Namely, the kinetic wave of free arachidonic acid and prostacyclin concentration with respect to thromboxane concentration appears after introduction of the drugs.
Mol Biol (Mosk)
PMID:[Kinetic model of a multienzyme system of blood prostanoid synthesis. II. Dynamic responses to pharmacological agents--inhibitors of prostaglandin H synthetases]. 309 46

The purpose of this study was to assess the influence of the calcium paradox (5 min calcium-free perfusion followed by 15 min calcium repletion) on the release of immunoreactive leukotriene C4 and 6 Keto-prostaglandin F1 alpha from rat and guinea-pig hearts. Under control conditions or during the 5 min calcium-free perfusion period no immunoreactive leukotriene C4 was detectable in the coronary effluent. Following reperfusion with calcium-containing medium a large release of leukotriene C4 was observed although the amount was significantly greater in the rat heart. 6 keto-prostaglandin F1 alpha was detected during normal and calcium-free perfusion and the release was significantly stimulated during calcium repletion. Treatment with ibuprofen, a cyclo-oxygenase inhibitor, prevented the release of 6 keto-prostaglandin F1 alpha but increased the efflux of immunoreactive LTC4 during calcium repletion. Arachidonic acid, the substrate for prostaglandin and leukotriene synthesis increased the efflux of 6 keto-prostaglandin F1 alpha but decreased the release of leukotriene C4. The latter effect was reversed by perfusion with ibuprofen, and mimicked by prostacyclin, the primary cardiac prostaglandin. This study shows that the calcium paradox is a potent stimulus for eicosanoid release from rat and guinea-pig hearts, a phenomenon likely due to the activation of calcium-dependent enzymes. The study also suggests that endogenous prostaglandins inhibit leukotriene synthesis in cardiac tissue.
J Mol Cell Cardiol 1987 Mar
PMID:Calcium paradox-evoked release of prostacyclin and immunoreactive leukotriene C4 from rat and guinea-pig hearts. Evidence that endogenous prostaglandins inhibit leukotriene biosynthesis. 311 Apr 22

Circulatory blood corpuscles have enzymes catalyzing arachidonic acid. Platelets have cyclo-oxygenase system which produce highly vasoconstrictive and thrombogenic thromboxane A2 (TXA2). Neutrophils have another type of arachidonate metabolism system, lipoxygenase enzymes, which produce hydroxyeicosatetraenoic acids (HETE) and leukotrienes (LT), mediating inflammatory reactions. These arachidonate metabolites were found to play important roles in the evolution of myocardial ischemia. Thromboxane B2 (TXB2) a stable metabolite of TXA2, was elevated in peripheral blood of patients with angina pectoris. This elevation of TXB2 was supposed to be derived from platelet activation in coronary circulation due to altered production of TXA2 and prostacyclin (PGI2). Augmentation of TXA2 was also observed in patients with acute myocardial infarction. TXA2 synthetase inhibitors decreased plasma levels of TXB2 in these patients accompanied by attenuation of infarct size. Neutrophils were found to accumulate in ischemic myocardium and were augmented at reperfusion phase especially at interface between infarcted and risk zone. These infiltrated neutrophils may also provide deleterious effects on myocardial cells by producing lipoxygenase metabolites. In fact, a chemotactic and vasoconstrictive lipoxygenase product, 12-HETE, was produced selectively in ischemic myocardial tissue of an occlusion-reperfusion model. During evolution of myocardial cell damage, platelets and neutrophils, accumulated in ischemic tissue, may contribute to the exacerbation of microcirculatory disorders by producing vasoactive prostanoids, leading to expansion of myocardial necrosis. We should gain insights into these cellular interactions through arachidonate metabolism under normal and catastrophic conditions of coronary circulation.
J Mol Cell Cardiol 1988 Mar
PMID:Arachidonate metabolism in myocardial ischemia and reperfusion. 313 47

Twelve rabbits underwent 20-min of complete cerebral ischemia. They were given PGI2 for 3 min before and during ischemia and for 15 min after ischemia. Control animals with complete cerebral ischemia over the same period of time were not given PGI2 medication. The animals treated with PGI2 were found to have recovered bioelectric activity of the cerebral cortex in half the time that it took the control group. A positive effect of PGI2 on some parameters of the peripheral blood system after ischemia was observed. Under the conditions of this experiment PGI2 did not effect the ultrastructural changes in motor cortex neuron nuclei. The changes were manifested in numerous vesicular structures and nuclear inclusions. The inclusions took the forms of clusters, rodlets, and lattices constructed of filaments and/or tubules. The number of vesicular structures and inclusions grew with the lapse in time after ischemia.
Exp Mol Pathol 1988 Apr
PMID:The effects of prostacyclin on early ultrastructural changes in the neuron nuclei of the motor cortex in rabbits after complete 20-min cerebral ischemia. 328 Mar 43

Rabbits fed an atherogenic diet for 60 days resulted in high levels of plasma lipid peroxides as well as extreme hypercholesterolemia. Both levels stayed high until 35 days after the atherogenic diet stopped. At the same time, plasma PGI2 level was remarkably decreased while TXA2 and platelet aggregability were increased. Atherosclerotic aortas contain high levels of lipid peroxides associated with decreased PGI2 and increased TXA2 generation. Atherosclerotic plaques had the highest level of lipid peroxides and TXA2 while PGI2 production was the least, as compared with nonplaque tissue of the same artery and the normal arteries. The condition of normal arteries was just the reverse. There was a negative correlation between lipid peroxides and prostacyclin production, and a positive correlation between lipid peroxides and TXA2, in both plasma and aorta of rabbits. These results suggest that there is a close correlation between atherosclerosis, elevated lipid peroxides, and disturbances in PGI2/TXA2 balances.
Exp Mol Pathol 1988 Apr
PMID:Effects of lipid peroxides on prostacyclin and thromboxane generation in hypercholesterolemic rabbits. 328 Mar 42

Increased levels of the major metabolites of thromboxane (TxA2) and prostacyclin (PGI2) are found in venous blood draining the ischaemic region of the myocardium of dogs subjected to acute coronary artery occlusion. This suggests that these arachidonic acid derivatives are released under conditions of myocardial ischaemia and may be considered as mediators of some of the consequences of coronary blood flow reduction, including arrhythmogenesis. The present experimental evidence suggests that thromboxane release is detrimental both in the early stages of ischaemia and in reperfusion since the severity of both ischaemia and reperfusion-induced arrhythmias is reduced by selective inhibition of thromboxane synthesis or by thromboxane receptor blockade. Since the local administration of prostacyclin (or iloprost) or the promotion of local prostacyclin production (with nafazatrom) reduces the severity of ischaemia and reperfusion-induced arrhythmias, it is suggested that prostacyclin may act as a local, endogenous antiarrhythmic agent. The conclusion thus far from these experimental studies suggests that the prostacyclin-thromboxane balance is one important factor involved in determining the severity of ischaemia and reperfusion-induced arrhythmias but that the mechanisms have not as yet been clearly defined.
J Mol Cell Cardiol 1987 Oct
PMID:Eicosanoids and susceptibility to ventricular arrhythmias during myocardial ischaemia and reperfusion. 332 37

We established culture lines derived from the subendothelial region of the porcine aortic valve. These cells were isolated by extensive collagenase digestion of valvular tissue and were serially propagated with stable morphology. In sparse culture, valve subendothelial cells resembled skin fibroblasts. When confluent, the valve subendothelial cells formed ridges and piles similar to vascular smooth muscle cells. Endogenous in vitro labeling experiments using 35S-methionine showed that valve subendothelial cells synthesized and released several proteins not observed in parallel experiments using porcine skin fibroblasts and smooth muscle cells. Mitogen assays using media conditioned by porcine aortic valvular endothelial cells showed that the valve subendothelial cells, when compared to skin fibroblasts and smooth muscle cells, were particularly avid responders to the growth factors released by valve endothelial cells in vitro. The valve subendothelial cells also released 10-fold more prostacyclin in response to arachidonate than did skin fibroblasts or smooth muscle cells. We conclude that valve subendothelial cells show features that distinguish them from other cultured mesenchymal cells, and that this culture system will be useful for studies of the cellular basis of valvular heart disease.
J Mol Cell Cardiol 1987 Dec
PMID:Porcine cardiac valvular subendothelial cells in culture: cell isolation and growth characteristics. 332 49

The hypothesis that prostacyclin (PGI2) might have a direct cytoprotective action in ischaemic cardiac tissue was investigated. Myocardial ischaemia was induced in perfused rabbit hearts by ligating the left main coronary artery. Coronary flow, oxygen uptake, and turnover of lactate and purines were measured before and up to 120 min after coronary occlusion. After this, ischaemic tissue was separated from perfused myocardium, and levels of lactate, adenine nucleotides and creatine phosphate were determined in specimens from non ischaemic, ischaemic and border zones. PGI2 (final conc. 10(-7) M) was infused before or 30 min after ligation and the results were compared to those in control hearts. Coronary ligation reduced coronary flow and oxygen consumption by about 50%. The fractional extraction of lactate decreased from 20% to close to zero and purine release increased 5-fold. In the non-ischaemic area the tissue levels of ATP and creatine phosphate were high, with a low content of lactate, but in the ischaemic area the levels of ATP and creatine phosphate were considerably reduced and the content of lactate was high. Although coronary flow and oxygen uptake were elevated after treatment with PGI2, no change in lactate or purine turnover was observed. Neither the weight of the non-perfused myocardium nor the tissue levels of the adenine nucleotides, creatine phosphate and lactate were affected by PGI2 treatment. The data indicate that in this model, in which effects on cardiac work, collateral flow and platelets are eliminated, PGI2 does not limit ischaemic myocardial injury. Hence, the hypothesis of a direct cytoprotective action of PGI2 in ischaemic myocardial tissue was not supported.
J Mol Cell Cardiol 1986 Oct
PMID:Effect of prostacyclin on the severity of ischaemic injury in rabbit hearts subjected to coronary ligation. 353 19


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