Effects of PGI2 and PGI analogues on cAMP levels in cultured endothelial and smooth muscle cells derived from bovine arteries

Dembińska-Kieć, A.; Rücker, W.; Schönhöfer, P. S.

doi:10.1007/bf00500304

Cited by 49 publications

(11 citation statements)

References 8 publications

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“…was decreased only 38% after endothelium removal (vs. 69% with indomethacin), it suggests that approximately half of the PGs that mediate basal activity are derived from the endothelium and halfare from the VSM. Removal of the endothelium is more likely to have decreased the amount of agonist present than the amount of enzyme because studies of cultured cells indicate that arterial cAMP production is primarily in VSM, particularly when the proportion of cell types present is considered (33).…”

Section: Discussionmentioning

confidence: 99%

Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery. Alterations after prolonged hypoxia in the rat.

et al. 1991

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IntroductionProstacyclin is a critical mediator of structure and function in the pulmonary circulation, causing both the inhibition of vascular smooth muscle growth and vasodilatation via the stimulation ofadenylate cyclase. To examine the potential role ofalterations in prostacyclin production or mechanism of action in chronic hypoxic pulmonary hypertension, we determined the effects of prolonged (7 d Hypoxic pulmonary hypertension is one of the critical mechanisms underlying persistent pulmonary hypertension ofthe neonate and the development of pulmonary hypertension in older children and adults with a variety of cardiac and respiratory illnesses (1, 2). This phenomenon has been well studied in the adult rat, yielding both physiologic and anatomic findings similar to those noted in the human (3-5). In the rat model, pulmonary hypertension is evident almost immediately after the onset of acute severe hypoxia, and it is also present with accompanying anatomic changes after more prolonged periods of hypoxia of milder degree. These events in the pulmonary circulation of the rat are contrasted by the maintenance of normal systemic blood pressure, mimicking the clinical experience with this problem (1, 4, 6, 7). Studies in the rat and other species indicate that locally-produced prostacyclin is important in the regulation ofvasomotor tone and vascular cell differentiation and growth in the pulmonary circulation (8, 9). These actions are mediated through the plasma membrane-bound enzyme adenylate cyclase, with prostacyclin stimulation of cyclic AMP (cAMP) production resulting in vasodilatation and the inhibition ofsmooth muscle cell growth (10, 1 1). In vivo experiments and in vitro studies with perfused isolated lung preparations have demonstrated that pulmonary production ofthis potent vasodilator increases with acute hypoxia, resulting in a degree of attenuation of the vasoconstrictor response (12,13). However, despite the initial increase in prostacyclin production, further hypoxia leads to the development of pulmonary hypertension with medial hypertrophy of muscular arteries and extension of vascular smooth muscle (VSM)' into peripheral, normally nonmuscular, arteries (3, 4). These alterations are prevented in the rat when angiotensin II is administered during the hypoxia period, most likely related to its ability to release prostaglandins (PG) (8). This suggests that changes in PG synthesis or PG-mediated mechanisms may be involved in the pathogenesis of chronic hypoxic pulmonary hypertension.To examine the potential role ofalterations in prostacyclin production or mechanism ofaction in chronic hypoxic pulmonary hypertension, we determined the effects ofprolonged (7 d) in vivo hypoxia on in vitro prostacyclin production and mediation of adenylate cyclase activity in rat main pulmonary arteries. PGE2 production and mediation ofadenylate cyclase activity were also investigated to determine if the results for prostacyclin are specific to that vasodilatory prostanoid. Based on the findings with acute hypox...

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Section: Discussionmentioning

confidence: 99%

Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery. Alterations after prolonged hypoxia in the rat.

et al. 1991

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“…Thus, it may be that ATP induces relaxation through two separate and distinct cyclic nucleotide-dependent mechanisms. The mechanism by which ATP elevates cAMP does not appear to be due to ATP-induced formation of prostacyclin by the endothelial cells (Boeynaems and Galand, 1983;Pearson et al, 1983), and subsequent elevation of cAMP within the smooth muscle due to prostacyclin (Kukovetz et al, 1979;Dembinska-Kiec et al, 1980;Holzmann et al, 1980), since cAMP levels were unaltered by the cyclooxygenase inhibitor, indomethacin (Flower, 1974). Indomethacin has been shown to inhibit adenosine di-and triphosphateinduced formation of prostacyclin from endothelial cells (Boeynaems and Galand, 1983).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of adenosine triphosphate-, thrombin-, and trypsin-induced relaxation of rat thoracic aorta.

Rapoport¹,

Draznin²,

Murad³

1984

Circulation Research

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SUMMARY. The mechanisms by which adenosine triphosphate, thrombin, and trypsin cause relaxation of vascular smooth muscle were investigated. Relaxation of the rat thoracic aorta with adenosine triphosphate, thrombin, and/or trypsin was associated with increased levels of cyclic guanosine monophosphate in both time-and concentration-dependent manners. Thrombin and trypsin did not alter cyclic adenosine monophosphate levels, whereas adenosine triphosphate increased cyclic adenosine monophosphate levels after significant relaxation occurred. Removal of the endothelium abolished adenosine triphosphate-, thrombin-, and trypsin-induced relaxation and the associated increased levels of cyclic nucleotides. Relaxation due to these agents was also inhibited by exposure to nordihydroguaiaretic acid, a lipoxygenase inhibitor, and eicosatetraynoic acid, a lipoxygenase and cyclooxygenase inhibitor. Indomethacin, a cyclooxygenase inhibitor, potentiated relaxation to these agents, whereas the increased levels of cyclic nucleotides due to adenosine triphosphate were unaltered. Bromophenacyl bromide, a phospholipase A 2 inhibitor, decreased relaxation due to adenosine triphosphate, thrombin, and trypsin and the associated increased levels of cyclic nucleotides. Removal of extracellular calcium, which also presumably inhibits phospholipase A2, prevented the elevated levels of cyclic nucleotides and the inhibitory effects of adenosine triphosphate and trypsin on contraction. In contrast, sodium nitroprussideinduced relaxation and/or increased levels of cyclic guanosine monophosphate were unaltered by nordihydroguaiaretic acid, eicosatetraynoic acid, bromophenacyl bromide, and removal of extracellular calcium. After incubation of intact tissue with 32 P-orthophosphate, the patterns of protein phosphorylation caused by adenosine triphosphate, thrombin, and trypsin were indistinguishable from those of acetylcholine, sodium nitroprusside and 8-bromo cyclic guanosine monophosphate. All these agents dephosphorylated myosin light chain. Thus, the present study supports the hypothesis that relaxation induced by adenosine triphosphate, thrombin, and trypsin is mediated through the formation of an endothelial factor which elevates cyclic guanosine monophosphate levels and causes cyclic guanosine monophosphate-dependent protein phosphorylation and dephosphorylation of myosin light chain. (Circ Res 55: 468-479, 1984) ENDOTHELIUM-dependent vasodilation induced by acetylcholine, histamine and Ca ++ ionophore A23187 has recently been shown to be associated with the formation of cyclic guanosine monophosphate (cGMP) in both a time-and concentrationdependent manner in rat thoracic aorta . Furthermore, an inhibitor of phospholipase A 2 , quinacrine, and an inhibitor of lipoxygenase and cyclooxygenase, eicosatetraynoic acid (ETYA), inhibited acetylcholine-induced relaxation and the formation of cGMP . These results confirmed those of others (Furchgott and Zawadzki, 1980a;Furchgott et al., 1981;Furchgott, 1983) which suggested that relaxation cause...

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“…Both dilators act via increases in cyclic nucleotides: NO-induced dilation involves guanosine 3',5'-cyclic monophosphate (cGMP), whereas prostacyclin is mediated by adenosine 3',5'-cyclic monophosphate (cAMP). 12 - 13 To analyze the possible influence of lipoproteins on cyclic nucleotide-mediated dilator mechanisms, we studied the effects of N-LDL and Ox-LDL on cGMP and cAMP content and of dilator responses induced by cyclic nucleotide-increasing agonists in isolated rabbit and human arteries. Forskolin (Fo) was used as a stimulus for adenylate cyclase and sodium nitroprusside (SNP) as a stimulus for guanylate cyclase.…”

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confidence: 99%

Inhibition of cyclic AMP- and cyclic GMP-mediated dilations in isolated arteries by oxidized low density lipoproteins.

Galle

Bauersachs

Busse

et al. 1992

Arterioscler Thromb

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We studied the effects of native (N) and oxidized (Ox) low density lipoproteins (LDLs) on adenosine 3',5'-cyclic monophosphate (cAMP)-mediated and on guanosine 3',5'-cyclic monophosphate (cGMP) -mediated dilator mechanisms in isolated, perfused human mammary and rabbit femoral arteries. Dilations were induced in preconstricted, deendothelialized segments by either forskolin (Fo) or sodium nitroprusside (SNP) (intraluminal or adventitial application). Lipoproteins (0.5 mg/ml) were administered to the segments from the intraluminal side. N-LDL had no effect on Fo-induced dilation and caused a weak attenuation of SNP-induced dilation only when SNP was also administered into the intraluminal perfusate. In contrast, Ox-LDL inhibited both Fo-and SNP-induced dilation, independent of the route of dilator application. The effects of Ox-LDL were specific for dilation mediated by cyclic nucleotides. Dilation elicited by the Ca 2+ antagonist nitrendipine was inhibited neither by N-LDL nor by Ox-LDL. Determination of basal and stimulated (SNP, Fo) cGMP and cAMP content in rabbit femoral segments after preincubatlon with N-LDL and Ox-LDL revealed a significant decrease of stimulated vascular cGMP and cAMP content by Ox-LDL, whereas N-LDL had no effect. These data indicate that Ox-LDL selectively inhibits vascular smooth muscle relaxation elicited by increases in cyclic nucleotides. This inhibition might contribute to the attenuation of vasodilation in hypercholesterolemia and atherosclerosis. (Arteriosclerosis and Thrombosis 1992;12:180-186)

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Effects of PGI2 and PGI analogues on cAMP levels in cultured endothelial and smooth muscle cells derived from bovine arteries

Cited by 49 publications

References 8 publications

Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery. Alterations after prolonged hypoxia in the rat.

Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery. Alterations after prolonged hypoxia in the rat.

Mechanisms of adenosine triphosphate-, thrombin-, and trypsin-induced relaxation of rat thoracic aorta.

Inhibition of cyclic AMP- and cyclic GMP-mediated dilations in isolated arteries by oxidized low density lipoproteins.

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