Trybulec M., Dudek R., Radziszewski W., Świerkosz T, Zembowicz A.: Quantification of the potencies of EDRF-releasers from isolated rabbit aortic strips. Acta Physiol. Pol. 1990, 41(1-3): 78-86. We have compared several known releasers of endothelium-derived relaxing factor (EDRF)(13) in respect to their potencies to generate EDRF by endothelium of rabbit aortic strips (RbA) superfused with Krebs’ buffer. The vasorelaxation by EDRF which is equivalent to 10 pmoles of GTN was evoked by 0.7 pmoles of substance P(SP), 50 pmoles of acetylcholine (Ach), 521 pmoles of calcium ionophore A 23187, 2720 pmoles of ADP. Threshold potencies of these agonists are inversely proportional to the maximum amount of EDRF released. Phospholipase C (PLC) from Clostridium perfringens at a dose of 0.1 U caused the relaxation of a similar magnitude. Phospholipase A2 (1 U), thrombin (1 U), bradykinin (30 nmoles) and serotonin (10 pmoles) did not release EDRF. It is concluded that endothelial cells of RbA differ from endothelial cells of other species in their susceptibility to release EDRF in response to various agonists.
Święs J., Grodzińska L., Sławiński M., Gryglewski R. J.: Kallikrein-thrombolytic and hypotensive action in cats - preliminary results. Acta Physiol. Pol. 1990, 41 (1-3): 87-95. An intravenous injection of kallikrein produced hypotensive and thrombolytic effects in anasthetized cats, using the blood superfused tendon technique. The thrombolytic action of kallikrein was mediated by an unstable substance. The generation of this substance was abolished by either acetylsalicylic acid (ASA) or aprotonin and enhanced by captopril. The hypotensive action of kallikrein was only partially inhibited by ASA. It is proposed that both these pharmacological effects of kallikrein are mediated by bradykinin which in turn releases prostacyclin from the endothelium. However, in contrast to the thrombolytic effect of kallikrein which is totally mediated by prostacyclin the hypotensive action of kallikrein depends not only on prostacycylin but also on another endothelium-derived vasorelaxant, e.g. EDRF.
The endothelium-dependent (acetylcholine, bradykinin, substance P) and the endothelium-independent (gliceryl trinirate, 3-morpholinsydnominine, sodium nitroprusside) vasodilators were studied in the Langendorff-perfused heart of the guinea pig. The involvement of prostanoids and EDRF in the endothelium-dependent responses were assessed by using indomethacin, an inhibitor of cyclooxygenase, and NG -nitro-L-Arginine, an inhibitor of NO synthase. The endothelium-independent agents were used as reference compounds. Both indomethacin and NG -nitro- L-Arginine elevated significantly baseline coronary perfusion pressure, indicating that prostanoids (most likely PGI₂ and PGE₂ ) and EDRF modulate the resting tone of the guinea pig coronary circulation. NG-nitro-L-Arginine, but not indomethacin, considerably reduced receptor-stimulated responses. It is concluded that acetylcholine, bradykinin or substance P-induced vasodilation is mediated by EDRF. In contrast, prostanoids do not contribute to endothelium-dependent responses. In addition, short-term tachyphylaxis to bolus injection of gliceryl trinitrate but not of sodium nitroprusside was demonstrated, suggesting that this preparation may be of value for studying nitrate tolerance.
Production of arachidonic acid (AA) metabolites - prostacyclin (PGI2) in large vessels and prostaglandin E2 (PGE2) in microcirculation is intrinsically involved in maintenance of vascular wall homeostasis. EA.hy 926 is a hybrid cell line, is derived by fusion of HUVEC with A549 cells. The aim of this study was to examine the production of prostacyclin and PGE2 in resting and IL-1ß-stimulated EA.ha 926 cells, in comparison with its progenitor cells. Non-stimulated EA.hy 926 cells has been found to produce much lower amounts of prostacyclin than resting HUVEC. Resting hybrid cells produced more PGE2 than prostacyclin, despite they expressed high levels of COX-1 and PGI2 synthase. On the contrary to HUVEC and A549, EA.hy 926 cells did not respond to IL-1ß with COX-2 induction and increase of prostaglandin production, however they did it in response to lysophosphatidylcholine (LPC). The characteristics of EA.hy 926 cells in terms of the pattern of prostanoid formation could facilitate studies on endothelial metabolism and role of these important lipid mediators.
The endothelial cells which line the blood vessels as a monolayer exert a remarkable control over the vascular system. Indeed, the endothelium can be regarded as a highly active metabolic and endocrine organ in its own right. On the hand, vasoactive substances such as serotonin and bradykinin are inactivated and on the other the cells can enzymatically produce the vasoconstrictor, angiotensin II and secrete endothelin-1 ((ET-1). Perhaps more importantly, the cells also produce two unstable vasodilator substances, which potently inhibit platelet clumping: prostacyclin and endothelium-derived relaxing factor (EDRF) which has been identified as nitric oxide (NO; 1). Both substances seem well designated as local hormones, released to influence adjacent cells. The endothelial cell, therefore, exerts control over the cardiovascular system by elaborating dilator substances as well as vasconstrictors.
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There are few findings indicating that nicotinamide may potentially influence intravascular thrombosis. Interestingly, N-methylnicotinamide, one of the metabolites of nicotinamide - could be more potent than its parent compound. In the present study we have investigated the influence of N-methylnicotinamide on arterial thrombosis in normotensive and renovascular hypertensive rats. The contribution of platelets, coagulation and fibrinolytic systems in the mode of N-methylnicotinamide action was also determined. Furthermore, we examined the role of nitric oxide/prostacyclin in the mechanisms of N-methylnicotinamide action. N-methylnicotinamide, but not nicotinamide, administered intravenously into renovascular hypertensive rats developing electrically induced arterial thrombosis caused dose-dependent decrease of thrombus weight, collagen-induced platelet aggregation and plasma antigen/activity of plasminogen activator inhibitor - 1, without changing of occlusion time, routine coagulation parameters and plasma activity of tissue plasminogen activator. Indomethacin - an inhibitor of prostacyclin synthesis, completely abolished the antithrombotic and antiplatelet effect of N-methylnicotinamide, and the plasma level of 6-keto-PGF1alpha, prostacyclin metabolite, increased simultaneously with the inhibition of thrombus formation. Our study shows that N-methylnicotinamide via production/release of prostacyclin inhibits arterial thrombosis development. The antithrombotic effect of N-methylnicotinamide is accompanied by platelet inhibition and enhanced fibrinolysis, due to the decrease production of plasminogen activator inhibitor - 1.
Many diseases of the heart and circulatory system have been linked with both dysfunction of vascular endothelium and insufficient deformability of erythrocytes. Using shear stress laser diffractometry we investigated whether deformability of erythrocytes would be regulated endogenously by generation of two endothelial secretogogues: prostacyclin and nitric oxide. Experiments were performed in rats ex vivo and with whole blood or isolated erythrocytes in vitro. Iloprost - a stable analogue of prostacyclin (10 µg/kg i.v.) and SIN-1 (NO-donor) at a dose of 2 mg/kg/min i.v induced a significant improvement of deformability of erythrocytes ex vivo. Improvements of deformability by these two compounds were also evident in vitro when they were applied at a range of concentrations of 1 µM and 3 µM, respectively. Cyclooxygenase (indomethacin 20 mg.kg i.v.) and nitric oxide synthase (L-NAME 10 mg/kg i.v.) inhibitors while worsening deformability ex vivo, they did not affect (3 mM and 10 µM, respectively) rheological functions of erythocytes in vitro. Aggravating effects of these inhibitors on erythrocyte deformability ex vivo were reversed by prostacyclin and nitric oxide supplemented exogenously. Aspirin at a low (1 mg/kg i.v.) and high dose (50 mg/kg i.v.), contrary to indomethacin and L- NAME, aggravated erythrocyte deformability either ex vivo or in vitro. It is concluded that autocrine function of vascular endothelium plays an important role in regulation of rheology of red blood cells in flowing blood. The mechanism of this phenomenon is unclear but some possible explanations are discussed. In addition, in our experiments aspirin revealed unique erythrocyte damaging properties, possibly independent of inhibition of cyclooxygenase, but related to a direct protein acetylation.