iloprost and sulotroban

The aim of our study was (1) the pharmacological characterization of EP(3) receptors in human pulmonary arteries and (2) the examination of the potential involvement of these receptors in the regulation of neurogenic tachycardia in pithed rats. L-826266 served as the EP(3) receptor antagonist.. Experiments were performed on isolated human pulmonary arteries and pithed rats.. The prostanoid EP(1)/EP(3) receptor agonist sulprostone (1 nM - 100 μM) concentration-dependently contracted isolated human pulmonary arteries (pEC50, 6.88 ± 0.10). The EP(1) receptor antagonist SC 19920 (100 μM) did not affect the vasoconstriction induced by sulprostone, the TP receptor antagonist sulotroban (10 μM) only slightly attenuated the effects elicited by sulprostone >>3 μM, whereas L-826266 (10 μM) shifted its concentration-response curve to the right (apparent pA(2) value 6.18; incubation time 0.5 h). In rings exposed to L-826266 (0.1, 1 or 10 μM) for 3 h, a concentration-dependent inhibitory effect against the sulprostone-induced vasoconstriction was obtained, yielding a Schild plot-based pA(2) value of 7.39. In pithed rats, sulprostone (10 - 1,000 nmol/kg), but not the IP/EP(1) receptor agonist iloprost (1-100 nmol/kg), inhibited the electrically evoked increase in heart rate (HR) dose-dependently, maximally by at least 80%. L-826266 (3 μmol/kg) did not affect basal HR and diastolic blood pressure, but reduced the inhibitory effect of sulprostone 1,000 nmol/kg by about 20%.. EP(3) receptors (1) located postsynaptically strongly contract human pulmonary arteries and (2) located presynaptically on sympathetic nerve fibers supplying the heart of pithed rats strongly inhibit the neurogenic tachycardia.

Topics: Acrylamides; Aged; Animals; Decerebrate State; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Heart; Heart Rate; Humans; Iloprost; Male; Middle Aged; Naphthalenes; Pulmonary Artery; Rats; Rats, Wistar; Receptors, Prostaglandin E, EP3 Subtype; Signal Transduction; Sulfonamides; Sympathetic Nervous System; Tachycardia; Vasoconstriction

The platelet-activating factor (PAF) induced a marked increase of the thromboxane (TX) B2-formation in the incubation medium of isolated myocardium and tissue from other organs. The content of the 6-oxo-prostaglandin (PG)F1 alpha, the inactive metabolite of PGI2, remained uninfluenced or showed a small decrease. PAF, given in a concentration of 2.10(-9) mol/l or a single dose of 100 ng, significantly reduced the contraction force and the coronary flow of isolated guinea-pig hearts. This effect was connected with a high efflux of TXA2. The PAF-antagonist, WEB 2086, nearly abolished the cardiac effects of PAF, and iloprost or a pretreatment with indomethacin markedly reduced the PAF-influence on the heart. The TXA2-antagonist BM 13177 was ineffective. The results indicate a close interaction between the myocardial PAF-effect and the TXA2-formation of the heart tissue, but gave no suggestion for a mediation of the PAF-effect by TXA2. The PAF-antagonistic action of WEB 2086, iloprost and indomethacin could be of some interest in the therapy of cardiovasculatory diseases.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Azepines; Guinea Pigs; Heart; Iloprost; In Vitro Techniques; Indomethacin; Myocardial Contraction; Perfusion; Platelet Activating Factor; Prostaglandins; Sulfonamides; Thromboxane A2; Thromboxane B2; Triazoles

Topics: Animals; Cell Division; Iloprost; Indomethacin; Rats; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Thromboxane A2; Tumor Cells, Cultured

Septic shock was induced by intravenous infusion of live Escherichia coli in pigs to investigate the influences on central hemodynamic, coagulation, and fibrinolytic reactions by a thromboxane A2 (TxA2)-receptor blocker (BM 13.177; n = 6) and a prostacyclin analogue (iloprost or ZK 36,374; n = 7). The early pulmonary vasoconstriction following E coli infusion was attenuated, but not abolished, by BM 13.177. Only minor effects were seen after pretreatment with iloprost. Neither drug had any major effect on the coagulation and fibrinolytic activation. These results confirm that TxA2 is an important, but not the only, mediator of early pulmonary vascular response in porcine septicemia and that neither TxA2 nor prostacyclin is of major importance for the hemostatic reactions in this shock model.

Topics: Animals; Blood Pressure; Epoprostenol; Escherichia coli Infections; Female; Hemodynamics; Hemostasis; Iloprost; Male; Platelet Aggregation; Pulmonary Circulation; Receptors, Prostaglandin; Receptors, Thromboxane; Shock, Septic; Sulfonamides; Vascular Resistance

The stable PGI2-analogue iloprost and the TXA2-receptor antagonist sulotroban were investigated for possible cooperative effects on platelet function and experimental thrombus formation in guinea pigs and rats. Iloprost and sulotroban inhibit intravascular platelet aggregation in guinea pigs and rats induced by the stable endoperoxide U 46.619 and collagen, with iloprost being the more potent and (for collagen) more efficacious drug. Combinations of both compounds show synergistic or additive effects on in vivo platelet function. Thrombus formation in rats induced by vascular damage is strongly reduced by combining doses of iloprost and sulotroban (BM 13.177) which given alone are ineffective. These results suggest a cooperative enhancement of antiplatelet and antithrombotic effects for combinations of iloprost and sulotroban. In view of disadvantages of currently used platelet inhibitors this cooperativity may offer a new approach in antiplatelet therapy.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Cardiovascular Agents; Collagen; Drug Synergism; Epoprostenol; Fibrinolytic Agents; Guinea Pigs; Iloprost; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Rats; Sulfonamides; Thrombocytopenia; Thrombophlebitis; Thromboxanes

The stable PGI2-analogue iloprost and the TXA2-receptor antagonist sulotroban (BM 13177) were investigated for possible synergistic effects on platelet aggregation in human platelet rich plasma in vitro. Iloprost and sulotroban synergistically inhibited U 46619, collagen, and the second wave of ADP-induced platelet aggregation. Iloprost and sulotroban at concentrations showing little or no inhibition alone resulted, in combination, in marked or complete inhibition of U 46619 or collagen induced aggregation. Combination of iloprost 10(-10) M, which had no effect on the concentration-response curve (CRC) to U 46619, with sulotroban 5 x 10(-6) M, which shifted the CRC to U 46619 by a factor of 3 to the right, resulted in a rightward shift of the U 46619 CRC by a factor of 4.5. To attain a 4.5-fold shift with either compound alone, a concentration of 5 x 10(-10) M iloprost or 10(-5) M sulotroban was required. A similar mutual enhancement of inhibitory effects was seen for combinations of the PGI2-analogue cicaprost (ZK 96.480) with sulotroban or the TXA2-receptor antagonist SQ 29548 with iloprost. When the TXA2-dependent part of collagen-induced aggregation was fully inhibited by sulotroban, the concentrations of iloprost necessary for 90% inhibition were reduced by a factor of 2.5 - 3. In the presence of acetylsalicylic acid, the synergistic action of sulotroban and iloprost was reduced and merely additive effects against U 46619-induced platelet aggregation were found, suggesting that the release of endogenous TXA2 plays an important role for the synergistic effect of the two compounds. The combination of a PGI2-analogue and a TXA2-antagonist may lead to a safer and more effective control of platelet activation than with either compound alone.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate; Aspirin; Bridged Bicyclo Compounds, Heterocyclic; Collagen; Drug Synergism; Epoprostenol; Fatty Acids, Unsaturated; Humans; Hydrazines; Iloprost; In Vitro Techniques; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Prostaglandins, Synthetic; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides

Substances shifting the balance between thromboxane (TX) and prostacyclin (PGI2) in favour of PGI2 could be of therapeutic value for arrhythmia treatment. This seems to be independent of the pathogenetic mechanism. The TX receptor antagonist BM 13177, the lipoxygenase inhibitor esculetin were effective in ouabain and aconitine induced arrhythmias while the PGI2 formation stimulating substance nafazatrom was only effective in aconitine induced arrhythmia. BM 13177 and esculetin could also counteract the arrhythmogenic effect of PAF. TX synthetase inhibition by HOE 944 was ineffective or partially effective, resp..

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Anti-Arrhythmia Agents; Arachidonic Acids; Arrhythmias, Cardiac; Epoprostenol; Guinea Pigs; Heart; Iloprost; Ouabain; Prostaglandin Endoperoxides, Synthetic; Reference Values; Sulfonamides

Increased adherence of leucocytes to the vessel wall is thought to be a key event in potentially deleterious leucocyte-vessel wall interactions in a variety of diseases associated with microvasculatory dysfunction. As measured by videomicroscopy in mesenteric venules (phi 40 +/- 8 microns) of anaesthetized rats, an injury caused by one short electrical stimulus to the venule wall led to a prolonged increase of marginated (sticking and rolling) leucocytes from 228/mm2 to 797/mm2 without affecting red cell velocity and shear rate. Iloprost (0.1 micrograms/kg/min i.v.), PGE1 (2.0 micrograms/kg/min i.a.), BW 755 C (40 mg/kg s.c.), forskolin (0.3 mg/kg i.v.), and hirudin (500 IU/kg + 200 IU/kg/h i.v.) all significantly attenuated injury-induced leucocyte margination. Indomethacin (10 mg/kg s.c.) had no effect and sulotroban (0.5 mg/kg/min) showed borderline efficacy. Platelet depletion by rat antiplatelet serum completely inhibited increased leucocyte margination. PGI2 mimetics, drugs interfering with lipoxygenase metabolism, and thrombin inhibitors may therefore be useful to prevent exaggerated leucocyte-vessel wall interactions.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Alprostadil; Animals; Cell Adhesion; Colforsin; Electric Stimulation; Epoprostenol; Hirudins; Iloprost; Indomethacin; Leukocytes; Male; Mesenteric Veins; Rats; Rats, Inbred Strains; Sulfonamides; Thrombocytopenia; Venules

The influence of red blood cells on spontaneous platelet aggregation (SPA) has been studied ex vivo. Platelet aggregation was quantified by measuring the fall in single platelet count using a new whole blood platelet counter. When aliquots of whole blood and autologous platelet rich plasma (PRP) were roller-mixed at 37 degrees C, a marked fall in platelet count occurred in whole blood due to SPA but platelet count remained almost unchanged in PRP. When blood from healthy young controls, aged 20-35 years, was compared with healthy old controls, aged 48-80 years, and patients with thrombotic complications, the extent of SPA was in the order: thrombotic patients greater than old controls greater than young controls. Prostacyclin and the new stable prostacyclin analogue Iloprost, at 8 nM effectively inhibited SPA. 2-Chloroadenosine (10 microM) which is an inhibitor of ADP-induced platelet aggregation was also an effective inhibitor of SPA. Acetylsalicylic acid (56 microM) and the thromboxane A2 receptor blocker BM13.177 (0.5 microM) only partially inhibited SPA. ADP from red blood cells is suspected to mediate red cell-induced SPA. However, the possibility that the red cells have an important physical role in SPA cannot be ruled out.

Topics: 2-Chloroadenosine; Adenosine; Adult; Aged; Aspirin; Epoprostenol; Erythrocytes; Humans; Iloprost; In Vitro Techniques; Middle Aged; Platelet Aggregation; Platelet Count; Sulfonamides; Thrombosis