bq-485 and Disease-Models--Animal

This study tests whether the hemostatic action of poly-N-acetyl glucosamine (p-GlcNAc) fiber material involves vasoconstrictor release leading to closure of an aortic laceration.. A 22-gauge cannula was inserted into an infrarenal aortic segment of a rat. Surrounding ligatures were tied, and the aorta was flushed with 60 mL of saline from a reservoir held at 80 cm. A 23-gauge aortic puncture was made. The time taken to empty the reservoir was recorded.. Control patches led to an emptying time of 295 seconds, whereas p-GlcNAc patches increased this time to greater than 600 seconds. Ten minutes after patch removal, the emptying time decreased to 330 seconds. The rats were treated intravenously with endothelin receptor antagonists BQ-485 or JKC-301. The emptying time shortened to control values, despite the use of the p-GlcNAc fiber-based patch.. The mechanism of hemostasis by poly-N-acetyl glucosamine involves endothelin release independent of formed elements of blood.

Topics: Acetylglucosamine; Administration, Topical; Animals; Aorta, Abdominal; Azepines; Bandages; Disease Models, Animal; Drug Evaluation, Preclinical; Endothelin A Receptor Antagonists; Female; Hemorrhage; Hemostatic Techniques; Hemostatics; Male; Oligopeptides; Rats; Receptor, Endothelin A; Time Factors; Wounds, Penetrating

The physiological and pathophysiological functions of endothelin-1 in modulating the regional blood flow of normal and spontaneously hypertensive rats (SHR) were studied in the perfused mesenteric vascular bed, a useful model for investigating resistance vessels.. We used 12-week-old SHR and Wistar-Kyoto (WKY) rats. Endothelin A (ETA) receptor responsiveness was evaluated by endothelin-1 (0.2-2 mumol/l) concentration-response curves, and repeated in the presence of indomethacin and the ETA and endothelin B (ETB) receptor antagonists BQ-485 and BQ-788, respectively. ETB receptor responsiveness was tested by sarafotoxin S6c concentration-response curves, obtained in the noradrenaline-precontracted mesenteric vascular bed, and repeated after treatment with BQ-788 and after endothelial denudation.. In both groups, endothelin-1 induced concentration-dependent contraction; SHR exhibited a markedly increased maximal effect compared with WKY rats (P < 0.01). BQ-485 produced a shift to the right for endothelin-1 concentration-response curves in both groups, with a higher pA2 (negative common logarithm of the antagonist that produces an agonist dose ratio of 2) value in SHR than in WKY rats (P < 0.01). The increase in the maximal effect produced by endothelin-1 in SHR was prevented by indomethacin, which also induced a significant increase in the endothelin-1 concentration producing the half-maximal response (EC50) in SHR (P < 0.05). Sarafotoxin S6c produced an ETB-dependent endothelium-mediated relaxant effect in WKY rats, which was not observed in SHR.. The higher vasoconstriction induced by endothelin-1 in SHR may be related to a greater number of available ETA receptors, due to the presence of an ETA receptor subtype. This mechanism may be linked to the production of prostanoids that add to the direct endothelin-1-evoked vasoconstriction. These results, together with the lack of relaxation in response to sarafotoxin S6c in SHR, suggest that an imbalance in the endothelin-1 ability to induce both contraction and relaxation is present in SHR with sustained hypertension, manifesting as a greater contractile effect evoked in this strain.

Topics: Animals; Antihypertensive Agents; Azepines; Blood Pressure; Cyclooxygenase Inhibitors; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Hypertension; Indomethacin; Mesenteric Arteries; Oligopeptides; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Vascular Resistance; Vasoconstriction

We investigated the effects of selective and non-selective endothelin (ET) antagonists on warm ischemia-reperfusion injury of the early phase in the murine liver under propofol anesthesia. We examined portal pressures, O2 consumptions and liver enzymes to estimate injuries using perfused isolated murine liver model. Experiment 1: we compared the perfusate only group, the soy oil (as vehicle) group, and the propofol group without ischemic loading to determine whether propofol and its vehicles themselves have any effect. Experiment 2: we determined the effects of ET antagonists on reperfusion injury after warm ischemia of 40 minute's cutoff of perfusate under propofol anesthesia and compared five groups up to 90 min after reperfusion; the propofol only group (control; 4 mg.l-1), the BQ-485 group (20 microM), the BQ-788 group (50 microM), the bosentan group (40 microM), and the BQ-485 + BQ-788 group. The soy oil group showed significantly more liver damage, and the propofol group showed no damage. In addition, propofol did not alter the effect of ET antagonists on reperfusion injury. Clinical dose of propofol did not seem to alter the effects of ET antagonists on the murine liver in the early phase of ischemia-reperfusion injury.

Topics: Anesthesia, Intravenous; Anesthetics, Intravenous; Animals; Azepines; Bosentan; Disease Models, Animal; Endothelins; Free Radical Scavengers; In Vitro Techniques; Liver; Male; Oligopeptides; Piperidines; Propofol; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sulfonamides

Endothelin-1 (ET-1) plays an important role in the physiologic or pathophysiologic regulation of cerebral circulation. To evaluate the effects of the newly synthesized ETA receptor-selective antagonist, BQ-485 (N-perhydroazepin-l-ylcarbonyl-Leu-D-Trp-D-Trp-OH), on the cerebral metabolism of oxygen during the delayed cerebral hypoperfusion that follows global cerebral ischemia, we occluded the ascending aorta and caval veins of 10 beagle dogs for 12.5 min. The animals were randomized into two groups. BQ-485 was given directly into the carotid artery at 0.03 mg/kg per min for 30 min, starting 15 min after reperfusion in the treatment group (n = 5). Isotonic saline was infused in the control group (n = 5). A fiberoptic catheter was inserted into the superior sagittal sinus to monitor its oxygen saturation (SssO2) continuously. Arterial O2 content (CaO2), and sagittal sinus O2 content (CssO2) were monitored before and at 0.5, 1, 2, 4, 6 and 8 h after the ischemic insult. BQ-485 significantly prevented the expected decrease in SssO2 and increase in the cerebral O2 utilization coefficient at 4, 6 and 8 h after the ischemic insult (P < 0.05). Thus, BQ-485 ameliorated the mismatch between O2 supply and demand in the delayed hypoperfusion phase. We conclude that ET may be involved in the pathogenesis of delayed cerebral hypoperfusion after cardiac arrest.

Topics: Analysis of Variance; Animals; Azepines; Brain; Cerebrovascular Circulation; Disease Models, Animal; Dogs; Endothelin Receptor Antagonists; Heart Arrest; Injections, Intra-Arterial; Ischemic Attack, Transient; Oligopeptides; Oxygen Consumption; Random Allocation; Receptor, Endothelin A

This study investigated the effects of portal hypertension on gastric motor and secretory functions and the role of endothelin in rats. Control; sham-operated; endothelin-A receptor blocker, BQ 485 (1 microgram/kg)-treated; portal hypertensive; and portal hypertension +, endothelin-A receptor blocker-treated rats were subjected to tests of gastric secretory, motor, and mucosal function studies as well as gastric wall polymorphonuclear infiltration. Portal hypertension was induced by partial portal vein ligation. Portal hypertension suppressed gastric acid and total fluid secretion and delayed gastric emptying. An increase in mucosal permeability and no alteration in gastric wall myeloperoxidase activity were observed. The effects of portal hypertension on gastric secretory, motor, and mucosal functions were reversed by treatment with endothelin-A receptor blocker, BQ-485. It is concluded that portal hypertension suppresses the gastric motor and secretory functions and endothelin plays an important role in the pathophysiology of gastric alterations associated with portal hypertension.

Topics: Analysis of Variance; Animals; Azepines; Cell Membrane Permeability; Disease Models, Animal; Drug Evaluation, Preclinical; Endothelin Receptor Antagonists; Endothelins; Female; Gastric Acid; Gastric Emptying; Gastric Mucosa; Hypertension, Portal; Oligopeptides; Peroxidase; Proteins; Rats; Rats, Wistar; Stomach