bq-485 and Reperfusion-Injury

The aim of the present study was to assess the role of endothelin (ET) in ischemia-reperfusion (I/R)-induced mucosal injury. Mucosal permeability ((51)Cr-EDTA clearance) and tissue myeloperoxidase (MPO) activity were significantly increased after 30 min of ischemia followed by 30 min of reperfusion. The I/R-induced increases in mucosal permeability and polymorphonuclear leukocyte (PMN) infiltration were significantly attenuated by pretreatments with ET(A) (BQ-485) and/or ET(B) (BQ-788) receptor antagonists. Monoclonal antibody (MAb) directed against intercellular adhesion molecule-1 (ICAM-1; MAb 1A29) and superoxide dismutase (SOD) pretreatments significantly attenuated the increased mucosal permeability and PMN infiltration in a similar manner as with ET receptor antagonists. Superior mesenteric artery blood flow was significantly reduced during the reperfusion period. Both ET receptor antagonists caused a significant rise in blood flow compared with an untreated I/R group. In conclusion, our data suggest that ET(A) and/or ET(B) receptors, ICAM-1, and superoxide play an important role in I/R-induced mucosal dysfunction and PMN infiltration. Furthermore, ET is involved in the pathogenesis of post-reperfusion-induced damage and beneficial effects of ET receptor antagonism are related to an improvement of disturbed blood flow during the reperfusion period.

Topics: Animals; Antibodies, Monoclonal; Azepines; Blood Flow Velocity; Blood Pressure; Cell Membrane Permeability; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Female; Intercellular Adhesion Molecule-1; Intestinal Mucosa; Male; Mesenteric Artery, Superior; Neutrophils; Oligopeptides; Peroxidase; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reperfusion Injury; Superoxide Dismutase

This study aimed to investigate the roles of endothelin (ET) receptors in biliary dysfunction and cell injury in postischemic livers. Rat livers perfused with oxygenated Krebs-Henseleit solution were exposed to reoxygenation following 20-minute hypoxia. The anoxic perfusion decreased bile output and reduced cyclic guanosine monophosphate (cGMP) contents, an index of nitric oxide (NO) generation. Upon reoxygenation, the decreased bile was not fully recovered, and the resistance increased biphasically: an early transient spike accompanied by an elevated release of ET-1 and a rise accompanied by a cGMP elevation in the later period. The initial vasoconstriction appeared to be mediated by both ET(A) and ET(B) receptors, as judged by inhibitory effects of their antagonists, BQ-485 and BQ-788, respectively, while the late elevation of the resistance was not attenuated by these reagents, but rather enhanced by the ET(B) blockade. The BQ-788 treatment attenuated the reoxygenation-induced cGMP elevation and induced bile acid-dependent choleresis. However, such a change upon the ET(B) blockade coincided with dissociation of a recovery of phospholipids and aggravation of cell injury. The BQ-788-elicited deterioration of reoxygenation-elicited changes was attenuated by NO supplement with S-nitroso-N-acetyl penicillamine. N(omega)-Nitro-L-arginine methyl ester, an NO synthase inhibitor, mimicked biliary changes elicited by the ET(B) blockade but without causing notable cell injury. Under these circumstances, coadministration of clotrimazole, an inhibitor of cytochrome P450 mono-oxygenases, elicited the injury comparable with that observed under the ET(B) blockade. These results suggest that ET(B)-mediated signaling limits excessive bile acid excretion and plays a protective role against reoxygenation injury through mechanisms involving both NO-dependent and -independent processes.

Topics: Animals; Azepines; Bile; Bile Acids and Salts; Cholestasis; Endothelin Receptor Antagonists; Ischemia; Male; Nitric Oxide; Oligopeptides; Perfusion; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin B; Receptors, Endothelin; Renal Circulation; Reperfusion Injury; Vascular Resistance

Endothelin-1 (ET-1), a novel vasoconstrictor, possibly plays a role in the mediation of ischemia/reperfusion (I/R) injury. Tacrolimus (FK506) and cyclosporin A (CsA) were reported to maintain tissue microcirculation of the liver subjected to I/R. This study investigated the effects of these immunosuppressants on intestinal I/R in terms of intestinal tissue microcirculation associated with ET-1.. Male S-D rats were pretreated twice with FK506 (0.2 mg/kg), CsA (10 mg/kg) or only saline solution (0.5 mL). The tissue microcirculation in the control was reduced after I/R (29% +/- 10%) accompanied by hypotension, increased tissue ET-1 expression (25.0% +/- 6.4% to 67.9% +/- 5.0% 60 minutes after reperfusion), and increased ET-1 level in the portal blood (3.4 +/- 0.9 to 23.6 +/- 6.1 pg/mL). FK506 suppressed ET-1 expression (27.3% +/- 5.2%, 4.1 +/- 2.2 pg/mL), maintained microcirculation (96% +/- 16%), and blood pressure, reduced histologic damage, and improved survival. CsA had a similar but weaker effect compared with FK506. An additional experiment was performed with BQ485Na (BQ), an ETA receptor antagonist, to evaluate the genuine role of ET-1. BQ showed almost the same effects as FK506.. FK506 and CsA, particularly the former, maintain microcirculation and protect the tissue from I/R injury by suppressing the production and release of ET-1.

Topics: Animals; Azepines; Blood Pressure; Cyclosporine; Endothelin Receptor Antagonists; Endothelin-1; Hypotension; Immunosuppressive Agents; Intestine, Small; Ischemia; Male; Microcirculation; Oligopeptides; Portal System; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin; Reperfusion Injury; Survival Rate; Tacrolimus; Time Factors

The objective of the present study was to clarify the differential effects of endothelinA (ETA) and ETB antagonism in the early phase of ischemia-reperfusion damage. Male Sprague Dawley rats were randomly divided into 4 groups: control (n = 10), bosentan (40 nM; n = 10), BQ-485 (20 nM; n = 10), and BQ-788 (50 nM; n = 10) to compare the effects of ETA or ETB or both ETA and ETB antagonists against the warm ischemia-reperfusion damage of murine livers. Isolated livers were perfused with oxygenated Krebs-Henseleit bicarbonate buffer solution and ET antagonists for 30 min before inducing warm ischemia (non-recirculating system). After 40 min without perfusate, measurements (portal pressure, O2 tensions of influent and effluent perfusate, liver enzymes, etc.) were taken up to 60 min after reperfusion. The BQ-788 group had significantly more liver damage than did the other groups, and more O2 consumption than did the bosentan group. BQ-485 and bosentan were more protective at some points after reperfusion. Antagonism of only the ETB receptors is detrimental, but antagonism of the ETA receptors appears to have a role in protecting the liver from warm ischemia-reperfusion damage in the early phase.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Azepines; Bosentan; Endothelin Receptor Antagonists; L-Lactate Dehydrogenase; Liver; Male; Mice; Oligopeptides; Oxygen Consumption; Piperidines; Portal Pressure; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sulfonamides

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