title: Renal protection by a dual ETA/ETB endothelin antagonist, L-754,142, after aortic cross-clamping in the dog.
abstract: Renal insufficiency is a significant complication that occurs after surgical procedures, requiring cross-clamping of the aorta. The mechanism for this renal dysfunction is currently not known, but studies suggest a potential role of endothelin in mediating the insufficiency. Accordingly, the role of endothelin was assessed using the nonpeptidyl, dual ETA/ETB endothelin antagonist L-754,142 in a model of renal insufficiency in the anesthetized dog induced by cross-clamping the suprarenal aorta for 60 min, followed by 2 h of reperfusion. In vehicle-treated animals (saline, n = 8) after 2 h of reperfusion, plasma [ET-1] increased 66% and renal blood flow (RBF) was reduced by 38% compared with baseline. This decline was associated with an 84% increase in renal vascular resistance and a 54% reduction in GFR (baseline, 46 +/- 5 ml/min; 21 +/- 3 ml/min at 2 h; P < 0.01) and sodium reabsorption (baseline, 6.7 +/- 0.7 microEq/min; 3.0 +/- 0.5 microEq/min at 2 h, P < 0.01). After baseline measurements, pretreatment with L-754,142 at 0.3 mg/kg bolus + 0.1 mg/kg per h continuous infusion (low dose; n = 8) or 3.0 mg/kg bolus + 1 mg/kg per h infusion (high dose; n = 8) initiated 45 min before aortic cross-clamp led to a dose-dependent normalization of RBF and renal vascular resistance within 2 h of cross-clamp removal. GFR was also improved and returned to within 75% of baseline (P < 0.01 versus vehicle) by 2 h of reperfusion with L-754,142 (baseline, 55 +/- 5 ml/min; 42 +/- 5 ml/min at 2 h with the high dose). The improvement of GFR with L-754,142 treatment was associated with a preservation of sodium reabsorption compared with vehicle-treated animals. This study supports a role of endothelin in the pathogenesis of renal insufficiency after aortic cross-clamping and demonstrates that pretreatment with the dual ETA/ETB endothelin antagonist L-754,142 preserves RBF and sodium reabsorption, leading to a significant improvement in GFR.
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Krause
authors.forename: T F
authors.initials: TF
authors.lastname: Walsh
authors.forename: W J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: R
authors.initials: R
authors.lastname: Ranaei
authors.forename: D L
authors.initials: DL
authors.lastname: Williams
authors.forename: S D
authors.initials: SD
authors.lastname: Kivlighn
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D058186:Acute Kidney Injury / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D001011:Aorta / Q000601:surgery*; D003250:Constriction; D004195:Disease Models, Animal; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007511:Ischemia / Q000188:drug therapy / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D011183:Postoperative Complications / Q000209:etiology / Q000517:prevention & control; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology; D012079:Renal Circulation / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D000081:Acetamides; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; C097296:L 754142; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin