Protective effects of endothelin receptor antagonists in dogs with aortic cross-clamping.
Endothelin (ET) may play an important role in the pathogenesis of vasoconstriction and acute renal failure after aortic cross-clamping (ACC). However, the relative contribution of the ET(A) and ET(B) receptors to the physiopathology of ischemic acute renal failure is poorly understood. This study was carried out to evaluate the potential protective effect of a selective ET(A) antagonist versus combined ET(A)/ET(B) antagonist on altered systemic, pulmonary, and renal hemodynamics induced by cross-clamping the suprarenal aorta for 1 h, followed by 2-h reperfusion. Studies were performed in three groups of anesthetized mongrel dogs. After baseline measurements, treatment (3 mg/kg i.v. bolus + 3 mg/kg/h infusion) with either a selective ET(A) antagonist, Ro 61-1790 (n = 5), or a combined ET(A)/ET(B) antagonist, bosentan (n = 5) or vehicle (n = 8) was initiated 5 min before ACC. There were marked increases in total peripheral (TPR), pulmonary (PVR), and renal (RVR) vascular resistances, and significant decreases in cardiac output (CO) and glomerular filtration rate (GFR) and tubular sodium reabsorption after ACC in the vehicle group. Both Ro 61-1790 and bosentan prevented the marked increases in TPR, PRV, and RVR, and attenuated the declines in CO, GFR, and tubular sodium reabsorption. We concluded that the profound systemic, pulmonary, and renal vasoconstriction, as well as the impairments in glomerular and tubular functions associated with ACC, is mostly ET mediated and that the ET(A) receptor activation makes a major contribution to the ET-mediated impairments of hemodynamics and renal function after ACC.
Roux
S
S
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland. sebastien.roux@roche.com
Qiu
C
C
Sprecher
U
U
Osterwalder
R
R
Clozel
J P
JP
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D000077300:Bosentan; D004146:Dioxanes / Q000494:pharmacology*; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000502:physiology; D008297:Male; D011725:Pyridines; D011743:Pyrimidines / Q000494:pharmacology*; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides / Q000494:pharmacology*; D013777:Tetrazoles
D004146:Dioxanes; D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan; D000077300:Bosentan