Protective effects of endothelin receptor antagonists in dogs with aortic cross-clamping

Endothelin (ET) may play an important role in the pathogenesis of vasoconst riction and acute renal failure after aortic cross-clamping (ACC). However, the relative contribution of the ETA and ETB receptors to the physiopathol ogy of ischemic acute renal failure is poorly understood. This study was ca rried out to evaluate the potential protective effect of a selective ETA an tagonist versus combined ETA/ETB 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 ETA antagonist, R o 61-1790 (n = 5), or a combined ETA/ETB antagonist, bosentan (n = 5) or ve hicle(n = 8) was initiated 5 min before ACC. There were marked increases in total peripheral (TPR), pulmonary (PVR), and renal (RVR) vascular resistan ces, and significant decreases in cardiac output (CO) and glomerular filtra tion rate (GFR) and tubular sodium reabsorption after ACC in the vehicle gr oup. Both Ro 61-1790 and bosentan prevented the marked increases in TPR, PR V, and RVR, and attenuated the declines in CO, GFR, and tubular sodium reab sorption. We concluded that the profound systemic, pulmonary, and renal vas oconstriction, as well as the impairments in glomerular and tubular functio ns associated with ACC, is mostly ET mediated and that the ETA receptor act ivation makes a major contribution to the ET-mediated impairments of hemody namics and renal function after ACC.