ETA-receptor blockade impairs vasoconstriction after hemorrhage in xenon-anesthetized dogs treated with an AT1-receptor antagonistThis article is one of a selection of papers published in the special issue (part 1 of 2) on Forefronts in Endothelin.

Abstract

The effects of endothelin receptor subtype A (ETA) blockade on hemodynamics and hormonal adaptation during hemorrhage were studied in xenon/remifentanil-anesthetized dogs (n = 6) pretreated with an angiotensin II type 1 (AT1)-receptor blocker. Controls: after a baseline awake period, anesthesia was induced in the dogs with propofol and maintained with xenon/remifentanil (baseline anesthesia). Sixty minutes later, 20 mL·kg–1 of blood was withdrawn within 5 min and the dogs observed for another hour (hemorrhage). AT1 group followed the same protocol as controls except the AT1-receptor blocker losartan (i.v. 100 μg·kg–1·min–1) was started at the beginning of the experiment. AT1+ETA group was the same as AT1 group but with the addition of the ETA-receptor blocker atrasentan (i.v. 1 mg·kg–1, then 0.01 mg·kg–1·min–1). In controls, mean arterial pressure (MAP) remained unchanged during baseline anesthesia, whereas systemic vascular resistance (SVR) increased from 3282 ± 281 to 7321 ± 803 dyn·s·cm–5, heart rate (HR) decreased from 86 ± 4 to 40 ± 3 beats·min–1, and cardiac output (CO) decreased from 2.3 ± 0.2 to 0.9 ± 0.1 L·min–1 (p < 0.05), with no further changes after hemorrhage. In AT1-inhibited dogs, MAP (71 ± 6 mm Hg) and SVR (5939 ± 611 dyn·s·cm–5) were lower during baseline anesthesia and after hemorrhage, but greater than those in AT1+ETA (66 ± 7 mm Hg, 5034 ± 658 dyn·s·cm–5) (p < 0.05). HR and CO were not different between groups. Plasma concentration of vasopressin was highest with AT1+ETA inhibition after hemorrhage. Combined AT1+ETA-receptor blockade impaired vasoconstriction more than did AT1-receptor blockade alone, both during baseline xenon anesthesia and after hemorrhage. Even a large increase in vasoconstrictor hormones could not prevent the decrease in blood pressure and the smaller increase in SVR. Thus, endothelin is an important vasoconstrictor during hemorrhage, and both endothelin and angiotensin II are essential hormones for cardiovascular stabilization after hemorrhage.