ENDOTHELIN BLOCKADE LOWERS TOTAL PERIPHERAL RESISTANCE IN HEMORRHAGIC-SHOCK RECOVERY

To determine whether endothelin (ET) has a role in maintaining circula tory support during hypotensive hemorrhage, we (I) examined cardiac an d systemic hemodynamics after a 6-mL hemorrhage in the presence and ab sence of the ET(A) receptor blocker BQ-123, (2) examined cardiac and s ystemic hemodynamics during BQ-123 infusion in nonhemorrhaged rats, (3 ) measured changes in circulating immunoreactive endothelin (IR-ET) af ter a 6-mL hemorrhage, and (4) infused pathophysiological doses of ET- 1 into rats anesthetized with thiobutabarbital. Twenty minutes after h emorrhage, cardiac output and mean arterial pressure had stabilized in part because of an increase in systemic vascular resistance from 0.86 +/-0.04 (baseline) to 1.04+/-0.05 (20 minutes) mm Hg/mL per minute. Th e rise in systemic vascular resistance was temporally associated with a significant (24%) increase in circulating IR-ET from 29+/-2 to 36+/- 3 pg/mL 20 minutes after hemorrhage. During BQ-123 infusion mean arter ial pressure at 5, 10, and 20 minutes after hemorrhage was 9+/-2, 23+/ -4, and 23+/-3 mm Hg lower than values obtained after hemorrhage alone (P<.05). Mean arterial pressure was unaffected by BQ-123 infusion at baseline and 30 minutes after hemorrhage. Systemic vascular resistance was not affected at baseline by BQ-123 infusion. However, systemic va scular resistance was significantly lower 5, 10, 20, and 30 minutes af ter hemorrhage during BQ-123 infusion compared with hemorrhage alone a t each time point. Infusion of BQ-123 into nonhemorrhaged rats had no effect on mean arterial pressure, systemic vascular resistance, or car diac output. Infusion of ET-1 at 75 ng/kg per minute for 45 minutes in a separate group of rats resulted in similar changes in IR-ET and res ulted in increases in systemic vascular resistance from 0.92+/-0.07 to 1.76+/-0.31 mm Hg/mL per minute and mean arterial pressure from 125+/ -3 to 144+/-4 mm Hg. The following findings together support a role fo r endothelin in maintaining pressure homeostasis during hemorrhagic sh ock by enhancing systemic vascular resistance: (1) IR-ET increases dur ing hypotensive hemorrhage in association with an increase in systemic vascular resistance, (2) ET(A) receptor blockade after hypotensive he morrhage decreases mean arterial pressure and systemic vascular resist ance; and (3) pathophysiological infusion of ET-1 increases systemic v ascular resistance and mean arterial pressure.