Endothelin Blockade Lowers Total Peripheral Resistance in Hemorrhagic Shock Recovery

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To determine whether endothelin (ET) has a role in maintaining circulatory support during hypotensive hemorrhage, we (1) examined cardiac and systemic hemodynamics after a 6-mL hemorrhage in the presence and absence of the ETA receptor blocker BQ-123, (2) examined cardiac and systemic hemodynamics during BQ-123 infusion in nonhemorrhaged rats, (3) measured changes in circulating immunoreactive endothelin (IR-ET) after a 6-mL hemorrhage, and (4) infused pathophysiological doses of ET-1 into rats anesthetized with thiobutabarbital. Twenty minutes after hemorrhage, 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. The 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 arterial 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 vascular resistance was significantly lower 5, 10, 20, and 30 minutes after hemorrhage during BQ-123 infusion compared with hemorrhage alone at each time point. Infusion of BQ-123 into nonhemorrhaged rats had no effect on mean arterial pressure, systemic vascular resistance, or cardiac 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 resulted 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 for endothelin in maintaining pressure homeostasis during hemorrhagic shock by enhancing systemic vascular resistance: (1) IR-ET increases during hypotensive hemorrhage in association with an increase in systemic vascular resistance, (2) ETA receptor blockade after hypotensive hemorrhage decreases mean arterial pressure and systemic vascular resistance, and (3) pathophysiological infusion of ET-1 increases systemic vascular resistance and mean arterial pressure.

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