Circulating calcitonin gene-related peptide (CGRP) concentrations are elevated in experimental and clinical sepsis. CGRP causes hypotension and tachycardia, suggesting that the peptide might mediate the acute circulatory changes in sepsis. To test this hypothesis we administered Escherichia coli endotoxin (8 mg/kg iv) to Nembutal- (pentobarbital sodium; 50 mg/kg) anesthetized rats. Endotoxin caused hypotension and tachycardia within 60 min that stabilized for 90 min. After 2 h more severe hypotension developed, and 80% of rats died spontaneously after 3 h. In other endotoxic rats we administered 20 nmol of the CGRP receptor antagonist hCGRP (8-37) intravenously at 60 min. hCGRP (8-37) transiently reversed tachycardia (from 469 +/- 11 to 407 +/- 7 beats/min, P < 0.05) and increased mean blood pressure (from 63 +/- 4 to 93 +/- 11 mmHg, P < 0.05) over 30 min, after which hemodynamics and survival rates were no different from untreated animals. The results suggest that CGRP plays an important role in the acute circulatory changes of endotoxemia. More detailed work is necessary to determine the effects of CGRP antagonism on cardiac function, regional blood flow, and overall survival rates in sepsis.