To investigate the role of calcitonin gene-related peptide (CGRP) in blood pressure regulation, we used rats with hypertension, induced by the chronic infusion of norepinephrine or angiotensin II, and examined changes in the systemic hemodynamics using the radioactive microspheres method. CGRP (0.05 micrograms/kg per min) administered simultaneously with norepinephrine (1.8 mg/kg per day) significantly reduced the systolic blood pressure of conscious rats compared with norepinephrine infusion alone. Similarly CGRP given with angiotensin II (0.9 mg/kg per day) significantly reduced the systolic blood pressure compared with angiotensin II alone. The antihypertensive effect of CGRP was sustained for 6 days. CGRP infusion decreased the total peripheral resistance but caused no change in cardiac output compared with rats given only pressor substances. Thus, a subdepressor dose of CGRP can modulate the vasopressor effects of norepinephrine and angiotensin II. CGRP may be involved in the regulation of blood pressure via an effect on peripheral vascular resistance.