Rat calcitonin gene-related peptide (CGRP alpha; EC50, 1 nM) was shown to stimulate cAMP formation in cultured rat renal mesangial cells. CGRP concentration dependently (EC50, 1 nM) also inhibited contraction of mesangial cells by angiotensin II (10 nM). Angiotensin II (10 nM) caused a transient increase of the intracellular calcium concentration from 140 nM to 480 nM in the mesangial cells, but these calcium transients were not altered by CGRP. CGRP (10 nM) decreased vascular resistance in the isolated rat kidney perfused at constant pressure (100 mm Hg; P less than 0.01). The decreased vascular resistance was accompanied by a rise of the glomerular filtration fraction. CGRP, moreover, attenuated the effects of angiotensin II on renal vascular resistance and glomerular filtration (P less than 0.01). In conclusion, CGRP causes relaxation of renal mesangial cells and decreases renal vascular resistance. As a result CGRP raises glomerular filtration and the filtration fraction. The effect may be linked to cyclic AMP formation. Thus, regulation of renal vascular and glomerular function may represent a novel action of CGRP apart from its cardiovascular effects.