Using front-surface fluorometry and fura-2-loaded medial strips of the porcine coronary artery, we simultaneously monitored the cytosolic Ca++ concentration ([Ca++]i) and force development to investigate the mechanisms of vasorelaxation induced by calcitonin gene-related peptide (CGRP). CGRP actively decreased [Ca++]i of the strips at rest both in the presence and in the absence of extracellular Ca++. In the presence of extracellular Ca++, CGRP inhibited concentration-dependently the steady-state elevations of [Ca++]i and force induced by high-K+ depolarization and by histamine (HIS). The extent of the inhibition of force was much greater than the extent of reductions of [Ca++]i would lead one to expect. The [Ca++]i (abscissa)-force (ordinate) relationship at the peak levels of force during HIS-induced contractions shifted to the left of that observed with high-K+ depolarization. The [Ca++]i-force relationships of the contractions induced by high-K+ depolarization and by HIS shifted to the right as a result of the treatment with CGRP. In the absence of extracellular Ca++, CGRP inhibited the transient elevations of [Ca++]i induced by HIS but not by caffeine. Our results suggest that CGRP relaxes the porcine coronary artery by the following mechanisms: 1) the inhibition of Ca++ influx stimulated by HIS and by high-K+ depolarization, 2) the reduction of HIS-induced release of intracellular Ca++, without affecting a caffeine-sensitive mechanism, 3) an active decrease in the resting levels of [Ca++]i and 4) a decrease in the Ca(++)-sensitivity of the contractile apparatus.