In previous experiments, intra-articular administration of calcitonin gene-related peptide (CGRP) failed to elicit plasma protein extravasation into synovial fluid. In the present study, using a sensitive technique to assay protein in synovial fluid, intra-articular perfusion of CGRP (10(-6) M) was found to produce protein extravasation which was sustained throughout the period of infusion. Both lower (10(-7) M) and higher (10(-5) M) concentrations of CGRP failed to produce extravasation. This failure at the highest concentration of CGRP was the likely consequence of a significant fall in arterial blood pressure which occurred with administration of CGRP at this concentration. In the presence of arterial hypotension induced by an alpha-adrenoceptor antagonist, 10(-6) M CGRP failed to produce extravasation. Plasma extravasation induced by CGRP was a specific effect and not merely a consequence of its potent vasodilator properties as similar vasodilator responses induced by a beta-adrenoceptor agonist failed to induce protein leakage. These findings indicate that CGRP can alter blood vessel permeability and therefore could additionally contribute to neurally mediated inflammatory responses.