HUMAN ALPHA-CALCITONIN GENE-RELATED PEPTIDE STIMULATES ADENYLATE-CYCLASE AND GUANYLATE-CYCLASE AND RELAXES RAT THORACIC AORTA BY RELEASING NITRIC-OXIDE

1 The signal transduction pathway for vasorelaxation induced by human alpha-calcitonin gene-related peptide (human alpha-CGRP) was studied in rat thoracic aortic rings preconstricted with noradrenaline (10(-7) M). 2 Vasorelaxation by human alpha-CGRP was inhibited by haemogobin (10(-6) m) and methylene blue (10(-5) m) but was unaffected by ibuprofen (10(-5) m). 3 Acetylcholine caused a 16 fold increase in levels of guanosine 3':5'-cyclic monophosphate (cyclic GMP) with levels of adenosine 3':5'-cyclic monophosphate (cyclic AMP) being unaltered. Human alpha-CGRP caused a 12 fold increase in levels of cyclic GMP but, in contrast to acetylcholine, evoked a 2.5 fold rise in levels of cyclic AMP. The rises in cyclic nucleotides evoked by human alpha-CGRP and acetylcholine were dependent on the presence of an intact endothelium. 4 N(G)-nitro-L-arginine (L-NOARG: 10(-5) m), which inhibits nitric oxide synthase, inhibited the relaxant response to human alpha-CGRP and cyclic GMP accumulation without affecting the cyclic AMP accumulation. 5 The data presented in this paper suggests that human alpha-CGRP relaxes the rat thoracic aorta by releasing nitric oxide and stimulating guanylate cyclase. The stimulation of adenylate cyclase by human alpha-CGRP probably precedes the activation of nitric oxide synthase but could be unrelated to the relaxant response.