Human α‐calcitonin gene‐related peptide stimulates adenylate cyclase and guanylate cyclase and relaxes rat thoracic aorta by releasing nitric oxide

Abstract

1 The signal transduction pathway for vasorelaxation induced by human a-calcitonin gene-related peptide (human a-CGRP) was studied in rat thoracic aortic rings preconstricted with noradrenaline (10-7 M). 2 Vasorelaxation by human a-CGRP was inhibited by haemogobin (10-6M) 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 a-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 a-CGRP and acetylcholine were dependent on the presence of an intact endothelium. 4 N0-nitro-L-arginine (L-NOARG: 10-5 M), which inhibits nitric oxide synthase, inhibited the relaxant response to human a-CGRP and cyclic GMP accumulation without affecting the cyclic AMP accumulation. 5 The data presented in this paper suggests that human a-CGRP relaxes the rat thoracic aorta by releasing nitric oxide and stimulating guanylate cyclase. The stimulation of adenylate cyclase by human a-CGRP probably precedes the activation of nitric oxide synthase but could be unrelated to the relaxant response.

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“…The involvement of ATP-sensitive potassium channels [48] in the vasodilator mechanism of CGRP has been suggested and subsequently extended to channels sensitive to glibenclamide or charybdotoxin (large-conductance Ca 2+ -activated K + channels) in rat pial arterioles [49]. Exceptions to endothelium-independent relaxation to CGRP occur only in a few tissues, including the rat aorta, where the relaxation to CGRP depends on the presence of an intact endothelium and is attenuated by inhibitors of NO synthase, implying an NO-dependent mechanism [12,50]. In human internal mammary artery [51] and rat pulmonary artery [52], a similar endothelium-dependent mechanism of relaxation has also been seen.…”

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