CGRP enhances induction of NO synthase in vascular smooth muscle cells via a cAMP-dependent mechanism.
Experiments were designed to examine whether calcitonin gene-related peptide (CGRP), a potent adenosine 3',5'-cyclic monophosphate (cAMP)-dependent vasodilator, affects the production of NO evoked by interleukin-1 beta) (IL-1 beta) in cultured rat aortic smooth muscle cells (SMC). CGRP, in a concentration-dependent manner, enhanced the release of nitrite (a stable oxidation product of NO) and the formation of L-citrulline from L-arginine caused by IL-1 beta. Two cAMP-dependent vasodilators, forskolin and isoproterenol, and the activator of the cAMP-dependent protein kinase, Sp-cAMPS, also enhanced the release of nitrite and the formation of L-citrulline evoked by IL-1 beta. The enhancing effect of isoproterenol required the presence of the vasodilator during the induction of NO synthase (NOS). IL-1 beta-treated vascular SMC inhibited the aggregation of indomethacin-treated platelets. Inhibition of platelet aggregation was more marked with SMC exposed to a combination of IL-1 beta and either CGRP or isoproterenol than with cells exposed to IL-1 beta alone. This inhibition was prevented by methylene blue and oxyhemoglobin. IL-1 beta induced the expression of inducible NOS mRNA in vascular SMC, which was enhanced by coincubation of IL-1 beta with either CGRP, isoproterenol, or forskolin. These observations indicate that CGRP via a cAMP-dependent mechanism potentiates the IL-1-beta-induced production of NO by enhancing the expression of inducible NOS. Therefore CGRP may contribute to the substantial production of NO in the vasculature during septic shock, which accounts, at least in part, for the collapse of the vascular system.
Schini-Kerth
V B
VB
Zentrum der Physiologie, Johann-Wolfgan-Goethe-Universität, Frankfurt, Germany.
Fisslthaler
B
B
Busse
R
R
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D000818:Animals; D001013:Aorta, Thoracic; D001120:Arginine / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002478:Cells, Cultured; D002956:Citrulline / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D019001:Nitric Oxide Synthase; D010974:Platelet Aggregation; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013873:Thionucleotides / Q000494:pharmacology
D007375:Interleukin-1; D012333:RNA, Messenger; D013873:Thionucleotides; D005576:Colforsin; C016957:adenosine-3',5'-cyclic phosphorothioate; D002956:Citrulline; D001120:Arginine; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D011494:Protein Kinases; D015740:Calcitonin Gene-Related Peptide; D007545:Isoproterenol