Simultaneous activation of adenylyl cyclase and protein kinase C induces production of nitric oxide by vascular smooth muscle cells

• Published in: Molecular pharmacology Vol. 46; no. 2; pp. 274 - 282
• Main Authors: Scott-Burden, T, Elizondo, E, Ge, T, Boulanger, C M, Vanhoutte, P M
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.08.1994
• Subjects: Adenylyl Cyclases - metabolism; Amino Acid Oxidoreductases - biosynthesis; Amino Acid Oxidoreductases - metabolism; Animals; Cells, Cultured; Colforsin - pharmacology; Cyclic AMP - pharmacology; Enzyme Activation; Gene Expression Regulation, Enzymologic; GTP Cyclohydrolase - antagonists & inhibitors; GTP Cyclohydrolase - genetics; GTP Cyclohydrolase - metabolism; Indoles - pharmacology; Interleukin-1 - pharmacology; Maleimides - pharmacology; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - metabolism; Nitric Oxide - biosynthesis; Nitric Oxide Synthase; Protein Kinase C - metabolism; Rats; RNA, Messenger - metabolism; Signal Transduction
• ISSN: 0026-895X; 1521-0111

Rat aortic smooth muscle cells produced large quantities of nitric oxide (NO) after exposure to interleukin-1 beta, and this was depressed in the presence of the protein kinase C inhibitor bisindolylmaleimide. Intracellular cAMP levels were elevated mildly in cytokine-treated smooth muscle cells, and the presence of forskolin enhanced both the cAMP levels and NO production. Inhibition of GTP:cyclohydrolase I by 2,4-diamino-6-hydroxypyrimidine attenuated NO production by interleukin-1 beta-treated cells. GTP:cyclohydrolase is the regulatory enzyme for de novo tetrahydrobiopterin synthesis, and the latter is a required cofactor for NO synthase activity. Treatment of smooth muscle cells with forskolin induced GTP:cyclohydrolase mRNA expression, and simultaneous treatment of cells with forskolin and phorbol esters elicited NO production. Angiotensin II and arginine-vasopressin, acknowledged agonists for protein kinase C, elicited production of NO by forskolin-treated smooth muscle cells. These observations confirm the importance of GTP:cyclohydrolase activity for NO production by cultured smooth muscle cells and implicate both adenylyl cyclase and protein kinase C in this process.