This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marumo, T. Articles by Saruta, T. Search for Related Content PubMed PubMed Citation Articles by Marumo, T. Articles by Saruta, T.

(Hypertension. 1995;25:764-768.)
© 1995 American Heart Association, Inc.

Articles

Cyclosporin A Inhibits Nitric Oxide Synthase Induction in Vascular Smooth Muscle Cells

Takeshi Marumo; Toshio Nakaki; Keiichi Hishikawa; Hiromichi Suzuki; Ryuichi Kato; Takao Saruta

From the Departments of Internal Medicine (T.M., K.H., H.S., T.S.) and Pharmacology (T.M., T.N., R.K.), Keio University School of Medicine, Tokyo, Japan.

Correspondence to Toshio Nakaki, MD, PhD, Department of Pharmacology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan.

Abstract The effect of cyclosporin A on induction of nitric oxide synthase in rat aortic smooth muscle cells was examined. A combination of interleukin-1 (100 U/mL) and tumor necrosis factor- (5000 U/mL) induced accumulation of nitrite/nitrate, the stable end products of nitric oxide, in culture media within 48 hours. Cyclosporin A inhibited this nitrite/nitrate accumulation in a concentration-dependent manner with an IC₅₀ of 4x10^-7 mol/L when applied simultaneously with the cytokines. The expression of inducible nitric oxide synthase messenger RNA (mRNA) induced by the combination of interleukin-1 and tumor necrosis factor– was inhibited by the cyclosporin A cotreatment. Cyclosporin A did not decrease inducible nitric oxide synthase mRNA stability in the presence of transcription inhibitor actinomycin D (5 µg/mL). Induction of nitrite/nitrate production by the combination of tumor necrosis factor– and bacterial lipopolysaccharide or that of interleukin-1 and interferon gamma (100 U/mL) was also inhibited by cyclosporin A cotreatment. Another inhibitor of calcineurin, FK506 (up to 10^-6 mol/L), had no effect on the induction of nitrite/nitrate production, suggesting the possibility that the inhibitory effect of cyclosporin A may be exerted by means of a novel pathway other than inhibition of calcineurin. These results indicate that cyclosporin A inhibits inducible nitric oxide synthase induction at the mRNA level and that inducible nitric oxide synthase in vascular smooth muscle cells can be a target for cyclosporin A, providing a possible mechanism for the interference of the drug with the balance of vasoactive substances.

Key Words: cyclosporine • nitric oxide • interleukin-1 • tumor necrosis factor • interferon type II

This article has been cited by other articles:

				J. M. Foster, P. K. Carmines, and J. S. Pollock PP2B-dependent NO production in the medullary thick ascending limb during diabetes Am J Physiol Renal Physiol, August 1, 2009; 297(2): F471 - F480. [Abstract] [Full Text] [PDF]

				B.-K. Chen, C.-C. Huang, W.-C. Chang, Y.-J. Chen, U. Kikkawa, K.-i. Nakahama, I. Morita, and W.-C. Chang PP2B-mediated Dephosphorylation of c-Jun C Terminus Regulates Phorbol Ester-induced c-Jun/Sp1 Interaction in A431 Cells Mol. Biol. Cell, March 1, 2007; 18(3): 1118 - 1127. [Abstract] [Full Text] [PDF]

				S. Sano, S. Itami, and K. Yoshikawa Treatment of Primary Erythromelalgia with Cyclosporine N. Engl. J. Med., August 21, 2003; 349(8): 816 - 817. [Full Text] [PDF]

				G. LIGTENBERG, R. J. HENÉ, P. J. BLANKESTIJN, and H. A. KOOMANS Cardiovascular Risk Factors in Renal Transplant Patients: Cyclosporin A Versus Tacrolimus J. Am. Soc. Nephrol., February 1, 2001; 12(2): 368 - 373. [Abstract] [Full Text]

				J. Lee, S. W. Kim, H. Kook, D. G. Kang, N. H. Kim, and K. C. Choi Effects of L-arginine on cyclosporin-induced alterations of vascular NO/cGMP generation Nephrol. Dial. Transplant., November 1, 1999; 14(11): 2634 - 2638. [Abstract] [Full Text] [PDF]

				J. Tian and M. Karin Stimulation of Elk1 Transcriptional Activity by Mitogen-activated Protein Kinases Is Negatively Regulated by Protein Phosphatase 2B (Calcineurin) J. Biol. Chem., May 21, 1999; 274(21): 15173 - 15180. [Abstract] [Full Text] [PDF]

				Y. Takeda, I. Miyamori, K. Furukawa, S. Inaba, and H. Mabuchi Mechanisms of FK 506–Induced Hypertension in the Rat Hypertension, January 1, 1999; 33(1): 130 - 136. [Abstract] [Full Text] [PDF]

				N. A. Bobadilla, G. Gamba, E. Tapia, R. Garcia-Torres, A. Bolio, P. Lopez-Zetina, and J. Herrera-Acosta Role of NO in cyclosporin nephrotoxicity: effects of chronic NO inhibition and NO synthases gene expression Am J Physiol Renal Physiol, April 1, 1998; 274(4): F791 - F798. [Abstract] [Full Text] [PDF]

				S. Aiko, E. M. Conner, J. A. Fuseler, and M. B. Grisham Effects of Cyclosporine or FK506 in Chronic Colitis J. Pharmacol. Exp. Ther., February 1, 1997; 280(2): 1075 - 1084. [Abstract] [Full Text]

				T. Obata, A. Kashiwagi, H. Maegawa, Y. Nishio, S. Ugi, H. Hidaka, and R. Kikkawa Insulin Signaling and Its Regulation of System A Amino Acid Uptake in Cultured Rat Vascular Smooth Muscle Cells Circ. Res., December 1, 1996; 79(6): 1167 - 1176. [Abstract] [Full Text]