Circulation Research, Vol 73, 808-812, Copyright © 1993 by American Heart Association

ARTICLES

Negative feedback regulation of endothelial cell function by nitric oxide

GM Buga, JM Griscavage, NE Rogers and LJ Ignarro
Department of Pharmacology, University of California, School of Medicine, Los Angeles.

The objective of this study was to determine whether nitric oxide (NO) could function as a negative feedback modulator of endothelial cell function by inhibiting NO synthase in vascular endothelial cells. The rationale for this approach was a previous study from this laboratory, which revealed that NO inhibits neuronal NO synthase from rat cerebellum. In the present study, NO and NO-donor agents noncompetitively inhibited NO synthase derived from bovine aortic endothelial cells. Oxyhemoglobin blocked the inhibitory action of NO and by itself increased NO synthase activity. This finding suggests that NO acts as a negative feedback modulator of NO synthase. In intact aortic endothelial cells grown on microcarrier beads and perfused in a bioassay cascade system, pretreatment of cells with NO-donor agents caused a marked inhibition of endothelial NO biosynthesis in response to bradykinin and increased fluid shear or flow. When isolated bovine pulmonary arterial rings precontracted by phenylephrine were used, pretreatment of arterial rings with NO-donor agents diminished endothelium-dependent arterial relaxation involving the L-arginine-NO pathway without altering endothelium-independent relaxation to NO itself. On the basis of these studies, NO is suggested to play an important negative feedback regulatory role on endothelial NO synthase and, therefore, vascular endothelial cell function.

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				P. Pancera, P. Minuz, L. Rossi, M. Ribul, E. Arosio, A. Lechi, and P. Pancera Postischemic Hyperemia in Subjects with Lower Limbs Obstructive Arteriopathy: Role of PGI2 and Endothelin Angiology, February 1, 1997; 48(2): 149 - 155. [Abstract] [PDF]

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				R. Draijer, A. B. Vaandrager, C. Nolte, H. R. de Jonge, U. Walter, and V. W.M. van Hinsbergh Expression of cGMP-Dependent Protein Kinase I and Phosphorylation of Its Substrate, Vasodilator-Stimulated Phosphoprotein, in Human Endothelial Cells of Different Origin Circ. Res., November 1, 1995; 77(5): 897 - 905. [Abstract] [Full Text]

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				D. Ungureanu-Longrois, J.-L. Balligand, W. W. Simmons, I. Okada, L. Kobzik, C. J. Lowenstein, S. L. Kunkel, T. Michel, R. A. Kelly, and T. W. Smith Induction of Nitric Oxide Synthase Activity by Cytokines in Ventricular Myocytes Is Necessary but Not Sufficient to Decrease Contractile Responsiveness to ß-Adrenergic Agonists Circ. Res., September 1, 1995; 77(3): 494 - 502. [Abstract] [Full Text]

				A. J. Kanai, H. C. Strauss, G. A. Truskey, A. L. Crews, S. Grunfeld, and T. Malinski Shear Stress Induces ATP-Independent Transient Nitric Oxide Release From Vascular Endothelial Cells, Measured Directly With a Porphyrinic Microsensor Circ. Res., August 1, 1995; 77(2): 284 - 293. [Abstract] [Full Text]

				A. F. Dominiczak and D. F. Bohr Nitric Oxide and Its Putative Role in Hypertension Hypertension, June 1, 1995; 25(6): 1202 - 1211. [Full Text]

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				B. Mayer, P. Klatt, E. R. Werner, and K. Schmidt Kinetics and Mechanism of Tetrahydrobiopterin-induced Oxidation of Nitric Oxide J. Biol. Chem., January 13, 1995; 270(2): 655 - 659. [Abstract] [Full Text] [PDF]

				F. Mohamed, J. C. Monge, A. Gordon, P. Cernacek, D. Blais, and D. J. Stewart Lack of Role for Nitric Oxide (NO) in the Selective Destabilization of Endothelial NO Synthase mRNA by Tumor Necrosis Factor–{alpha} Arterioscler Thromb Vasc Biol, January 1, 1995; 15(1): 52 - 57. [Abstract] [Full Text]

				J. Heger, A. Godecke, U. Flogel, M. W. Merx, A. Molojavyi, W. N. Kuhn-Velten, and J. Schrader Cardiac-Specific Overexpression of Inducible Nitric Oxide Synthase Does Not Result in Severe Cardiac Dysfunction Circ. Res., January 11, 2002; 90(1): 93 - 99. [Abstract] [Full Text] [PDF]