This Article Full Text Full Text (PDF) All Versions of this Article: 92/1/64    most recent 01.RES.0000048197.78764.D6v1 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 Flores, C. Articles by Sobrevia, L. Search for Related Content PubMed PubMed Citation Articles by Flores, C. Articles by Sobrevia, L. Related Collections Type 2 diabetes Other diabetes Glucose intolerance Endothelium/vascular type/nitric oxide Other Vascular biology

(Circulation Research. 2003;92:64.)
© 2003 American Heart Association, Inc.

Cellular Biology

Rapid Stimulation of L-Arginine Transport by D-Glucose Involves p42/44^mapk and Nitric Oxide in Human Umbilical Vein Endothelium

Carlos Flores, Susana Rojas, Claudio Aguayo, Jorge Parodi, Giovanni Mann, Jeremy D. Pearson, Paola Casanello, Luis Sobrevia

From the Cellular and Molecular Physiology Laboratory (C.F., S.R., C.A., J.P., P.C., L.S.), Department of Physiology, Faculty of Biological Sciences, and the Department of Obstetrics and Gynaecology (P.C.), Faculty of Medicine, University of Concepción, Concepción, Chile, and King’s College London (G.M., J.D.P.), Guy’s Campus, London, UK.

Correspondence to Dr L. Sobrevia, Cellular and Molecular Physiology Laboratory (CMPL), Department of Physiology, Faculty of Biological Sciences, University of Concepción, PO Box 160-C, Concepción, Chile. E-mail lsobrev{at}udec.cl

D-Glucose infusion and gestational diabetes induce vasodilatation in humans and increase L-arginine transport and nitric oxide (NO) synthesis in human umbilical vein endothelial cells. High D-glucose (25 mmol/L, 2 minutes) induced membrane hyperpolarization and an increase of L-arginine transport (V_max 6.1±0.7 versus 4.4±0.1 pmol/µg protein per minute) with no change in transport affinity (K_m 105±9 versus 111±16 µmol/L). L-[³H]Citrulline formation and intracellular cGMP, but not intracellular Ca²⁺, were increased by high D-glucose. The effects of D-glucose were mimicked by levcromakalim (ATP-sensitive K⁺ channel blocker), paralleled by p42/p44^mapk and Ser¹¹⁷⁷–endothelial NO synthase phosphorylation, inhibited by N^G-nitro-L-arginine methyl ester (L-NAME; NO synthesis inhibitor), glibenclamide (ATP-sensitive K⁺ channel blocker), KT-5823 (protein kinase G inhibitor), PD-98059 (mitogen-activated protein kinase kinase 1/2 inhibitor), and wortmannin (phosphatidylinositol 3-kinase inhibitor), but they were unaffected by calphostin C (protein kinase C inhibitor). Elevated D-glucose did not alter superoxide dismutase activity. Our findings demonstrate that the human fetal endothelial L-arginine/NO signaling pathway is rapidly activated by elevated D-glucose via NO and p42/44^mapk. This could be determinant in pathologies in which rapid fluctuations of plasma D-glucose may occur and may underlie the reported vasodilatation in early stages of diabetes mellitus.

Key Words: humans • endothelium • glucose • arginine • nitric oxide

This article has been cited by other articles:

				I. F. Schwartz, T. Chernichovski, N. Krishtol, A. Grupper, I. Laron, and D. Schwartz Sexual dimorphism in glomerular arginine transport affects nitric oxide generation in old male rats Am J Physiol Renal Physiol, July 1, 2009; 297(1): F80 - F84. [Abstract] [Full Text] [PDF]

				L. R. Queen, Y. Ji, B. Xu, L. Young, K. Yao, A. W. Wyatt, D. J. Rowlands, R. C. M. Siow, G. E. Mann, and A. Ferro Mechanisms underlying {beta}2-adrenoceptor-mediated nitric oxide generation by human umbilical vein endothelial cells J. Physiol., October 15, 2006; 576(2): 585 - 594. [Abstract] [Full Text] [PDF]

				O. Kourylko, C. Fradette, M. Arcand, and P. du Souich MODULATION OF CYP1A2 AND CYP3A6 CATALYTIC ACTIVITIES BY SERUM FROM RABBITS WITH A TURPENTINE-INDUCED INFLAMMATORY REACTION AND INTERLEUKIN 6 Drug Metab. Dispos., January 1, 2006; 34(1): 27 - 35. [Abstract] [Full Text] [PDF]

				C. J. Ray and J. M. Marshall The cellular mechanisms by which adenosine evokes release of nitric oxide from rat aortic endothelium J. Physiol., January 1, 2006; 570(1): 85 - 96. [Abstract] [Full Text] [PDF]

				H. Kinoshita, T. Azma, K. Nakahata, H. Iranami, Y. Kimoto, M. Dojo, O. Yuge, and Y. Hatano Inhibitory Effect of High Concentration of Glucose on Relaxations to Activation of ATP-Sensitive K+ Channels in Human Omental Artery Arterioscler Thromb Vasc Biol, December 1, 2004; 24(12): 2290 - 2295. [Abstract] [Full Text] [PDF]

				G. Vasquez, F. Sanhueza, R. Vasquez, M. Gonzalez, R. San Martin, P. Casanello, and L. Sobrevia Role of adenosine transport in gestational diabetes-induced L-arginine transport and nitric oxide synthesis in human umbilical vein endothelium J. Physiol., October 1, 2004; 560(1): 111 - 122. [Abstract] [Full Text] [PDF]