Reduction of NO- and EDHF-mediated vasodilatation in hypertension: role of asymmetric dimethylarginine.

Abstract

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase (NOS), and endothelial dysfunction is related to the elevation of ADMA level in hypertension. Besides the NO-mediated pathway, the endothelium-derived hyperpolarizing factor (EDHF)-mediated pathway is involved in endothelial dysfunction. The aims of the present study were to evaluate the changes of endothelium-dependent dilatation of arteries in hypertension and the role of ADMA in NO- and EDHF-mediated vasodilatation. The great omental arteries were isolated from essential hypertensive and normotensive patients, and mesenteric arteries were isolated from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. NO-, EDHF-, and prostaglandin (PGI(2))-mediated endothelium-dependent vasodilatation were measured, and plasma concentrations of ADMA were determined in rats. Cultured endothelial cells were treated with ADMA (1-10 microM) for 48 h, and the mRNA and protein level of small-conductance Ca(2+)-activated K(+) channel 3 (SK3), which has been thought to be a key mediator of EDHF, was determined. Both NO- and EDHF-mediated endothelium-dependent responses were decreased in the great omental arteries of hypertensive patients and mesenteric arteries of SHR. Plasma levels of ADMA were significantly increased in SHR. In cultured endothelial cells, the expressions of SK3 mRNA and protein were concentration-dependently down-regulated in the presence of ADMA. The present study suggests that the inhibitory effect of ADMA on endothelial function not only involves NO-mediated endothelium-dependent vasodilatation but also the EDHF-mediated pathways in hypertensive animals and humans, and that ADMA can down-regulate the expression of SK3 channels in endothelial cells.

• Authors: Jie Li, Zhi Zhou, De-Jian Jiang, Dai Li, Bin Tan, Hao Liu, Yuan-Jian Li
• Journal: Clinical and experimental hypertension (New York, N.Y. : 1993) (Clin Exp Hypertens) Vol. 29 Issue 7 Pg. 489-501 (Oct 2007) ISSN: 1064-1963 [Print] England
• PMID: 17994357 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biological Factors
• KCNN3 protein, human
• Kcnn3 protein, rat
• Potassium Channels, Calcium-Activated
• Small-Conductance Calcium-Activated Potassium Channels
• endothelium-dependent hyperpolarization factor
• Nitric Oxide
• N,N-dimethylarginine
• Arginine
• Epoprostenol
• Nitric Oxide Synthase

Topics

• Animals
• Arginine (analogs & derivatives, pharmacology)
• Biological Factors (metabolism)
• Cell Culture Techniques
• Down-Regulation
• Epoprostenol (pharmacology)
• Female
• Humans
• Hypertension (metabolism)
• Male
• Mesenteric Arteries (metabolism)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase (metabolism)
• Potassium Channels, Calcium-Activated (metabolism)
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Small-Conductance Calcium-Activated Potassium Channels (metabolism)
• Vasodilation (physiology)