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The results suggest that CGRP may work as an endogenous protective substance to counteract EPCs senescence in hypertension and the accelerated EPCs senescence in hypertension was related to the reduction of CGRP.

In the present study, we tested whether the decreased release of calcitonin gene-related peptide (CGRP) observed in nitroglycerin tolerance is associated with the decrease in aldehyde dehydrogenase (ALDH-2) activity. We further investigated the possible involvement of reactive oxygen species in the decrease in ALDH-2 activity. Tolerance was induced by exposure of isolated rat thoracic aortas and human umbical vein endothelial cells (HUVEC) to nitroglycerin in vitro or by pretreatment with nitroglycerin for 8 days in vivo. Pretreatment with ALDH-2 inhibitors and nitroglycerin significantly attenuated vasodilator responses to nitroglycerin concomitantly with a decrease in the release of CGRP from the isolated thoracic aorta. Nitroglycerin produced a depressor effect concomitantly with an increase in plasma concentrations of CGRP, and the effect of nitroglycerin was attenuated after pretreatment with an inhibitor of ALDH-2 or nitroglycerin for 8 days. Exposure of HUVEC to nitroglycerin for 16 h increased reactive oxygen species production and decreased ALDH-2 activity as well as cGMP production in a time-and concentration-dependent manner. Pretreatment with an ALDH-2 inhibitor also significantly decreased the cGMP production. However, tolerance to nitroglycerin in HUVEC was restored in the presence of N-acetylcysteine or captopril. The present results suggest that nitrate tolerance is, at least partially, associated with a decrease in endogenous CGRP release via a decrease in ALDH-2 activity as a result of stimulation of reactive oxygen species production.

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.