The endothelium-derived hyperpolarizing factor (EDHF) to maintain vascular tone actually exists

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Vascular endothelial cells synthesize and release various vasorelaxing factors, including nitric oxide (NO) and an endothelium-derived hyperpolarizing factor (EDHF), which regulate the tonus of underlying smooth muscle cells. It is now widely accepted that EDHF, together with NO, is associated with regulation of the vascular caliber in small arteries. However, there is not yet universal agreement on the nature of EDHF, the cellular processes that mediate EDHF-mediated hyperpolarization, or its physiological and pathophysiological significance. Thus, as a first step, the present study attempted to establish a real-time analysis for measurement of EDHF-mediated hyperpolarization and relaxation in vascular smooth muscle cells. Changes of the smooth muscle cell membrane potential and contraction-relaxation response were coincidentally determined using confocal fluorescence microscopy. The findings were used to examine the characteristics of the EDHF-mediated response in mesenteric arteries of SHR/NDmcr-cp (SHR-cp) rats, a rat model of metabolic syndrome.To measure the smooth muscle cell membrane potential induced by acetylcholine in rat mesenteric arteries, they were visualized using a membrane potential-sensitive fluorescence dye, DiBAC_4. The distance between wires inserted into a vessel was determined using the NIH image as a vasorelaxation response. We found that acetylcholine induced sustained and stable hyperpolarization in the presence of nitro-L-arginine methyl ester, an inhibitor of NO synthase. Furthermore, EDHF-mediated hyperpolarization and vasorelaxation in mesenteric arteries of SHR-cp rats were reduced compared with those of Wistar-Kyoto rats. In contrast, NO-mediated relaxation was increased in SHR-cp rats. These findings suggest that impairment of the EDHF-mediated response occurs in metabolic syndrome, and that the possibility of a back-up mechanism between NO and EDHF has important pathophysiological implications.