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      Involvement of NO and EDHF in Flow-Induced Vasodilation in Isolated Hamster Cremasteric Arterioles

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          Flow-induced vasodilation in hamster cremasteric arterioles was investigated with special reference to the roles of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). Arterioles (∼60 µm resting diameter) were cannulated, and suffused with MOPS solution at 37°C (mean intraluminal pressure: 80 cm H<sub>2</sub>O). Step increases in the perfusate flow elicited a dose-dependent vasodilation, which was almost proportional to the increases in calculated wall shear stress (WSS). N<sup>ω</sup>-nitro L-arginine methyl ester ( L-NAME, 100 µ M) reduced the flow-induced vasodilation by ∼50%, whereas indomethacin (10 µ M) produced no significant effect. In the presence of L-NAME, the residual vasodilation was eliminated by treatment with the cytochrome P-450 monooxygenase inhibitor 17-octadecynoic acid (17-ODYA, 50 µ M), sulfaphenazol (10 µ M), tetraethylammonium (TEA, 3 m M; a nonselective Ca<sup>2+</sup>-activated K<sup>+</sup> channel inhibitor), or charybdotoxin (ChTX, 0.1 µ M; intermediate or large conductance Ca<sup>2+</sup>-activated K<sup>+</sup> channel inhibitor). In the absence of L-NAME, the dilation was also reduced by ∼50% by treatment with 17-ODYA, TEA, or ChTX. The residual vasodilation was eliminated by additional treatment with L-NAME. The inhibitor of ATP-sensitive K<sup>+</sup> channels (K<sub>ATP</sub>), glibenclamide, also caused a significant, but partial, reduction of the flow-induced vasodilation. The residual vasodilation was completely reduced by additional treatment with 17-ODYA, but not L-NAME. These findings suggest that in hamster cremaster, higher flow rate produces NO, K<sub>ATP</sub>, and EDHF vasodilation of the arterioles under physiological conditions.

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          Most cited references 9

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          EDHF: bringing the concepts together

          Endothelial cells synthesize and release vasoactive mediators in response to various neurohumoural substances (e.g. bradykinin or acetylcholine) and physical stimuli (e.g. cyclic stretch or fluid shear stress). The best-characterized endothelium-derived relaxing factors are nitric oxide and prostacyclin. However, an additional relaxant pathway associated with smooth muscle hyperpolarization also exists. This hyperpolarization was originally attributed to the release of an endothelium-derived hyperpolarizing factor (EDHF) that diffuses to and activates smooth muscle K(+) channels. More recent evidence suggests that endothelial cell receptor activation by these neurohumoural substances opens endothelial cell K(+) channels. Several mechanisms have been proposed to link this pivotal step to the subsequent smooth muscle hyperpolarization. The main concepts are considered in detail in this review.
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            Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator.

            Flow-mediated vasodilation is endothelium dependent. We hypothesized that flow activates a potassium channel on the endothelium, and that activation of this channel leads to the release of the endogenous nitrovasodilator, nitric oxide. To test this hypothesis, rabbit iliac arteries were perfused at varying flow rates, at a constant pressure of 60 mm Hg. Increments in flow induced proportional increases in vessel diameter, which were abolished by L,N-mono-methylarginine (the antagonist of nitric-oxide synthesis). Barium chloride, depolarizing solutions of potassium, verapamil, calcium-free medium, and antagonists of the KCa channel (charybdotoxin, iberiotoxin) also blocked flow-mediated vasodilation. Conversely, responses to other agonists of endothelium-dependent and independent vasodilation were unaffected by charybdotoxin or iberiotoxin. To confirm that flow activated a specific potassium channel to induce the release of nitric oxide, endothelial cells cultured on micro-carrier beads were added to a flow chamber containing a vascular ring without endothelium. Flow-stimulated endothelial cells released a diffusible vasodilator; the degree of vasorelaxation was dependent upon the flow rate. Relaxation was abrogated by barium, tetraethylammonium ion, or charybdotoxin, but was not affected by apamin, glybenclamide, tetrodotoxin, or ouabain. The data suggest that transmission of a hyperpolarizing current from endothelium to the vascular smooth muscle is not necessary for flow-mediated vasodilation. Flow activates a potassium channel (possibly the KCa channel) on the endothelial cell membrane that leads to the release of nitric oxide.
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              Endothelium-dependent smooth muscle hyperpolarization: do gap junctions provide a unifying hypothesis?

               M. Griffith (2004)
              An endothelium-derived hyperpolarizing factor (EDHF) that is distinct from nitric oxide (NO) and prostanoids has been widely hypothesized to hyperpolarize and relax vascular smooth muscle following stimulation of the endothelium by agonists. Candidates as diverse as K(+) ions, eicosanoids, hydrogen peroxide and C-type natriuretic peptide have been implicated as the putative mediator, but none has emerged as a 'universal EDHF'. An alternative explanation for the EDHF phenomenon is that direct intercellular communication via gap junctions allows passive spread of agonist-induced endothelial hyperpolarization through the vessel wall. In some arteries, eicosanoids and K(+) ions may themselves initiate a conducted endothelial hyperpolarization, thus suggesting that electrotonic signalling may represent a general mechanism through which the endothelium participates in the regulation of vascular tone.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                April 2005
                13 April 2005
                : 42
                : 2
                : 137-147
                aDepartment of Physiology, Shinshu University School of Medicine, Matsumoto, bDivision of Internal Medicine, Fujimi-Kogen Hospital, Fujimi-cho, Suwa, Japan
                83652 J Vasc Res 2005;42:137–147
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 8, References: 36, Pages: 11
                Research Paper


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