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      Relaxation in Different-Sized Rat BloodVessels Mediated by Endothelium-Derived Hyperpolarizing Factor: Importance of Processes Mediating Precontractions


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          To clarify the mechanisms involved in relaxations mediated by endothelium-derived hyperpolarizing factor (EDHF), acetylcholine (ACh)-induced endothelium-dependent relaxations and hyperpolarizations were examined in the rat aorta, the main branch of the mesenteric artery (MBMA) and the first branch of the mesenteric aftery (FBMA). In the presence of 100 μ M N<sup>G</sup>-nitro- L-arginine ( L-NNA) and 10 μ M indomethacin, ACh (1 n M to 100 μ M) produced no relaxation in the phenylephrine-precontracted aorta. The L-NNA-resistant relaxations by ACh in MBMA precontracted with phenylephrine were eliminated in the presence of 1 μ M nifedipine where contractions were independent of L-type Ca<sup>2+</sup> channel activation. In FBMA precontracted with phenylephrine, the L-NNA-resistant relaxations were only partially inhibited by nifedipine. When vessels had been contracted with 300 n M phorbol-12,13-dibutyrate in the presence of nifedipine, ACh-induced L-NNA-resistant relaxations were observed in FBMA only. Pinacidil produced relaxations in all different-sized blood vessels, although sensitivity was inversely related to vessel size. The extent of the ACh hyperpolarizing responses was much smaller than that by pinacidil in the aorta. The membrane potential changes by ACh and pinacidil were almost the same in FBMA. These results indicate that the contribution of EDHF to endothelium-dependent relaxations increases as the vessel size decreases. This may be partly explained by precontractile processes dependent on Ca<sup>2+</sup> entry through L-type Ca<sup>2+</sup> channels, because Ca<sup>2+</sup> channel deactivation seems to be involved as a major mechanism of EDHF-mediated vasorelaxations. However, EDHF may also generate vasorelaxations by an additional mechanism, probably a reduced Ca<sup>2+</sup> sensitivity of contractile elements, as proposed for ATP-sensitive K<sup>+</sup> channel openers.

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          The importance of the hyperpolarizing mechanism increases as the vessel size decreases in endothelium-dependent relaxations in rat mesenteric circulation.

          Endothelium-dependent relaxations are achieved by a combination of endothelium-derived prostacyclin (PGI2), nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). However, it remains to be fully clarified whether the relative contribution of these three mechanisms to endothelium-dependent relaxations varies as a function of the vessel size. This study was designed to clarify this point. Acetylcholine (ACh)-induced endothelium-dependent relaxations were examined in isolated blood vessels taken from the aorta and the proximal and distal mesenteric arteries of the rat. The contributions of PGI2, NO, and EDHF were evaluated by the inhibitory effects of indomethacin, N omega-nitro-L-arginine methyl ester (L-NAME) in the presence of indomethacin, and KCl in the presence of indomethacin and L-NAME, respectively. The membrane potentials were recorded with microelectrodes. The expression of endothelial No synthase (eNOS) was examined by both immunostaining and immunoblotting. The contribution of PGI2 was negligible in three different-sized blood vessels. The contribution of NO was most prominent in the aorta, whereas that of EDHF was most prominent in the distal mesenteric arteries. The resting membrane potential was significantly deeper and the ACh-induced hyperpolarization was greater in the distal mesenteric arteries than those in the aorta. The expression of eNOS was the highest in the aorta and the lowest in the distal mesenteric arteries. These results indicate that the importance of EDHF increases as the vessel size decreases in endothelium-dependent relaxations in the rat mesenteric circulation.
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            Hyperpolarization and relaxation of arterial smooth muscle caused by nitric oxide derived from the endothelium.

            Stimulation of the endothelial lining of arteries with acetylcholine results in the release of a diffusible substance that relaxes and hyperpolarizes the underlying smooth muscle. Nitric oxide (NO) has been a candidate for this substance, termed endothelium-derived relaxing factor. But there are several observations that argue against the involvement of NO in acetylcholine-induced hyperpolarization. First, exogenous NO has no effect on the membrane potential of canine mesenteric arteries. Second, although haemoglobin (believed to bind and inactivate NO (refs 11-15)) and methylene blue (which prevents the stimulation of guanylate cyclase) inhibit relaxation, neither has an effect on hyperpolarization. Finally, nitroprusside, thought to generate NO in vascular smooth muscle, relaxes rat aorta without increasing rubidium efflux. Nevertheless, nitrovasodilators, nitroprusside and nitroglycerin cause hyperpolarization in some arteries. NO might therefore be responsible for at least part of the hyperpolarization induced by acetylcholine. We now report that hyperpolarization and relaxation evoked by acetylcholine are reduced by NG-monomethyl-L-arginine, an inhibitor of NO biosynthesis from L-arginine. Thus NO derived from the endothelium can cause hyperpolarization of vascular smooth muscle, which might also contribute to relaxation by closing voltage-dependent calcium channels. Our findings raise the possibility that hyperpolarization might be a component of NO signal transduction in neurons or inflammatory cells.
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              Endothelium-dependent hyperpolarization: a role in the control of vascular tone


                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                August 1999
                27 August 1999
                : 36
                : 4
                : 311-320
                Departments of Pharmacology and Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan
                25659 J Vasc Res 1999;36:311–320
                © 1999 S. Karger AG, Basel

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                Page count
                Figures: 7, References: 37, Pages: 10
                Research Paper


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