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      Epoxygenase Metabolites Contribute to Nitric Oxide-Independent Afferent Arteriolar Vasodilation in Response to Bradykinin


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          In the kidney, epoxyeicosatrienoic acids (EETs) have been suggested to be endothelium-derived hyperpolarizing factors (EDHFs). The aim of the present study was to determine the contribution of EETs to the preglomerular vasodilation elicited by bradykinin. Sprague-Dawley rats were studied utilizing an in vitro perfused juxtamedullary nephron preparation. The afferent arteriolar diameter was determined and the diameter averaged 19 ± 1 µm (n = 26) at a renal perfusion pressure of 100 mm Hg. Addition of 1, 10 and 100 n M bradykinin to the perfusate dose-dependently increased afferent arteriolar diameter by 5 ± 1, 12 ± 2 and 17 ± 2%, respectively. The nitric oxide inhibitor N<sup>ω</sup>-nitro- L-arginine reduced bradykinin-induced afferent arteriolar vasodilation by 50%, and the diameter increased by 9 ± 2% in response to 100 n M bradykinin. Epoxygenase inhibitors N-methylsulphonyl-6-(2-propargyloxyphenyl)hexanamide or miconazole greatly attenuated the nitric oxide-independent component of the vasodilation elicited by bradykinin. Cyclooxygenase (COX) inhibition attenuated the nitric oxide-independent vasodilation elicited by 1 n M bradykinin but did not significantly affect the vascular response to 100 n M bradykinin. Combined inhibition of nitric oxide, COX and epoxygenase pathways completely abolished bradykinin-mediated afferent arteriolar vasodilation. In additional studies, renal microvessels were isolated and incubated with bradykinin and samples were analyzed by NICI/GC/MS. Under control conditions, renal microvascular EET levels averaged 49 ± 9 pg/mg/20 min (n = 7). In the presence of bradykinin, EET levels were significantly higher and averaged 81 ± 11 pg/mg/20 min (n = 7). These data support the concept that EETs are EDHFs and contribute to the nitric oxide-independent afferent arteriolar vasodilation elicited by bradykinin.

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          Cytochrome P450 2C is an EDHF synthase in coronary arteries.

          In most arterial beds a significant endothelium-dependent dilation to various stimuli persists even after inhibition of nitric oxide synthase and cyclo-oxygenase. This dilator response is preceded by an endothelium-dependent hyperpolarization of vascular smooth muscle cells, which is sensitive to a combination of the calcium-dependent potassium-channel inhibitors charybdotoxin and apamin, and is assumed to be mediated by an unidentified endothelium-derived hyperpolarizing factor (EDHF). Here we show that the induction of cytochrome P450 (CYP) 2C8/34 in native porcine coronary artery endothelial cells by beta-naphthoflavone enhances the formation of 11,12-epoxyeicosatrienoic acid, as well as EDHF-mediated hyperpolarization and relaxation. Transfection of coronary arteries with CYP 2C8/34 antisense oligonucleotides results in decreased levels of CYP 2C and attenuates EDHF-mediated vascular responses. Thus, a CYP-epoxygenase product is an essential component of EDHF-mediated relaxation in the porcine coronary artery, and CYP 2C8/34 fulfils the criteria for the coronary EDHF synthase.
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            Bioassay of an Endothelium-Derived Hyperpolarizing Factor from Bovine Coronary Arteries: Role of a Cytochrome P450 Metabolite

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

              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 G -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 2+ 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 2+ entry through L-type Ca 2+ channels, because Ca 2+ 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 2+ sensitivity of contractile elements, as proposed for ATP-sensitive K + channel openers.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                June 2001
                25 May 2001
                : 38
                : 3
                : 247-255
                aDepartment of Physiology, Tulane University School of Medicine, New Orleans, La., bDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Tex., cDepartment of Medicine, Vanderbilt University Medical School, Nashville, Tenn., USA
                51053 J Vasc Res 2001;38:247–255
                © 2001 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 28, Pages: 9
                Research Paper


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