Effects of cytochrome P450 inhibitors on potassium currents and mechanical activity in rat portal vein

Edwards, Gillian; Zygmunt, Peter M.; Högestätt, Edward D.; Weston, A.H.

doi:10.1111/j.1476-5381.1996.tb15728.x

Cited by 61 publications

(34 citation statements)

References 32 publications

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“…96 Additionally, in numerous vascular preparations from various species, EETs evoke no or minor relaxations and/or hyperpolarization, indicating that in these arteries non-NO-non-PGI 2 -mediated responses are unlikely to rely on this metabolite of arachidonic acid. 7 The lack of selectivity of the available tools 97,98 has made it difficult to determine whether the activation of the endothelial potassium channels IK Ca and/or SK Ca or the release of EETs underlies non-NO-non-PGI 2 -mediated responses. For instance, clotrimazole, a reference inhibitor of cytochrome P450 epoxygenases, also blocks IK Ca .…”

Section: Other Identified Endothelium-derived Hyperpolarizing Substancesmentioning

confidence: 99%

Endothelium-Derived Hyperpolarizing Factor

Félétou

Vanhoutte

2006

ATVB

423

274

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Abstract-The endothelium controls vascular tone not only by releasing nitric oxide (NO) and prostacyclin but also by other pathways causing hyperpolarization of the underlying smooth muscle cells. This characteristic was at the origin of the denomination endothelium-derived hyperpolarizing factor (EDHF). We know now that this acronym includes different mechanisms. In general, EDHF-mediated responses involve an increase in the intracellular calcium concentration, the opening of calcium-activated potassium channels of small and intermediate conductance and the hyperpolarization of the endothelial cells. This results in an endothelium-dependent hyperpolarization of the smooth muscle cells, which can be evoked by direct electrical coupling through myo-endothelial junctions and/or the accumulation of potassium ions in the intercellular space. Potassium ions hyperpolarize the smooth muscle cells by activating inward rectifying potassium channels and/or Na ϩ /K ϩ -ATPase. In some blood vessels, including large and small coronary arteries, the endothelium releases arachidonic acid metabolites derived from cytochrome P450 monooxygenases. The epoxyeicosatrienoic acids (EET) generated are not only intracellular messengers but also can diffuse and hyperpolarize the smooth muscle cells by activating large conductance calcium-activated potassium channels. Additionally, the endothelium can produce other factors such as lipoxygenases derivatives or hydrogen peroxide (H 2 O 2 ). These different mechanisms are not necessarily exclusive and can occur simultaneously.

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Section: Other Identified Endothelium-derived Hyperpolarizing Substancesmentioning

confidence: 99%

Endothelium-Derived Hyperpolarizing Factor

Félétou

Vanhoutte

2006

ATVB

423

274

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“…The differences among the studies in human subcutaneous arteries may result from different CYP450 inhibitors used, which have their own limitations. For example, it has been shown that nonspecific inhibitors of CYP450 such as micanazole and other imidazoles may also block K ϩ channels (14) or impair the agonist-induced increase in intracellular Ca 2ϩ in endothelial cells (20). This could prevent EDHF-mediated effects on smooth muscle rather than affecting the synthesis/release of EDHF itself.…”

Section: Role For Aa Metabolites In Edhf-mediated Responsesmentioning

confidence: 99%

The mechanism of EDHF-mediated responses in subcutaneous small arteries from healthy pregnant women

Luksha¹,

Nisell²,

Kublickiene³

2004

American Journal of Physiology-Regulatory, Integrative and Comp

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Luksha, Leonid, Henry Nisell, and Karolina Kublickiene. The mechanism of EDHF-mediated responses in subcutaneous small arteries from healthy pregnant women. Am J Physiol Regul Integr Comp Physiol 286: R1102-R1109, 2004. First published January 29, 2004 10.1152/ajpregu.00550.2003.-We studied the importance of endothelium-derived hyperpolarizing factor (EDHF) vs. nitric oxide (NO) and prostacyclin (PGI2) in bradykinin (BK)-induced relaxation in isolated small subcutaneous arteries from normal pregnant women. We also explored the contribution of cytochrome P-450 (CYP450) product of arachidonic acid (AA) metabolism, hydrogen peroxide (H2O2), and gap junctions that have been suggested to be involved in EDHF-mediated responses. Isolated arteries obtained from subcutaneous fat biopsies of normal pregnant women (n ϭ 30) undergoing planned cesarean section were mounted in a wire-myography system. In norepinephrine-constricted vessels, incubation with N G -nitro-Larginine methyl ester (L-NAME) resulted in a significant reduction in relaxation to BK. Simultaneous incubation with L-NAME and indomethacin failed to modify this response further. BK-mediated dilatation in the presence of K ϩ -modified solution was decreased to similar level as obtained after incubation with L-NAME. Incubation with L-NAME abolished BK-induced responses in K ϩ -modified solution. Sulfaphenazole, a specific inhibitor of CYP450 epoxygenase, and catalase (an enzyme that decomposes H2O2) did not affect the EDHFmediated relaxation because concentration-response curves to BK were similar in arteries after incubation with L-NAME vs. L-NAME ϩ sulfaphenazole and L-NAME ϩ catalase. The inhibitor of gap junctions, 18␣-glycyrrhetinic acid, significantly reduced BK-mediated relaxation both without and with incubation with L-NAME. We found that both NO and EDHF, but not PGI2, are involved in the endothelium-dependent dilatation to BK. BK-induced relaxation is almost equally mediated by NO and EDHF. CYP450 epoxygenase metabolites of AA or H2O2 do not account for EDHF-mediated response; however, gap junctions are involved in the EDHF-mediated responses to BK in subcutaneous small arteries in normal pregnancy. endothelium-dependent relaxation; gap junctions; endothelium-derived hyperpolarizing factor; hydrogen peroxide MATERNAL CARDIOVASCULAR ADAPTATION to normal pregnancy is associated with decreased peripheral vascular resistance that plays an important role for blood pressure reduction despite an increase in plasma volume and cardiac output. The vascular adaptation to normal pregnancy is believed to be dependent on an enhanced endothelium-dependent dilatation (3,18,25). However, the pathways underlying these changes are not fully understood and need further investigation because an impaired cardiovascular adaptation is associated with the development of preeclampsia (18,25,42). It is generally accepted that preeclampsia is an endothelial cell disorder, and the increased vascular resistance and blood pressure during this pregnancyrelated disease are due to en...

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“…Indeed, the production of EDHF from coronary arteries can be inhibited by the suicide P450 inhibitor, 17-octadecynoic acid in bioassay experiments [29, 31]. It is however likely that more than one EDHF exists since the hyperpolarizing factor released from the rabbit aorta [32], guinea pig carotid [33] and rat mesenteric and hepatic arteries [34, 35] or the rat portal vein [36] exhibits very different pharmacological characteristics to that of the ‘coronary EDHF’. Recently, a specific cannabinoid receptor (CB1) antagonist has been shown to attenuate EDHF-induced relaxation of isolated rat mesenteric vessels while anandamide (arachidonoylethanolamide), an endogenous ligand for central cannabinoid receptors [37, 38], elicited EDHF-like relaxations [39].…”

Section: Endothelium-derived Autacoidsmentioning

confidence: 99%

Pulsatile Stretch and Shear Stress: Physical Stimuli Determining the Production of Endothelium-Derived Relaxing Factors

Busse

Fleming²

1998

J Vasc Res

227

155

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Mechanical forces generated at the endothelium by fluid shear stress and pulsatile stretch are important in ensuring the continuous release of vasoactive endothelial autacoids. Although the mechanism by which endothelial cells are able to detect and convert these physical stimuli into chemical signals is unclear, this process involves the activation of integrins, G proteins and cascades of protein kinases. The constitutive endothelial nitric oxide synthase (NOS III), classified as a Ca²⁺/calmodulin-dependent isoform, can be activated by shear stress and isometric contraction in the absence of a maintained increase in [Ca²⁺]_i via a mechanism involving its redistribution within the cytoskeleton/caveolae and the activation of one or more regulatory NOS-associated proteins. Thus it would appear that the intracellular cascades activated by Ca²⁺-elevating receptor-dependent agonists, such as bradykinin, and hemodynamic stimuli are distinct. Rhythmic vessel distension is also able to elicit the synthesis of superoxide anions and the endothelium-derived hyperpolarizing factor which play a role in modulating arterial compliance in certain vascular beds.

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Effects of cytochrome P450 inhibitors on potassium currents and mechanical activity in rat portal vein

Cited by 61 publications

References 32 publications

Endothelium-Derived Hyperpolarizing Factor

Endothelium-Derived Hyperpolarizing Factor

The mechanism of EDHF-mediated responses in subcutaneous small arteries from healthy pregnant women

Pulsatile Stretch and Shear Stress: Physical Stimuli Determining the Production of Endothelium-Derived Relaxing Factors

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