Effects of cytochrome P450 inhibitors on EDHF‐mediated relaxation in the rat hepatic artery

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

doi:10.1111/j.1476-5381.1996.tb15517.x

Cited by 85 publications

(77 citation statements)

References 32 publications

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“…Moreover, EDHF-mediated responses in renal arteries from SHR were markedly less sensitive to the gap peptides than were vessels from WKY rats (Büssemaker, unpublished observations). Although cytochrome P450 epoxygenases play a crucial role in EDHFmediated responses in some species, several studies, 35,36 including one performed using rat renal arteries, 37 have reported that the EDHF-mediated relaxation of vessels from WKY and Sprague-Dawley rats does not require the activation of a cytochrome P450 enzyme. Cytochrome P450 epoxygenases can, however, be induced by several pathways associated with the induction of hypertension.…”

Section: Discussionmentioning

confidence: 99%

Aged Spontaneously Hypertensive Rats Exhibit a Selective Loss of EDHF-Mediated Relaxation in the Renal Artery

et al. 2003

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Abstract-Endothelium-dependent relaxation is frequently attenuated in hypertension. We hypothesized that the contribution of the endothelium-derived hyperpolarizing factor (EDHF) to the acetylcholine (ACh)-induced, endotheliumdependent relaxation is attenuated with aging in the renal artery of spontaneously hypertensive rats (SHR) compared with age-matched Wistar-Kyoto (WKY) rats. ACh-induced, NO-mediated relaxation was identical in young (8-weekold) WKY and SHR, whereas EDHF-mediated relaxations (assessed in the presence of N -nitro-L-arginine and diclofenac) were much more pronounced in SHR than WKY. KCl-induced relaxations were more pronounced in vessels from young WKY rats than from young SHR. The cytochrome P450 inhibitor sulfaphenazole significantly inhibited EDHF-mediated relaxation in vessels from young SHR but not WKY. Vessels from old (22 months) SHR exhibited a slightly reduced NO-mediated relaxation but a complete loss of EDHF-mediated responses. In contrast, aging did not affect EDHF-mediated responses in WKY. Moreover, ACh-induced hyperpolarization and resting membrane potential were decreased in old SHR but not in WKY. KCl-induced relaxation increased with age in WKY, whereas no response to KCl was recorded in arteries from aged SHR. In vessels from old WKY but not old SHR, mRNA expression of the Na-K-ATPase subunit ␣ 2 was increased by 2-fold compared with young animals. These data indicate that the increase in EDHF responses in renal arteries from aged WKY can be attributed to the release of K ϩ ions from the endothelium, whereas increased EDHF responses in renal arteries from young SHR can be attributed to a sulfaphenazole-sensitive cytochrome P450-dependent EDHF. Key Words: endothelium Ⅲ nitric oxide Ⅲ acetylcholine Ⅲ endothelium-derived factors Ⅲ animal models of hypertension Ⅲ renal artery T hree different endothelium-derived vasodilators, prostacyclin, nitric oxide (NO), and the endothelium-derived hyperpolarizing factor (EDHF), play an important role in the control of local vascular tone. 1 In hypertension, endotheliumdependent relaxation is attenuated (a phenomenon referred to as endothelial dysfunction) and contributes to the increased peripheral resistance. 2,3 Moreover, treatment of hypertension improves endothelium-dependent relaxation by increasing the NO-mediated and the EDHF-mediated relaxation. 4,5 Endothelial dysfunction in hypertension has been linked to a decrease in NO bioavailability reflecting the impaired generation of NO and/or the enhanced scavenging and inactivation of NO by oxygen-derived free radicals. 6,7 The mechanisms leading to the attenuation of EDHF-mediated relaxations in hypertension are poorly understood but are reportedly unrelated to enhanced vascular oxidative stress. 8 Part of the problem in addressing the factors affecting EDHF-mediated responses is that more than one EDHF may exist and that different hyperpolarizing mechanisms dominate in different arteries. There is a general consensus that EDHFmediated effects are exquisitely sensitive to the combinati...

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Section: Discussionmentioning

confidence: 99%

Aged Spontaneously Hypertensive Rats Exhibit a Selective Loss of EDHF-Mediated Relaxation in the Renal Artery

et al. 2003

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“…In the rat hepatic artery, the possibility that EDHF could be an EET was excluded by the failure of synthetic EETs to relax the tissue and by the inability of 17-ODYA (an inhibitor of the EET-generating pathway) to antagonize EDHF-induced relaxations (Zygmunt et al, 1996a). Furthermore, proadifen and clotrimazole antagonized levcromakalim-induced relaxations in the rat hepatic artery (Zygmunt et al, 1996a) and inhibited K-currents in rat portal vein (Zygmunt et al, 1996b), a tissue in which there are no reports of EDHF as an endogenous factor.…”

Section: Discussionmentioning

confidence: 99%

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

Edwards

Zygmunt

Högestätt

et al. 1996

British J Pharmacology

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1 The effects of the cytochrome P450 inhibitors, proadifen, clotrimazole and 17-octadecynoic acid (17-ODYA) on K-currents in freshly-isolated single cells derived from rat portal vein and on mechanical activity in whole veins were studied. 2 When cells were stepped from -90 mV to a series of test potentials (from -80 to +50 mV), a delayed rectifier current (IKV) and an A-type current (IK(A)) could be identified. Proadifen (10 yM), clotrimazole (30 gM) and 17-ODYA (5 uM) each inhibited IKV but had little effect on IK(A)-3 When cells were held at -10 mV to inactivate the time-dependent K-currents, IKW) and IK(A), levcromakalim (3 gM) induced a time-independent outward K-current (IK(ATP)) which was totally inhibited by clotrimazole (30 gM) and almost fully inhibited by proadifen (10 yM). 17-ODYA (5 pM) had no effect on IK(ATP) and exerted only a minor inhibitory action on this current at 20 /M. 4 17-ODYA (5 gM) potentiated current flow through the large conductance, Ca-sensitive K-channel (BKCa). In contrast, proadifen (10 gM) had no effect on IBK(Ca) whereas clotrimazole (30 gM) exerted a small but significant inhibitory action.5 Proadifen (10 gM) and clotrimazole (30 gM) each inhibited the magnitude but increased the frequency of spontaneous contractions in whole portal veins. 17-ODYA (5 pM) had no effect on spontaneous contractions but these were inhibited when the concentration of 17-ODYA was increased to 50 gM. 6 The spasmolytic effect of levcromakalim on spontaneous contractions was antagonized by proadifen (10-30 pM) in a concentration-dependent manner but 17-ODYA (up to 50 pM) was without effect. 7 These results in portal vein show that cytochrome P450 inhibitors exert profound effects on a variety of K-channel subtypes. This suggests that enzymes dependent on this cofactor may be important regulators of K-channel activity in smooth muscle. The relevance of these findings for the identification of the pathway involved in the synthesis of the endothelium-derived hyperpolarizing factor is discussed.

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“…Narins et al also found that in patients with stable CAD, adverse outcomes were more prevalent in patients with painful vs silent ischemia. 99 In a separate low-risk group of 116 medically managed patients with CAD, 39% had ambulatory evidence of ischemic ST segment depression, with 82% being silent. However, the incidence of cardiac events was not increased in the group with silent ischemia.…”

Section: Prognostic Significance Of Silent Myocardial Ischemiamentioning

confidence: 99%

Silent Myocardial Ischemia

Gutterman

2009

Circ J

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Although much progress has been made in reducing mortality from ischemic cardiovascular disease, this condition remains the leading cause of death throughout the world. This might in part be due to the fact that over half of patients have a catastrophic event (heart attack or sudden death) as their initial manifestation of coronary disease. Contributing to this statistic is the observation that the majority of myocardial ischemic episodes are silent, indicating an inability or failure to sense ischemic damage or stress on the heart. This review examines the clinical characteristics of silent myocardial ischemia, and explores mechanisms involved in the generation of angina pectoris. Possible mechanisms for the more common manifestation of injurious reductions in coronary flow; namely, silent ischemia, are also explored. A new theory for the mechanism of silent ischemia is proposed. Finally, the prognostic importance of silent ischemia and potential future directions for research are discussed. (Circ J 2009; 73: 785 -797)

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Effects of cytochrome P450 inhibitors on EDHF‐mediated relaxation in the rat hepatic artery

Cited by 85 publications

References 32 publications

Aged Spontaneously Hypertensive Rats Exhibit a Selective Loss of EDHF-Mediated Relaxation in the Renal Artery

Aged Spontaneously Hypertensive Rats Exhibit a Selective Loss of EDHF-Mediated Relaxation in the Renal Artery

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

Silent Myocardial Ischemia

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