Inhibitors of the cytochrome P450‐mono‐oxygenase and endothelium‐dependent hyperpolarizations in the guinea‐pig isolated carotid artery

Corriu, Catherine; Félétou, Michel; Canet, Emmanuel; Vanhoutte, Paul M.

doi:10.1111/j.1476-5381.1996.tb15233.x

Cited by 95 publications

(59 citation statements)

References 19 publications

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“…Weintraub et al reported that the nature of acetylcholine-induced EDHF in porcine coronary arteries may not be a metabolite of cyclooxygenase or cytochrome P450 monooxygenase (27). Corriu et al reached the same conclusion with the guinea pig carotid artery (28). In the present study, bradykinin-induced relaxations and hyperpolarizations were not affected by cytochrome P450 inhibitor, SKF 525a.…”

Section: Discussionsupporting

confidence: 75%

“…Previous studies demonstrated that the endothelium-dependent relaxations and hyperpolarizations in the presence of inhibitors of PGI 2 and NO synthesis are markedly suppressed by K channel inhibitors (10)(11)(12)(13)(14)(15)(16)28). However, no consensus has been made regarding the subtype of K channel that mediates EDHF-induced hyperpolarization.…”

Section: Discussionmentioning

confidence: 93%

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Importance of endothelium-derived hyperpolarizing factor in human arteries.

Shimokawa²,

et al. 1997

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The endothelium plays an important role in maintaining the vascular homeostasis by releasing vasodilator substances, including prostacyclin (PGI 2 ), nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). Although the former two substances have been investigated extensively, the importance of EDHF still remains unclear, especially in human arteries. Thus we tested our hypothesis that EDHF plays an important role in human arteries, particularly with reference to the effect of vessel size, its vasodilating mechanism, and the influences of risk factors for atherosclerosis.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 93%

Importance of endothelium-derived hyperpolarizing factor in human arteries.

Shimokawa²,

et al. 1997

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“…Moreover, evidence has been reported suggesting that the process of relaxation involves hyperpolarization of endothelial cells (Edwards et al, 1998; and consequent gap junctional transmission between endothelium and smooth muscle, resulting in smooth muscle hyperpolarization and relaxation (Davies et al, 1988;Beny, 1990;Chaytor et al, 1998). Regardless of the con¯icting evidence for the proposed candidates, there is consensus that EDHF responses are mediated by an increase in K + conductance and thus are sensitive to depolarizing solutions of K + (Adeagbo & Triggle, 1993;Corriu et al, 1996a) and by inhibitors of certain types of K + channels. The possibility that acetylcholine-and bradykinin-induced vasodilator responses in the bovine eye were produced by an EDHF was therefore investigated further.…”

Section: Discussionmentioning

confidence: 99%

Dominant role of an endothelium‐derived hyperpolarizing factor (EDHF)‐like vasodilator in the ciliary vascular bed of the bovine isolated perfused eye

McNeish

Wilson

Martin

2001

British J Pharmacology

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1 The roles of the endothelium-derived nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor (EDHF) in mediating vasodilator responses to acetylcholine and bradykinin were assessed in the ciliary vascular bed of the bovine isolated perfused eye preparation. 2 Vasodilatation to acetylcholine or bradykinin was una ected by the nitric oxide synthase inhibitor, L-NAME (100 mM), or the cyclo-oxygenase inhibitor,¯urbiprofen (30 mM), but was virtually abolished following treatment with a high concentration of KCl (30 mM), or by damaging the endothelium with the detergent, CHAPS (0.3%, 2 min). 3 Acetylcholine-induced vasodilatation was una ected by glibenclamide (10 mM), an inhibitor of ATP-sensitive K + channels (K + ATP ), but was signi®cantly attenuated by TEA (10 mM), a nonselective inhibitor of K + channels. 4 The small conductance calcium-sensitive K + channel (SK + Ca ) inhibitor, apamin (100 nM), and the large conductance calcium-sensitive K + channel (BK + Ca ) inhibitor, iberiotoxin (50 nM), had no signi®cant e ect on acetylcholine-induced vasodilatation. In contrast, the intermediate (IK + Ca )/large conductance calcium-sensitive K + channel inhibitor, charybdotoxin (50 nM), powerfully blocked these vasodilator responses, and uncovered a vasoconstrictor response. 5 The combination of apamin (100 nM) with a sub-threshold concentration of charybdotoxin (10 nM) signi®cantly attenuated acetylcholine-induced vasodilatation, but the combination of apamin (100 nM) with iberiotoxin (50 nM) had no e ect. 6 In conclusion, blockade by a high concentration of KCl, by charybdotoxin, or by the combination of apamin with a sub-threshold concentration of charybdotoxin, strongly suggests that vasodilatation in the bovine isolated perfused eye is mediated by an EDHF. British Journal of Pharmacology (2001) 134, 912 ± 920

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“…In some studies, inhibitors of cytochrome P-450 block the relaxations to bradykinin and acetylcholine, whereas in other studies, these inhibitors are without effect or also inhibit relaxations to K ϩ channel activators, such as cromakalim or pinacidil. 1,2,4,5,[7][8][9][10][11] This latter finding suggests possible nonspecific actions of these inhibitors, including the direct inhibition of K ϩ channels. In this respect, several reports have indicated that the cytochrome P-450 inhibitor, clotrimazole, directly inhibits Ca 2ϩ -activated K ϩ (BK Ca ) channels; however, this property does not seem to be shared by other imidazole-containing inhibitors of cytochrome P-450.…”

mentioning

confidence: 93%

14,15-Epoxyeicosa-5( Z )-enoic Acid

Gauthier

Deeter

Krishna

et al. 2002

Circulation Research

180

130

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Abstract-Endothelium-dependent hyperpolarization and relaxation of vascular smooth muscle are mediated by endothelium-derived hyperpolarizing factors (EDHFs). EDHF candidates include cytochrome P-450 metabolites of arachidonic acid, K ϩ , hydrogen peroxide, or electrical coupling through gap junctions. In bovine coronary arteries, epoxyeicosatrienoic acids (EETs) appear to function as EDHFs. A 14,15-EET analogue, 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) was synthesized and identified as an EET-specific antagonist. In bovine coronary arterial rings preconstricted with U46619, 14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET induced concentration-related relaxations. Preincubation of the arterial rings with 14,15-EEZE (10 mol/L) inhibited the relaxations to 14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET but was most effective in inhibiting 14,15-EET-induced relaxations. 14,15-EEZE also inhibited indomethacin-resistant relaxations to methacholine and arachidonic acid and indomethacin-resistant and L-nitroarginineresistant relaxations to bradykinin. It did not alter relaxation responses to sodium nitroprusside, iloprost, or the K ϩ channel activators (NS1619 and bimakalim). Additionally, in small bovine coronary arteries pretreated with indomethacin and L-nitroarginine and preconstricted with U46619, 14,15-EEZE (3 mol/L) inhibited bradykinin (10 nmol/L)-induced smooth muscle hyperpolarizations and relaxations. In rat renal microsomes, 14,15-EEZE (10 mol/L) did not decrease EET synthesis and did not alter 20-hydroxyeicosatetraenoic acid synthesis. This analogue acts as an EET antagonist by inhibiting the following: (1) EET-induced relaxations, (2) the EDHF component of methacholineinduced, bradykinin-induced, and arachidonic acid-induced relaxations, and (3) the smooth muscle hyperpolarization response to bradykinin. Thus, a distinct molecular structure is required for EET activity, and alteration of this structure modifies agonist and antagonist activity. These findings support a role of EETs as EDHFs. Key Words: epoxyeicosatrienoic acids Ⅲ arachidonic acid Ⅲ endothelium-derived hyperpolarizing factors Ⅲ endothelium Ⅲ 20-hydroxyeicosatetraenoic acid E poxyeicosatrienoic acids (EETs) are cytochrome P-450 metabolites of arachidonic acid. They are synthesized by the vascular endothelium and released in response to vasoactive agonists, such as bradykinin and acetylcholine, and are stimulated by cyclic stretch. [1][2][3][4][5][6] Additionally, in the coronary circulation, they cause vascular smooth muscle hyperpolarization and relaxation and, therefore, function as endothelium-derived hyperpolarizing factors (EDHFs). 2 To investigate the role of endogenous EETs in the relaxations induced by endothelium-dependent vasoactive substances, inhibitors of cytochrome P-450 are used, but these investigations have given variable results. In some studies, inhibitors of cytochrome P-450 block the relaxations to bradykinin and acetylcholine, whereas in other studies, these inhibitors are without effect or also inhibit relaxations to K ϩ ...

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Inhibitors of the cytochrome P450‐mono‐oxygenase and endothelium‐dependent hyperpolarizations in the guinea‐pig isolated carotid artery

Cited by 95 publications

References 19 publications

Importance of endothelium-derived hyperpolarizing factor in human arteries.

Importance of endothelium-derived hyperpolarizing factor in human arteries.

Dominant role of an endothelium‐derived hyperpolarizing factor (EDHF)‐like vasodilator in the ciliary vascular bed of the bovine isolated perfused eye

14,15-Epoxyeicosa-5( Z )-enoic Acid

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