Article: Pharmacological evaluation of an epoxide as the putative hyperpolarizing factor mediating the nitric oxide-independent vasodilator effect of bradykinin in the rat heart.
The Journal of pharmacology and experimental therapeutics
1998 Volume 287, Issue 2, Page(s) 497–503
Abstract: A cytochrome P450-derived metabolite of arachidonic acid, namely an epoxyeicosatrienoic acid (EET), has many of the properties of a hyperpolarizing factor that mediates endothelium-dependent, nitric oxide-independent vasodilation. As there are four EET ... ...
| Abstract | A cytochrome P450-derived metabolite of arachidonic acid, namely an epoxyeicosatrienoic acid (EET), has many of the properties of a hyperpolarizing factor that mediates endothelium-dependent, nitric oxide-independent vasodilation. As there are four EET regioisomers, we used pharmacological criteria, based on previous observations with bradykinin (BK), to evaluate which, if any, of the EETs could be considered a potential mediator of vasodilator responses to BK in the rat isolated heart treated with indomethacin and nitroarginine to eliminate prostaglandin and nitric oxide components of the response. Nifedipine, used as a probe for dilator mechanisms dependent on closure of voltage-dependent Ca++ channels, almost abolished the vasodilator effect of cromakalim and attenuated those of BK and 5,6 EET. The vasodilator effects of the other EETs were not reduced and were excluded from consideration as mediators of BK-induced vasodilation. The vasodilator effect of 5,6 EET, as with that of BK, was markedly reduced by charybdotoxin but not iberiotoxin, suggesting the contribution of a similar type K+ channel to the vascular response to both agents. As expected for a putative endothelium- and cytochrome P450-derived mediator, the coronary vasodilator effect of 5,6 EET was not affected by either removal of the endothelium or inhibition of cytochrome P450 with clotrimazole, interventions that virtually abolished the vasodilator activity of BK. Thus, of the four EET regioisomers, 5,6 EET is the most likely mediator of the vasodilator effect of BK in the isolated heart under these experimental conditions. |
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| MeSH term(s) | 8,11,14-Eicosatrienoic Acid/analogs & derivatives ; 8,11,14-Eicosatrienoic Acid/metabolism ; Animals ; Bradykinin/pharmacology ; Calcium Channels/drug effects ; Calcium Channels/physiology ; Cytochromes/antagonists & inhibitors ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/physiology ; Enzyme Inhibitors/pharmacology ; Heart/drug effects ; Heart/physiology ; In Vitro Techniques ; Ion Channel Gating ; Male ; Nitric Oxide/physiology ; Potassium Channel Blockers ; Potassium Channels/metabolism ; Rats ; Rats, Wistar ; Vasodilator Agents/pharmacology |
| Chemical Substances | Calcium Channels ; Cytochromes ; Enzyme Inhibitors ; Potassium Channel Blockers ; Potassium Channels ; Vasodilator Agents ; Nitric Oxide (31C4KY9ESH) ; 8,11,14-Eicosatrienoic Acid (7324-41-6) ; 5,6-epoxy-8,11,14-eicosatrienoic acid (81246-84-6) ; Bradykinin (S8TIM42R2W) |
| Language | English |
| Publishing date | 1998-11 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. |
| ZDB-ID | 3106-9 |
| ISSN | 1521-0103 ; 0022-3565 |
| ISSN (online) | 1521-0103 |
| ISSN | 0022-3565 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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