The synthesis of 20-HETE in small porcine coronary arteries antagonizes EDHF-mediated relaxation.
Cardiovasc Res
; 65(2): 487-94, 2005 Feb 01.
Article
en En
| MEDLINE
| ID: mdl-15639488
ABSTRACT
OBJECTIVE:
Exogenous application of 20-hydroxyeicosatetraenoic acid (20-HETE) to small (300-500 microm) porcine coronary arteries elicits contraction by activating the Rho kinase and increasing the sensitivity of contractile proteins to Ca2+. Here, we determined whether 20-HETE is involved in the regulation of coronary artery tone as well as its role in the modulation of endothelium-derived hyperpolarizing factor (EDHF)-mediated responses. METHODS ANDRESULTS:
Small porcine coronary arteries expressed cytochrome P450 (CYP) 4A, as demonstrated by Western blot analysis, and generated 20-HETE. Moreover, 20-HETE production was increased two- and threefold over basal levels in response to isometric stretch or the thromboxane analogue U46619, respectively, and was inhibited by the CYP 4A inhibitor N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS). In vascular reactivity studies, DDMS attenuated U46619-induced contractions and induced a concentration-dependent but endothelium-independent relaxation of precontracted arterial rings. Endogenously generated 20-HETE significantly inhibited the EDHF-mediated relaxation of coronary arteries, which was potentiated by the phospholipase A2 inhibitors AACOCF3 and ONO-RS-082, as well as by the omega-hydroxylase inhibitors 17-octadecynoic acid and DDMS. EDHF-mediated relaxation was not affected by either the nonselective epoxygenase inhibitors miconazole and clotrimazole or the CYP 2C inhibitor sulfaphenazole but was abolished by the Na-K-ATPase inhibitor, ouabain. Exogenous application of 20-HETE inhibited EDHF-mediated relaxations and caused a concomitant increase in the phosphorylation of protein kinase Calpha (PKCalpha). This effect was reversed by the PKC inhibitor Ro-318220 and mimicked by the PKC activator phorbol-12 myristate 13-acetate.CONCLUSIONS:
These results indicate that vascular tone in small porcine coronary arteries is partly determined by the endogenous production of 20-HETE. In addition, 20-HETE functionally antagonizes EDHF-mediated relaxation via a PKCalpha-dependent mechanism, probably involving the inhibition of the Na-K-ATPase.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Vasodilatadores
/
Factores Biológicos
/
Ácidos Hidroxieicosatetraenoicos
/
Vasos Coronarios
Límite:
Animals
Idioma:
En
Revista:
Cardiovasc Res
Año:
2005
Tipo del documento:
Article
País de afiliación:
Alemania
Pais de publicación:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
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SCOTLAND
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UK
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UNITED KINGDOM