TY - JOUR
T1 - The synthesis of 20-HETE in small porcine coronary arteries antagonizes EDHF-mediated relaxation
AU - Randriamboavonjy, Voahanginirina
AU - Kiss, Ladislau
AU - Falck, J R
AU - Busse, Rudi
AU - Fleming, Ingrid
N1 - Funding Information:
Research described in this article was partly supported by Philip Morris, the Deutsche Forschungsgemeinschaft (FI 830/2-1), and the National Institute of Health (NIH GM31278, to JRF).
PY - 2005/2/1
Y1 - 2005/2/1
N2 - Exogenous application of 20-hydroxyeicosatetraenoic acid (20-HETE) to small (300-500 μm) porcine coronary arteries elicits contraction by activating the Rho kinase and increasing the sensitivity of contractile proteins to Ca 2+. 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. 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 A 2 inhibitors AACOCF 3 and ONO-RS-082, as well as by the ω-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 Cα (PKCα). This effect was reversed by the PKC inhibitor Ro-318220 and mimicked by the PKC activator phorbol-12 myristate 13-acetate. 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 PKCα-dependent mechanism, probably involving the inhibition of the Na-K-ATPase.
AB - Exogenous application of 20-hydroxyeicosatetraenoic acid (20-HETE) to small (300-500 μm) porcine coronary arteries elicits contraction by activating the Rho kinase and increasing the sensitivity of contractile proteins to Ca 2+. 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. 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 A 2 inhibitors AACOCF 3 and ONO-RS-082, as well as by the ω-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 Cα (PKCα). This effect was reversed by the PKC inhibitor Ro-318220 and mimicked by the PKC activator phorbol-12 myristate 13-acetate. 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 PKCα-dependent mechanism, probably involving the inhibition of the Na-K-ATPase.
KW - Endothelial factors
KW - Na/K-pump
KW - Protein kinase C
KW - Stretch/m-e coupling
KW - Vasoconstriction/dilation
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U2 - 10.1016/j.cardiores.2004.10.029
DO - 10.1016/j.cardiores.2004.10.029
M3 - Article
C2 - 15639488
AN - SCOPUS:11444267637
SN - 0008-6363
VL - 65
SP - 487
EP - 494
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 2
ER -