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Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas 77004
Endothelin-1 (ET-1) produces potent renal effects that we have
previously shown to be dependent on cytochrome P-450
(CYP450) metabolites of aracidonic acid (24) This study
evaluated the role of these metabolites in the effects produced by ET-1
on renal blood flow (RBF), cortical blood flow (CBF), medullary blood
flow (MBF), and mean arterial blood pressure (MBP). ET-1 (20-200
pmol/kg) increased MBP, renal vascular resistance (RVR), and MBF but
reduced CBF and RBF in a dose-dependent manner. The decreases in CBF
and RBF, and increases in MBP and RVR were blunted by BMS-182874, an
ETA receptor antagonist or BQ-788, an
ETB receptor antagonist. Similarly,
indomethacin, an inhibitor of cyclooxygenase activity, or
12,12-dibromododecenoic acid (DBDD), a CYP450-dependent inhibitor of
production of 20-hydroxyeicosatetraenoic acid (20-HETE), blunted these
effects. ET-3 elicited dose-related reduction in CBF and increase in
MBF. Indomethacin accentuated the reduction in CBF and attenuated the
increase in MBF, as did DBDD. ET-1-induced increase in MBF was
attenuated by BQ-788,
N
-nitro-L-arginine methyl ester
(L-NAME), an inhibitor of nitric oxide (NO) synthesis,
indomethacin, or DBDD. DBDD inhibited the hemodynamic effects of
L-NAME. Miconazole, the inhibitor of CYP450-dependent epoxygenase activity, was without effect. These results indicate that
hemodynamic changes produced by ET-1 are mediated by vasoconstrictor prostanoids and/or prostanoid-like substances, possibly, 20-HETE via
activation of ETA and
ETB receptors. However, the increase in
MBF is mediated by vasodilator prostanoids or by NO via
ETB receptor activation.
20-hydroxyeicosatetraenoic acid; cortical blood flow; medullary blood flow; mean arterial blood pressure; endothelin-1; nitric oxide
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