Role of NO and cytochromeP-450-derived eicosanoids in ET-1-induced changes in intrarenal hemodynamics in rats

Abstract

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 ET(A) receptor antagonist or BQ-788, an ET(B) 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(omega)-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 ET(A) and ET(B) receptors. However, the increase in MBF is mediated by vasodilator prostanoids or by NO via ET(B) receptor activation.

Distribution of Endothelin Receptor Subtypes ETA and ETB in the Rat Kidney

“…Although neither Hocher et al (1996) nor Yamamoto and Uemura (1998) could detect ET B receptors on vascular smooth muscle cells by in situ hybridization and IHC, respectively, in our study ET B receptor immunoreactivity of smooth muscle cells was obvious in interlobular arteries as well as in afferent and efferent arterioles. These findings agree with previous functional studies demonstrating vasoconstriction of afferent and efferent arterioles by ET-1 being sensitive to ET A and ET B receptor antagonists (Endlich et al 1996;Hercule and Oyekan 2000a) and with the observation of ET-3-mediated decreases in renal cortical blood flow (Hercule and Oyekan 2000b). In the medullary circulation we observed both ET A and ET B receptors in DVR.…”

“…ter, however, was converted into vasoconstriction upon cyclooxygenase blockade (Hercule and Oyekan 2000b), implying that ET B receptors in the medullary circulation are coupled to the generation of vasodilator cyclooxygenase products. Regulation of renal vascular tone by ET-1 has recently been demonstrated to be intimately linked to the cytochrome P450 (CYP450) system.…”

“…CYP450-derived 20-hydroxyeicosatetraenoic acid (20-HETE) markedly contributes to ET-1-induced vasoconstriction of renal vessels (Imig et al 1996;Oyekan et al 1997;Hercule and Oyekan 2000a), and inhibition of 20-HETE production was shown to dampen ET-1-induced vasoconstriction. In the rat preglomerular arteriole, both ET A and ET B receptors can mediate vasoconstriction through liberation of 20-HETE (Hercule and Oyekan 2000a); however, in the renal medulla there is an antagonism between ET A -receptor-dependent vasoconstriction mediated by 20-HETE and NO-mediated vasodilation in response to ET B receptor stimulation (Hercule and Oyekan 2000b). NO is well known to suppress ET-1 gene expression (Boulanger and Luscher 1990;Kourembanas et al 1993) and also interferes with the CYP450-system.…”

Endothelin A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition Are Synergistic via an Endothelin B Receptor–Mediated and Nitric Oxide–Dependent Mechanism

“…The greater fall in BP when indomethacin was co-administered with enalapril and BQ-123 may represent blockade of the action of these constrictor COX products. There is evidence from studies in animals that vasodilator prostaglandins may additionally be involved in the actions of ET-1 in the renal circulation, particularly the renal medulla (45,48). We could not demonstrate, however, any inhibitory effect of indomethacin on either the systemic or the renal hemodynamic effects of the combination of ACE inhibition and ETA receptor antagonism.…”

“…Thus, indomethacin may produce both vasodilation, by inhibition of reninmediated Ang II generation and COX-1-mediated thromboxane A2 synthesis, and vasoconstriction, by blocking synthesis of vasodilator prostanoids. Studies in animals also suggest that vasoconstrictor COX products, such as thromboxane A2 and prostaglandin H2, might be implicated in ET-1-induced vasoconstriction, particularly in disease models (43)(44)(45)(46)(47). The greater fall in BP when indomethacin was co-administered with enalapril and BQ-123 may represent blockade of the action of these constrictor COX products.…”