CytochromeP-450-derived eicosanoids participate in the renal functional effects of ET-1 in the anesthetized rat

Abstract

We evaluated the contribution of cytochrome P-450 (CYP450)-dependent arachidonic acid (AA) metabolites and prostanoids to the renal hemodynamic and tubular effects of endothelin-1 (ET-1) in anesthetized rats. Either ET-1 (0.3, 1.0, and 3 pmol ⋅ kg−1 ⋅ min−1) or vehicle was infused intravenously during two to three 30-min clearance experimental periods. Only high-dose ET-1 increased mean arterial pressure: control, 75 ± 3 mmHg vs. experimental, 84 ± 4 mmHg. A dose-dependent diuretic-natriuretic response to ET-1 occurred despite progressive declines in glomerular filtration rate (GFR) and renal blood flow. In the face of a 36% reduction in GFR in response to the highest dose of ET-1, urinary sodium excretion (UNaV) increased threefold from 0.57 ± 0.11 to 1.6 ± 0.10 μmol ⋅ 100 g−1 ⋅ min−1. Indomethacin (5 mg/kg) decreased basal GFR from 1.2 ± 0.3 ml ⋅ 100 g−1 ⋅ min−1to 0.8 ± 0.1 ml ⋅ 100 g−1 ⋅ min−1and potentiated the GFR lowering action of ET-1 associated with reductions in UNaV and urine volume. Cobalt chloride (CoCl2) and dibromododec-11-enoic acid (DBDD), which diminish CYP450-dependent AA metabolism through different mechanisms, were used to identify CYP450 products mediating the renal functional actions of ET-1. DBDD (12.5 μg/min) reduced urinary excretion of 20-hydroxyeicosatetraenoic acid from 3.4 ± 0.9 (control) to 1.1 ± 0.6 ng/h and abolished the negative effects of ET-1 on GFR while decreasing the diuretic-natriuretic action of ET-1. Similar effects were produced by CoCl2. Clotrimazole, an inhibitor of epoxygenase activity, was without effect on ET-1-induced renal functional changes. Thus the capacity of ET-1 to enhance prostaglandin production was primarily expressed in terms of positive effects on renal hemodynamics. In contrast, CYP450 products promoted sodium excretion despite negative effects on renal hemodynamics.

CytochromeP-450-dependent metabolism of arachidonic acid in the kidney of rats with diabetes insipidus

“…Recent studies have indicated that CYP metabolites of AA play an important role as second messengers in the regulation of the tubular and vascular effects of peptide hormones and growth factors (1,3,37,40). For example, ANG II and endothelin stimulate the renal formation of 20-HETE, which contributes to the renal vasoconstrictor and natriuretic actions of these hormones (11,12,35).…”

“…The release of 20-HETE in renal and peripheral blood vessels is stimulated by ANG II (5), phenylephrine (20a), endothelin (37), and serotonin (3). There is considerable evidence that 20-HETE contributes to the vasoconstrictor responses to these hormones by modulating potassium channel activity and calcium influx (1).…”

Cytochrome P450 and Cyclooxygenase Metabolites Contribute to the Endothelin-1 Afferent Arteriolar Vasoconstrictor and Calcium Responses

“…3,7,9 Actions of ET-1, via ET A and ET B receptors, include phospholipase A 2 stimulation and the resultant increase in arachidonic acid-derived mediators. 1,7,15,21 Previous studies have investigated the involvement of CYP450 hydroxylase and COX metabolites in the renal vasoconstrictor response to ET-1. 7,9,10,16, 22 Oyekan et al, using in vitro and in vivo techniques, have shown that the CYP450 hydroxylase pathway contributes to the ET-1-evoked decrease in renal blood flow, but the role of the COX pathway appears to be complex.…”

“…7,9,10,16, 22 Oyekan et al, using in vitro and in vivo techniques, have shown that the CYP450 hydroxylase pathway contributes to the ET-1-evoked decrease in renal blood flow, but the role of the COX pathway appears to be complex. 7,16,23 In the isolated perfused kidney, COX inhibition attenuated the renal vasoconstrictor response to ET-1, 16 but when studied in vivo, the COX inhibitor indomethacin potentiated the decrease in glomerular filtration rate elicited by ET-1. 7 These paradoxical findings demonstrating COX metabolites as positive and negative contributors to the ET-1-mediated vasoconstriction are not limited to the renal vasculature and may reflect experimental conditions or species variation.…”

“…Intrarenal infusion of ET-1 decreases renal blood flow and glomerular filtration rate while increasing sodium excretion. 3,7,8 Previous studies have demonstrated that ET-1 constricts the afferent arteriole 9 -13 ; however, the preglomerular vascular smooth muscle cellular signaling mechanisms responsible are not well understood. ET-1 activates G proteins that in turn stimulate phospholipase C and subsequent release of intracellular calcium ions ([Ca 2ϩ ] i ), leading to vascular smooth muscle cell contraction.…”