Renal oxygenases: differential contribution to vasoconstriction induced by ET-1 and ANG II

Abstract

In the rat isolated perfused kidney, 5,8,11,14-eicosatetraynoic acid, an inhibitor of all pathways of arachidonic acid (AA) metabolism, diminished endothelin-1 (ET-1)- and angiotensin II (ANG II)-induced renal vasoconstriction by approximately 60-70%. We then examined the individual contribution of each oxygenase, cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P-450 (CYP) to the vasoconstrictor effects of ET-1 and ANG II. Inhibition of COX with indomethacin reduced by 30-40% the vasoconstrictor responses to ET-1 and ANG II. Inhibition of 12-LOX with baicalein and 5- and 12-LOX with 5,8,11-eicosatriynoic acid attenuated ANG II-induced renal vasoconstriction by approximately 40-60% but did not affect responses to ET-1. In contrast, 12,12-dibromododec-11-enoic acid (DBDD), an inhibitor of the CYP omega/omega 1-hydroxylase pathway, diminished ET-1-induced renal vasoconstriction by 30-40%, an effect reproduced by depletion of CYP enzymes with CoCl2. Neither DBDD nor CoCl2 affected renal vasoconstriction elicited by ANG II. ET-1 increased efflux of 19- and 20-hydroxyeicosatetraenoic acid, an effect reduced by DBDD. Thus products of the COX and CYP pathways contribute to the renal vasoconstrictor response to ET-1, whereas COX- and LOX-derived eicosanoids contribute to the response to ANG II, accounting for > or = 80% of the vasoactivity of the peptides.

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

“…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 expression of CYP4A enzymes and the formation of 20-HETE are also elevated in the kidney of ANG II-infused hypertensive rats (1), and 20-HETE contributes to the development of hypertension and end-organ damage in this model (1,27,28).…”

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

“…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.…”

“…In the isolated perfused kidney, ET-1 increases the release of 20-HETE into the renal effluent. 16 ET-1 also has the capacity to increase production of vasodilatory prostaglandins (PGs), PGI 2 and PGE 2 , as well as vasoconstrictor COX metabolites, PGF 2␣a , PGH 2 , and TX. 1,10,14,21 Interestingly, the CYP450 hydroxylase metabolite 20-HETE can be transformed by COX to a vasoconstrictor PGH 2 analogue, 20-OH PGH 2 .…”

20-HETE contributes to the acute fall in cerebral blood flow after subarachnoid hemorrhage in the rat

“…20-HETE also increases Ca 2ϩ influx via L-type Ca 2ϩ channels in the cerebral vasculature (16) and plays a critical role in the mechanism underlying the autoregulation of cerebral blood flow in the rat (2,15,18). Vasoconstrictor peptides like angiotensin II and ET stimulate the formation of 20-HETE in VSM, and 20-HETE potentiates the vasoconstrictor response to these agents (11,31). Nitric oxide (NO) inhibits the formation of 20-HETE in VSM, and this contributes to the vasodilator actions of NO in the cerebral circulation (2,37).…”