Endothelin and Cyclosporin Nephrotoxicity

Cairns, HughS.; Rogerson, Mary; Fairbanks, L; Westwick, John; Neild, G.H.

doi:10.1016/s0140-6736(88)90978-6

Cited by 24 publications

(8 citation statements)

References 4 publications

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“…The intense, long-lasting renal vasoconstriction at the higher doses is particularly noteworthy. The same phenomenon has been observed in several species (Cocks et al, 1989;Minkes & Kadowitz, 1989) and in vitro (Firth et al, 1988;Cairns et al, 1988) and is associated with a marked decline in renal function (Lopez-Farr6 et al, 1989). On this basis endothelin has been implicated as a mediator in the pathogenesis of acute renal failure (Firth et al, 1988).…”

Section: Discussionsupporting

confidence: 68%

Differences in regional vascular sensitivity to endothelin‐1 between spontaneously hypertensive and normotensive Wistar‐Kyoto rats

Wright

Fozard

1990

British J Pharmacology

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1 The systemic and regional haemodynamic effects of porcine endothelin-1 (endothelin) have been measured in anaesthetized spontaneously hypertensive (SH) rats rendered areflexic by ganglion blockade; comparisons were made with age-matched Wistar-Kyoto (WKY) control animals. 2 In both SH and WKY rats endothelin (0.1-1 nmol kg-1 i.v.) elicited an initial, short-lived (<2 min), fall in blood pressure which was associated with substantial increases in hindquarter and carotid vascular conductances. Both the blood pressure falls and the peripheral vasodilator responses were greater in SH than in WKY rats. 3 The initial depressor effects of endothelin were followed by marked and sustained increases in blood pressure associated with constriction in carotid, hindquarter, renal and mesenteric vascular beds. Vasoconstrictor responses were quantitatively similar in the two rat strains. 4 Pretreatment with indomethacin (5mgkg-t i.p. or i.v.) did not alter the responses to endothelin, 1 nmol kg-1, in SH rats. 5 The regional haemodynamic effects of intravenously administered acetylcholine (0.01-1 pg kg-), nitroprusside (0.3-lOpgkg-') and angiotensin II (0.01-0.1 ugkg-1) were similar in SH and WKY rats. 6 Endothelin (10-10-3 x 10 -8M) contracted aortic rings from both SH rats and WKY control animals. Removal of the endothelium enhanced significantly the sensitivity of tissues from both WKY and SH rats to endothelin; the increase in sensitivity was greater in tissues from SH than WKY rats. 7 The results demonstrate qualitative similarities in the complex haemodynamic effects of endothelin in SH rats and WKY control animals. However, the SH rats display substantially greater vasodilator responses to endothelin than WKY. Eicosanoid generation is not the mechanism of the vasodilator action of endothelin in SH rats under the conditions of our experiments.

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Section: Discussionsupporting

confidence: 68%

Differences in regional vascular sensitivity to endothelin‐1 between spontaneously hypertensive and normotensive Wistar‐Kyoto rats

Wright

Fozard

1990

British J Pharmacology

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“…Following this hypothesis in the area of transplantation, it has been speculated that ET is a contributor to the mechanism of CSA nephrotoxicity (39) The etiology ofthe vasoconstrictive effects ofCSA has been shown in animal experiments to be due to the presence of ET and its subsequent effect upon vascular SMC (26,40). In these studies, the vasoconstriction of CSA is reversed or prevented with either the coadministration or pretreatment with an antibody specific to ET.…”

Section: Methodsmentioning

confidence: 99%

Cyclosporine-induced synthesis of endothelin by cultured human endothelial cells.

Bunchman

Brookshire²

1991

J. Clin. Invest.

243

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Endothelin (ET), a peptide synthesized by endothelial cells (EC), causes a decreased renal blood flow and glomerular filtration rate and an increased mean arterial pressure when infused in animals. In tissue culture, ET causes smooth muscle cell (SMC) proliferation and contraction by influx of extracellular calcium, which is inhibited by calcium channel antagonists. Infusion of cyclosporine (CSA) hemodynamically parallels ET action, and knowing that CSA effects EC, we hypothesize that the vasoconstrictive effects of CSA are a result of ET synthesis by EC.Varying concentrations of CSA were incubated with EC resulting in ET present in the supernatants in a dose-dependent manner peaking at 75% above basal activity. Coincubation of either cremophor alone or cycloheximide with CSA resulted in minimal ET present in the EC supernatants (P < 0.01 each).Incubation of conditioned media from CSA-treated EC with SMC caused proliferation at 114% above basal activity, which did not occur in the presence of CSA alone (P < 0.01). This activity is specifically inhibited in the presence of an anti-ET antibody or nonspecifically in the presence of calcium channel antagonists (P < 0.01 each).Therefore, CSA stimulates EC synthesis of ET which in turn causes SMC proliferation. This action is inhibited by the coincubation of a specific antibody to ET or a calcium channel antagonist. These findings may help in the understanding of CSA-induced hypertension and vasculopathy. (J. Clin. Invest.

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“…The intravenous administration of ET‐1 in rats produces a dose‐dependent sustained decrease in GFR [40]; these results have been reproduced in isolated kidney preparations [46]. This reduction in GFR was postulated to be caused by a decline in net filtration pressure (secondary to a reduced filtering surface area via mesangial contraction) and a reduced renal filtration coefficient (K F ) [38,40].…”

Section: Endothelins and The Urinary Tractmentioning

confidence: 99%