An oral ETA-selective endothelin receptor antagonist for contrast nephropathy?

John L. Haylor1, and Sameh K. Morcos2

1 Sheffield Kidney Institute, 2 Department of Diagnostic Imaging, Northern General Hospital, Sheffield, UK

Introduction

Endothelin (ET) has been proposed to play an important mediator role in contrast media (CM) nephropathy [1,2]. The first prevention trial in CM nephropathy using an anti-endothelin agent was undertaken at Dukes Medical Center in North Carolina employing SB 209670, an injectable, non-selective ET-receptor antagonist [3]. The choice of SB 209670 was surprising, since in animal studies it had failed to produce significant inhibition of even the acute fall in GFR induced by contrast agents [4,5] and its effect in CM nephropathy had not been reported. Treatment with SB 209670, however, increased, rather than decreased, the incidence of CM nephropathy in patients with reduced renal function from 15 to 28%, while in diabetics the incidence increased from 39 to 67%. The results of this study were proposed to question any role for endothelin as a mediator of CM nephropathy and to highlight the potential nephrotoxicity of endothelin antagonists. In this article, we suggest alternative explanations for the results of the SB 209670 trial and propose that a second study in CM nephropathy be undertaken using an orally active antagonist, selective for the ETA receptor.

Was SB 209670 present in the circulation when CM nephropathy was determined?

CM-induced nephropathy is generally assessed from the 48-h (post-contrast) serum creatinine and may be defined as an impairment of renal function detected by an increase in serum creatinine of more than 44 µmol/l (or 25%), occurring within 3 days of contrast administration, in the absence of an alternative cause [1]. In the SB 209670 human CM nephropathy trial, the ET antagonist was given as a 100 µg/kg loading dose, initiated 30–150 min prior to contrast administration followed by a 12-h intravenous infusion (1 µg/kg/min). However, pharmacokinetic studies in healthy volunteers, using a similar dosage regimen show that when the intravenous infusion is stopped, blood levels of SB 209670 fall very rapidly, being virtually undetectable 24 h after the infusion was started [6]. To provide sustained blood levels, the ET antagonist should be an orally active agent administered 1 day before and for 2–7 days following contrast delivery.

The importance of sustained drug cover in prevention studies for CM nephropathy has already been demonstrated with the calcium antagonist nitrendipine, where a protective response was obtained with a daily dose of 20 mg for 3 days [7] while a single 20 mg dose administered 1 h prior to contrast was ineffective [8].

SB 209670 increases the plasma ET-1 concentration

Plasma ET-1 concentrations were not reported in the SB 209670 human CM nephropathy trial. However, in healthy volunteers, a similar intravenous infusion of SB 209670 produced a 6-fold increase in the plasma ET-1 concentration [6]. Non-selective endothelin receptor antagonists such as SB 209670 are thought to increase the plasma ET-1 concentration through antagonism of an ETB clearance receptor located in the kidney [9]. It is also important to remember that CM themselves increase plasma ET-1 [10], an effect which is enhanced in patients with CM nephropathy [11]. Could the potentiation of CM nephropathy induced by SB 209670 be explained by ETB receptor blockade increasing plasma endothelin? Interestingly, a similar increase in plasma ET-1 generated by exogenous ET-1 infusion in human volunteers produced a 30% fall in renal plasma flow [12].

Could SB 209670 have prevented a fall in GFR mediated by endothelin?

The phrase ‘endothelin receptor antagonism’ included in the title of the paper by Wang et al. [3] maybe misleading. The ability of SB 209670 to potentiate CM nephropathy through elevating plasma endothelin is also evidence for the absence of antagonism at the renal ETA receptor in this study. Treatment with SB 209670 would therefore have been unable to inhibit any decrease in GFR caused by endothelin release following CM administration. In vitro radioligand binding studies, using cloned human ET receptors from CHO cell membranes, previously suggested that SB 209670 had a fivefold preferential selectivity for the ETA receptor [13]. In patients with reduced renal function, however, preferential antagonism for the ETB receptor would appear to have been achieved.

In the CM nephropathy trial, SB 209670 should have been able to block ET receptors at an earlier stage, such as the 12-h period following contrast injection. Studies in human volunteers have already shown SB 209670 to increase p-aminohippuric acid (PAH) clearance [6]. The results of the CM nephropathy trial might therefore indicate that early ET antagonism does not prevent the later increase in serum creatinine (48 h). Delayed events associated with CM and endothelin include the slow dissociation of ET from its receptor and the ability of CM, at least in culture, to stimulate endothelin mRNA [14]. Interestingly, animal evidence indicates that when the ETA receptor is blocked, the sustained administration of a non-selective ET antagonist, such as bosentan, can markedly reduce CM nephropathy [15].

SB 209670 and systemic blood pressure

Other non-selective endothelin receptor antagonists reduce both systolic and diastolic blood pressure in patients with essential hypertension [16] and in normotensive individuals [17], providing evidence of a role for endothelin in the control of blood pressure rather than as a mediator of hypertension [18]. Wang et al. [3] described hypotension or a transient decrease in blood pressure as adverse effects to treatment with i.v. SB 209670 in normotensive patients with reduced renal function, although the incidence was no higher than with placebo. Interestingly though, the increase in serum creatinine associated with contrast-media administration in such patients was reduced to levels seen with placebo. The absence of a small fall in blood pressure in the majority of patients receiving i.v. SB 209670 could also be taken as evidence of a lack of pharmacological antagonism at the ET receptor.

Consequence of the SB 209670 human CM nephropathy trial

The immediate consequence of the SB 209670 trial in human CM nephropathy is the requirement for a second trial to be performed with an orally active endothelin antagonist, selective for the ETA receptor [3]. However, the demonstration of a nephrotoxic response to SB 209670 in patients with reduced renal function has also delayed clinical testing of ET antagonists in other areas of renal disease where a mediator role for endothelin has been implicated.

Notes

Correspondence and offprint requests to: Dr J. Haylor, Sheffield Kidney Institute, Northern General Hospital, Herries Road, Sheffield S5 7AU, UK. Back

References

  1. Morcos SK. Contrast media-induced nephrotoxicity-questions and answers. Br J Radiol1998; 7: 357–365
  2. Kramer BK, Kammerl M, Schweda F, Schreiber M. A primer in radiocontrast-induced nephropathy. Nephrol Dial Transplant1999; 14: 2830–2834[Free Full Text]
  3. Wang A, Holcslaw T, Bashore TM et al. Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism. Kidney Int2000; 57: 1675–1680[ISI][Medline]
  4. Brooks DP, DePalma PD. Blockade of radiocontrast-induced nephrotoxicity by the endothelin antagonist, SB 209670. Nephron1996; 72: 629–636[ISI][Medline]
  5. Bird E, Giancarli MR, Megill JR, Durham SK. Effect of endothelin in radiocontrast-induced nephropathy in rats are mediated through endothelin-A receptors. J Am Soc Nephrol1996; 7: 1153–1157[Abstract]
  6. Freed MI, Wilson DE, Thompson KA, Harrui RZ, Ilson BE, Jorkasky D. Pharmacokinetics and pharmacodynamics of SB209670, an endothelin receptor antagonist: effects on the regulation of renal vascular tone. Clin Pharm Ther1999; 65: 473–482[ISI][Medline]
  7. Neumayer HH, Junge W, Kufner A, Wenning A. Prevention of radiocontrast-media-induced nephrotoxicity by the calcium channel blocker nitrendipine: a prospective randomised clinical trial. Nephrol Dial Transplant1989; 4: 1030–1036[Abstract]
  8. Carraro ML, Mancini W, Artero AM et al. Dose effect of nitrendipine on urinary enzymes and microproteins following non-ionic radiocontrast administration. Nephrol Dial Transplant1996; 11: 444–448[Abstract]
  9. Weber C, Schmitt R, Birnboeck H et al. Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects. Clin Pharmacol Ther1996; 60: 124–137[ISI][Medline]
  10. Clark BA, Kim D, Epstein FH. Endothelin and atrial natriuretic peptide levels following radiocontrast exposure in humans. Am J Kidney Dis1997; 30: 82–86[ISI][Medline]
  11. Maguiles KB, McKinley LJ, Burnett JC. Endothelin in human and canine radiocontrast nephropathy. Vascular Rec1990; 29: 163–164
  12. Kaasjager KAH, Shaw S, Koomans HA, Rabelink TJ. Role of endothelin receptor subtypes in the systemic and renal responses to ET-1 in humans. J Am Soc Nephrol1997; 8: 32–39[Abstract]
  13. Nambi P, Pullen M, Hsiao-Ling W et al. Non-peptide endothelin receptor antagonists. VII: Binding characteristics of [3H] SB 209670, a novel nonpeptide antagonist of endothelin receptors. J Pharm Exp Ther1996; 277: 1567–1571[Abstract]
  14. Sung J-M, Shu GHF, Tsai J-C, Huang J-J. Radiocontrast media induced endothelin-1 mRNA expression and peptide release in porcine aortic endothelial cells. J Formos Med Assoc1995; 95: 77–86
  15. Oldroyd SD, Haylor JL, Morcos SK. Bosentan, an orally active endothelin antagonist: effect on the renal response to contrast media. Radiology1995; 196: 661–665[Abstract]
  16. Krum H, Viskoper RJ, Lacourciere Y, Budde M, Charlton V. The effect of an endothelin receptor antagonist bosentan on blood pressure in patients with essential hypertension. N Engl J Med1998; 338: 784–790[Abstract/Free Full Text]
  17. Haynes WG, Ferro CJ, O'Kane KPJ, Somerville D, Lomax C, Webb DJ. Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans. Circulation1996; 93: 1860–1870[Abstract/Free Full Text]
  18. Haynes WG, Ferro CJ, Webb DJ. Bosentan in essential hypertension. N Engl J Med1998; 339: 346–347[Free Full Text]




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