Endothelin-A receptor antagonism modifies cardiovascular risk factors in CKD

Abstract

Arterial stiffness and impaired nitric oxide (NO) bioavailability contribute to the high risk for cardiovascular disease in CKD. Both asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO production, and endothelin-1 (ET-1) oppose the actions of NO, suggesting that ET-1 receptor antagonists may have a role in cardiovascular protection in CKD. We conducted a randomized, double-blind, three-way crossover study in 27 patients with proteinuric CKD to compare the effects of the ET(A) receptor antagonist sitaxentan, nifedipine, and placebo on proteinuria, BP, arterial stiffness, and various cardiovascular biomarkers. After 6 weeks of treatment, placebo and nifedipine did not affect plasma urate, ADMA, or urine ET-1/creatinine, which reflects renal ET-1 production; in contrast, sitaxentan led to statistically significant reductions in all three of these biomarkers. No treatment affected plasma ET-1. Reductions in proteinuria and BP after sitaxentan treatment was associated with increases in urine ET-1/creatinine, whereas reduction in pulse-wave velocity, a measure of arterial stiffness, was associated with a decrease in ADMA. Taken together, these data suggest that ET(A) receptor antagonism may modify risk factors for cardiovascular disease in CKD.

Trial registration: ClinicalTrials.gov NCT00810732.

Figures

Figure 1.

Selective endothelin-A receptor antagonism reduces serum urat, ADMA and urine ET-1/creat in CKD patients. Change from baseline in (A) serum uric acid, (B) ADMA, and (C) urine ET-1/creatinine after 3 and 6 weeks’ treatment with placebo (open bar), sitaxentan (speckled bar), and nifedipine (hashed bar). Values are expressed as mean ± SEM. *P<0.01 for sitaxentan versus placebo at 3 or 6 weeks; †P<0.05 for sitaxentan versus placebo at 3 weeks.

Figure 2.

Changes in arterial stiffness, blood pressure and proteinuria following endothelin-A antagonism relate to changes in ADMA and urine ET-1/creat. Relationships between (A) percentage change in PWV against percentage change in ADMA and (B) percentage change in proteinuria and (C) percentage change in mean arterial pressure against percentage change in urine ET-1/creatinine. MAP, mean arterial pressure; uET-1/creat, urine ET-1/creatinine.