Longitudinal Assessment of the Effect of Atrasentan on Thoracic Bioimpedance in Diabetic Nephropathy:A Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND: Fluid retention is a common adverse event in patients who receive endothelin (ET) receptor antagonist therapy, including the highly selective ETA receptor antagonist, atrasentan. OBJECTIVE: We performed longitudinal assessments of thoracic bioimpedance in patients with type 2 diabetes mellitus and nephropathy to determine whether a decrease in bioimpedance accurately reflected fluid retention during treatment with atrasentan. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled study in 48 patients with type 2 diabetes mellitus and nephropathy who were receiving stable doses of renin angiotensin system inhibitors and diuretics. METHODS: Patients were randomized 1:1:1 to placebo, atrasentan 0.5 mg, or atrasentan 1.25 mg once daily for 8 weeks. Thoracic bioimpedance, vital signs, clinical exams, and serologies were taken at weeks 1, 2, 4, 6, and 8, with the exception of serum hemoglobin, which was not taken at week 1, and serum brain natriuretic peptide, which was only taken at baseline, week 4, and week 8. RESULTS: Alterations in bioimpedance were more often present in those who received atrasentan than in those who received placebo, though overall differences were not statistically significant. Transient declines in thoracic bioimpedance during the first 2 weeks of atrasentan exposure occurred before or during peak increases in body weight and hemodilution (decreased serum hemoglobin). CONCLUSIONS: We conclude that thoracic bioimpedance did not reflect changes in weight gain or edema with atrasentan treatment in this study. However, the sample size was small, and it may be of interest to explore the use of thoracic bioimpedance in a larger population to understand its potential clinical use in monitoring fluid retention in patients with chronic kidney disease who receive ET receptor antagonists

CHARACTERIZATION OF FUNCTIONAL ENDOTHELIN RECEPTORS IN THE CANINE ISOLATED-PERFUSED SPLEEN

The endothelin receptor subtypes involved in the vasoconstriction, capsular smooth muscle contraction, prostaglandin E(2) and prostacyclin release induced by endothelin-l have been investigated in the canine isolated perfused spleen using both the endothelin ET(A) receptor antagonist FR 139317 and the endothelin ET(B) receptor agonist IRL 1620. The isolated canine spleen was perfused with warmed (37 degrees C) and oxygenated (95% O-2/5% CO2) Krebs solution at constant now with continuous recording of splenic arterial perfusion pressure and spleen weight, Samples of splenic venous effluent were collected to determine the amounts of prostaglandin E(2) and prostacyclin, measured by radioimmunoassay. Endothelin-1 (4-200 mu mol) and IRL 1620 (20-1000 pmol) dose-dependently increased splenic arterial perfusion pressure but the former was more potent on a molar basis (the molar dose ratio IRL/endothelin-1 required to increase splenic arterial vascular resistance by 25% was approximately 33). The infusion of the nitric oxide inibitor N-omega-nitro-L-arginine methyl ester (10 mu M), but not of the enantiomer N-omega-nitro-D-arginine methyl ester, significantly potentiated the increase in splenic arterial vascular resistance induced by endothelin-1. The infusion of FR 139317 (1 mu M) markedly attenuated the increased splenic arterial perfusion pressure induced by endothelin-1 without affecting that evoked by IRL 1620. At the highest dose (200 pmol, endothelin-1 induced a small but significant capsule contraction as reflected by the reduction in the spleen weight. The infusion of FR 139317 (1 mu M) abolished this contractile effect. IRL 1620 (in doses up to 1000 pmol) did not significantly affect the capsule tone. The administration of either endothelin-1 (20-200 pmol) or IRL 1620 (20-1000 pmol) caused the release of 6-oxo-prostaglandin F-1 alpha (breakdown product of prostacyclin) and prostaglandin E(2) into the splenic venous effluent. The amount of both prostanoids released by endothelin-1 was significantly greater than that induced by IRL 1620. FR 139317 (1 mu M) significantly reduced (P < 0.05) the release of both 6-oxo-prostaglandin F-1 alpha and prostaglandin E(2) by endothelin-1 without affecting that released by IRL 1620. The results demonstrate that the release of prostaglandins and nitric oxide modulates the vasoconstrictor activity of endothelin-1 in the splenic circulation. Furthermore, the vasoconstriction and eicosanoids (prostacyclin and prostaglandin E(2)) release by endothelin-1 are due to activation of both endothelin ET(A) and ET(B) receptors, although the former seems to be the predominant form. The splenic capsule contraction is mediated by activation of endothelin ET(A) receptors only.28241699576