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Renal effects of BG9719, a specific A 1 adenosine receptor antagonist, in congestive heart failure
Author(s) -
Wolff Andrew A.,
Skettino Sandra L.,
Beckman Evan,
Belardinelli Luiz
Publication year - 1998
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199811/12)45:3/4<166::aid-ddr12>3.0.co;2-p
Subject(s) - medicine , endocrinology , adenosine , natriuresis , heart failure , renal blood flow , adenosine receptor antagonist , fractional excretion of sodium , excretion , chemistry , renal function , adenosine receptor , receptor , agonist
A 1 adenosine receptors mediate renal afferent arteriolar vasoconstriction when distal tubular Na + concentrations increase (tubuloglomerular feedback, TGF). A 1 adenosine receptor stimulation also increases both proximal and distal tubular Na + reabsorption. Thus, an A 1 adenosine receptor antagonist might produce natriuresis while maintaining renal blood flow and glomerular filtration. BG9719 (also known as CVT‐124) is a selective A 1 adenosine receptor antagonist. Its natriuretic properties have been demonstrated both in healthy volunteers and in patients with congestive heart failure (CHF) in double‐blind, two‐period crossover studies of similar design. In each study, subjects received a single intravenous dose of BG9719 (0.30 mg/kg) or matching placebo on separate days. BG9719 increased Na + excretion in both volunteers and CHF patients; the effects were proportionately greater in CHF. In volunteers, mean Na + excretion during the first 3 h after BG9719 was more than double that after placebo (151.5 mEq vs. 63.8 mEq; P < 0.01); whereas in CHF patients, the increase was nearly fourfold (54.5 mEq vs. 15.0 mEq; P < 0.05). In contrast, effects on K + excretion were small. In volunteers, mean K + excretion was 22.7 mEq on BG9719 vs. 19.3 mEq on placebo ( P < 0.05); in CHF, these values were 11.8 mEq vs. 7.5 mEq, respectively ( P = 0.06). Uric acid was not retained and creatinine clearance was not affected in either group. Mean Cmax was similar in volunteers and CHF patients, but clearance of the drug was reduced in CHF, resulting in a longer half‐life. Increases in Na + excretion with minimal urinary K + losses suggest inhibition of both proximal tubular Na + reabsorption and distal Na + ‐K + exchange by BG9719. A stable creatinine clearance despite natriuresis is consistent with TGF interruption. These properties may render BG9719 especially useful in diuretic‐resistant patients with CHF complicated by renal dysfunction. Drug Dev. Res. 45:166–171, 1998. © 1998 Wiley‐Liss, Inc.