Published Online
on September 22, 2009

A more recent version of this article appeared on November 1, 2009

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Original Article

Urocortin 2 Inhibits Furosemide-induced Activation of Renin and Enhances Renal Function and Diuretic Responsiveness in Experimental Heart Failure

Miriam T. Rademaker¹; Chris J. Charles; M. Gary Nicholls and A. Mark Richards

Christchurch School of Medicine, Christchurch, New Zealand

^* Corresponding author; email: miriam.rademaker{at}chmeds.ac.nz

Background—Urocortin 2 (Ucn2), a novel peptide with therapeutic potential in heart failure (HF), and diuretics have opposing effects on renal function and the renin-angiotensin-aldosterone system. Since any prospective new treatment is likely to be used in conjunction with standard diuretic therapy, it is necessary to investigate the combined effects of these agents.

Methods and Results—Ucn2 and furosemide were administered for three hours, both singly and combined, in seven sheep with pacing-induced HF. Compared to time-matched controls, separate Ucn2 and furosemide administration significantly increased urine output (furosemide>Ucn2), urine sodium (furosemide>Ucn2), potassium (furosemide>Ucn2) and creatinine excretion (Ucn2>furosemide), and creatinine clearance (Ucn2>furosemide). Compared to furosemide treatment alone, Ucn2+furosemide produced a further diuresis (p<0.05), natriuresis (p<0.05) and sustained increase in creatinine excretion (p<0.05) and clearance (p<0.05), without additional potassium elimination. All active treatments reduced mean arterial pressure (Ucn2+furosemide=furosemide> Ucn2), left atrial pressure (Ucn2+furosemide>Ucn2> furosemide) and peripheral resistance (Ucn2+furosemide=Ucn2>furosemide), whereas only Ucn2, singly and in combination with furosemide, increased cardiac output and dP/dt(max). In contrast to the rise in plasma renin activity (PRA) elicited by furosemide alone, Ucn2 and Ucn2+furosemide markedly reduced PRA. All active treatments decreased plasma aldosterone (Ucn2+furosemide=Ucn2>furosemide), while only Ucn2 and Ucn2+furosemide reduced vasopressin and natriuretic peptide concentrations.

Conclusion—Ucn2 co-treatment with furosemide enhanced hemodynamic and renal function and diuretic responsiveness (without additional potassium depletion) in experimental HF. Furthermore, Ucn2 reversed furosemide-induced rises in PRA and induced greater decreases in plasma aldosterone and vasopressin. These data indicate that adjunct Ucn2 therapy with diuretics in HF is beneficial.

Key Words: diuretics • heart failure • hormones • Renal function • Urocortin 2