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

Abstract

Background— Urocortin 2 (Ucn2), a novel peptide with therapeutic potential in heart failure, and diuretics have opposing effects on renal function and the renin-angiotensin-aldosterone system. Because 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 3 hours, both singly and combined, in 7 sheep with pacing-induced heart failure. Compared with 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 with furosemide treatment alone, Ucn2+furosemide produced a further diuresis ( P <0.05), natriuresis ( P <0.05), and a 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 increase in plasma renin activity elicited by furosemide alone, Ucn2 and Ucn2+furosemide markedly reduced plasma renin activity. All active treatments decreased plasma aldosterone (Ucn2+furosemide=Ucn2>furosemide), whereas only Ucn2 and Ucn2+furosemide reduced vasopressin and natriuretic peptide concentrations. Conclusion— Ucn2 cotreatment with furosemide enhanced hemodynamic and renal function and diuretic responsiveness (without additional potassium depletion) in experimental heart failure. Furthermore, Ucn2 reversed furosemide-induced increases in plasma renin activity and induced greater decreases in plasma aldosterone and vasopressin. These data indicate that adjunct Ucn2 therapy with diuretics in heart failure is beneficial.

Interactions of Enhanced Urocortin 2 and Mineralocorticoid Receptor Antagonism in Experimental Heart Failure

“…The observed Ucn2-induced renal responses, which occurred in the face of prominent reductions in plasma atrial natriuretic peptide/brain natriuretic peptide, are similar to those seen in our earlier work with the peptide in ovine HF, [12][13][14][15] and are likely a consequence of improvements in glomerular filtration (as judged by the increase in CrCl), renal vasodilatation, 28 and attenuation of circulating antinatriuretic/antidiuretic factors (Ang II, aldosterone, and arginine vasopressin). Direct tubular actions of Ucn2 are also plausible given that not only is the CRF 2 receptor present in the proximal tubules of the kidney, 29 but also administration of the peptide is accompanied by increases in urine cAMP (Ucn2's intracellular second messenger).…”

“…When CA was given in combination with Ucn2, the resulting hemodynamic responses were largely comparable with those produced by Ucn2 alone with marked improvements in CO in association with substantial reductions (a halving) in peripheral resistance and LAP-effects observed previously in this model of HF. [12][13][14][15] Although the Ucn2-induced increase in CO is presumably in part a consequence of the large falls in peripheral resistance, with the peptide shown to directly reduce vascular tone, 9 Ucn2 also exhibits potent inotropic activity, 10,44 as evidenced here by the concurrent rise in dP/dt max . The reductions in LAP are probably secondary to the rise in CO, although the peptide is reported to have lusitropic 10,11 and venodilator 45 activity, which may also have contributed.…”

“…Administration of the combined agents was distinguished by a prompt transient rise in aldosterone followed by a gradual decline to below control, likely due to levels initially rising with MR blockade followed by subsequent suppression of aldosterone secretion. Although the RAAS-inhibitory actions of Ucn2, noted previously by our group, [12][13][14][15] are obviously beneficial in the setting of HF, as an adjunct therapy to MR antagonism it may have additional clinical benefits given that aldosterone seems to also have non-MR-mediated effects. 38,39 Both Ucn2 and CA treatments enhanced plasma cortisol levels in the present study.…”

“…Several studies have shown that Ucn2 improves cardiovascular and renal function in experimental HF, in association with suppression of a number of vasoconstrictor/volume-retaining hormone systems (including the RAAS). [11][12][13][14][15] In humans with stable systolic HF, Ucn2 increases left-ventricular ejection fraction and reduces systemic vascular resistance and cardiac work, with relative suppression of the RAAS and augmentation of renal parameters in the face of substantial falls in blood pressure. 16 These promising results prompted the recent trialing of Ucn2 as a short-term parenteral therapy in patients with acute decompensated HF.…”

Old and New Intravenous Inotropic Agents in the Treatment of Advanced Heart Failure

“…[65][66][67] A favorable interaction with diuretic treatment with increased diuretic responsiveness and blunting of furosemide-induced renin increase has also been shown. 68 Urocortin 3 (stresscopin) is now undergoing further assessment in larger clinical trials in patients with HF.…”