Urocortin 1 administration from onset of rapid left ventricular pacing represses progression to overt heart failure

Abstract

Rademaker MT, Charles CJ, Richards AM. Urocortin 1 administration from onset of rapid left ventricular pacing represses progression to overt heart failure. Am J Physiol Heart Circ Physiol 293: H1536-H1544, 2007. First published May 25, 2007; doi:10.1152/ajpheart.00377.2007.-Urocortin 1 (Ucn1) may be involved in the pathophysiology of heart failure (HF), but the impact of Ucn1 administration on progression of the disease is unknown. The aim of this study was to investigate the effects of Ucn1 in sheep from the onset of cardiac overload and during the subsequent development of HF. Eight sheep underwent two 4-day periods of HF induction by rapid left ventricular pacing (225 beats/min) in conjunction with continuous infusions of Ucn1 (0.1 g ⅐ kg Ϫ1 ⅐ h Ϫ1 iv) and a vehicle control (0.9% saline). Compared with control, Ucn1 attenuated the pacing-induced decline in cardiac output (2.43 Ϯ 0.46 vs. 3.70 Ϯ 0.89 l/min on day 4, P Ͻ 0.01) and increases in left atrial pressure (24.9 Ϯ 1.0 vs. 11.9 Ϯ 1.1 mmHg, P Ͻ 0.001) and peripheral resistance (38.7 Ϯ 9.4 vs. 25.2 Ϯ 6.1 mmHg ⅐ l Ϫ1 ⅐ min, P Ͻ 0.001). Ucn1 wholly prevented increases in plasma renin activity (4.02 Ϯ 1.17 vs. 0.87 Ϯ 0.1 nmol ⅐ l Ϫ1 ⅐ h Ϫ1 , P Ͻ 0.001), aldosterone (1,313 Ϯ 324 vs. 413 Ϯ 174 pmol/l, P Ͻ 0.001), endothelin-1 (3.8 Ϯ 0.5 vs. 2.0 Ϯ 0.1 pmol/l, P Ͻ 0.001), and vasopressin (10.8 Ϯ 4.1 vs. 1.8 Ϯ 0.2 pmol/l, P Ͻ 0.05) during pacing alone and blunted the progressive increases in plasma epinephrine (2,132 Ϯ 697 vs. 1,250 Ϯ 264 pmol/l, P Ͻ 0.05), norepinephrine (3.61 Ϯ 0.73 vs. 2.07 Ϯ 0.52 nmol/l, P Ͻ 0.05), and atrial (P Ͻ 0.05) and brain (P Ͻ 0.01) natriuretic peptide levels. Ucn1 administration also maintained urine sodium excretion (0.75 Ϯ 0.34 vs. 1.59 Ϯ 0.50 mmol/h on day 4, P Ͻ 0.05) and suppressed pacing-induced declines in creatinine clearance (P Ͻ 0.05). These findings indicate that Ucn1 treatment from the onset of cardiac overload has the ability to repress the ensuing hemodynamic and renal deterioration and concomitant adverse neurohumoral activation, thereby delaying the development of overt HF. These data strongly support a use for Ucn1 as a therapeutic option early in the course of the disease. cardiac output; hormones; renal function UROCORTIN 1 (Ucn1), a 40-amino acid peptide belonging to the corticotropin-releasing factor family (43), is reported to participate in regulation of the cardiovascular system. The peptide is present in high concentrations in the heart (24) and endothelial and smooth muscle cells of the systemic vasculature (12, 17), and its peripheral distribution closely matches that of the corticotropin-releasing factor receptor type 2, the G proteincoupled receptor reported to mediate its cardiovascular bioactivity (22,44). Systemic administration of Ucn1 induces sustained arterial (6,22,44) and venous (38) dilatation, increases in coronary blood flow and conductance, and positive inotropic and chronotropic effects (1,27,32,33,42). Ucn1 has also been shown to prevent cell death in cultured cardiac myocytes exposed to hyp...

Plasma Urocortin 1 in Human Heart Failure

“…In experimental heart failure, deliberate antagonism of endogenous urocortins clearly exacerbates hemodynamic, neurohormonal, and renal impairment. 3 Taken together with previous studies defining the bioactivity of the urocortins in experimental heart failure, [1][2][3][4][5] it seems likely that elevated plasma urocortin 1 in human heart failure reflects a beneficial compensatory response to this condition.…”

“…[1][2][3][4][5] In stable human heart failure infusions of urocortin 1, at the doses chosen, had little hemodynamic effect, whereas urocortin 2 markedly augmented cardiac output when reducing systemic vascular resistance. 6,7 Urocortins have cardioprotective effects in experimental ischemia/reperfusion.…”

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

“…Samples were taken into EDTA tubes on ice, centrifuged at 4°C, and stored at either Ϫ20°C or Ϫ80°C before assay for plasma renin activity (PRA), aldosterone, arginine vasopressin (AVP), endothelin-1, atrial natriuretic peptide, brain natriuretic peptide, and catecholamines. 20 For each hormone, all samples from individual animals were measured in the same assay to avoid interassay variability. Plasma electrolytes and hematocrit were measured with every blood sample taken.…”

Hemodynamic, Hormonal, and Renal Actions of Adrenomedullin 2 in Experimental Heart Failure

“…Samples were taken into EDTA tubes on ice, centrifuged at 4°C, and stored at either Ϫ20°C or Ϫ80°C before assay for cAMP, plasma renin activity (PRA), aldosterone, arginine vasopressin, cortisol, endothelin-1, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and catecholamines. 27 For each hormone, all samples from individual animals were measured in the same assay to avoid interassay variability. Hematocrit was measured with every blood sample taken.…”