The cardiovascular physiologic actions of urocortin II: acute effects in murine heart failure

Abstract

Corticotropin-releasing factor (CRF) and its paralogues urocortin (Ucn)I, -II, and -III signal by activating their receptors, CRF receptors (CRFR)1 and -2, to maintain homeostasis through endocrine, autonomic, and behavioral responses. CRFR2 is found in cardiomyocytes and in endothelial and smooth muscle cells of the systemic vasculature. Echocardiography and cardiac catheterization were used in mice to assess the physiologic effects of i.v. UcnII and CRFR2 deficiency on left ventricular function and the systemic vasculature. UcnII treatment augmented heart rate, exhibited potent inotropic and lusitropic actions on the left ventricle, and induced a downward shift of the diastolic pressure-volume relation. UcnII also reduced systemic arterial pressure, associated with a lowering of systemic arterial elastance (end-systolic pressure/stroke volume) and systemic vascular resistance. CRFR2-deficient mice showed no alteration in cardiac contractility or blood pressure in response to UcnII administration, suggesting that the effects of UcnII are specific to CRFR2 function. Pretreatment with a beta-adrenergic receptor antagonist, esmalol, had no effect on the inotropic or lusitropic effects of UcnII in vivo, indicating that its actions are independent of beta-adrenergic receptors. Single i.v. bolus administration of UcnII to a heart failure model (muscle-specific LIM protein-deficient mice) produced significant enhancement of inotropic and lusitropic effects on left ventricular function and improved cardiac output. These results demonstrate the potent cardiovascular physiologic actions of UcnII in both wild-type and cardiomyopathic mice and support a potential beneficial use of this peptide in therapy of congestive heart failure.

Fig. 1.

A micromanometer-impedance catheter recording of LV pressure and volume before and after administration of UcnII. (A) The raw signals for volume, pressure, and dP/dt. (B) Pressure-volume loops at control (black) and 2 min after i.v. UcnII (gray); note marked increase in stroke volume. (C) Pressure-volume loops recorded at high gain. Note the downward shift of in vivo diastolic pressure-volume relation in response to UcnII.

Fig. 2.

Effect of UcnII on LV peak (+) dP/dt, wild-type vs. CRFR2-deficient mice. (A) Increase in peak (+) dP/dt in wild-type but not CRFR2-deficient mice at 2 and 5 min post-i.v. UcnII (^*, P < 0.01 vs. basal state). (B) Comparison of increase in peak (+) dP/dt over basal state, UcnI (black) vs. UcnII (gray, cross-hatched). UcnII response was significantly greater at 5 min than that of UcnI (#, P < 0.05). (C) After β-AR blockade, infusion of UcnII causes significant enhancement of peak (+) dP/dt, with no change detected in CRFR2-deficient mice. Symbols are as in A and B.

Fig. 3.

(A) LV pressure-volume loops recorded during a transient constriction of transverse aorta of the wild-type mouse; control state shown in black and 5 min after UcnII bolus in gray; the points of maximal elastance (P/V) for each beat are curve-fitted to a second-order polynomial equation to derive E_max. Note the leftward and upward shift of E_max in response to UcnII. Effective arterial elastance (E_ff E_a), plotted on same volume axis, shifts downward. (B) Digitally averaged, steady-state, pressure-volume loops are shown from a second mouse.

Fig. 4.

Effect of paced increase in heart rate before and 5 min after administration of i.v. bolus of UcnII. UcnII enhances LV peak (+) dP/dt over and above that of heart rate alone and shifts the force-frequency relation upward and to the right (^*, P < 0.01 vs. control at same heart rate; ^, P < 0.05 vs. control at same heart rate). Arrow indicates point of UcnII administration.

Fig. 5.

LV function parameters in MLP-deficient mice before and 15 min after i.v. bolus of UcnII. (Bars = SEM.) (A) End-diastolic pressure. (B) EDV. (C) Peak (+) dP/dt. (D) τ. (E) Ejection fraction. (F) E_max. ^*, P ≤ 0.05 vs. control; ^**, P ≤ 0.01 vs. control; ^***, P ≤ 0.001 vs. control.