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 β-adrenergic receptor antagonist, esmalol, had no effect on the inotropic or lusitropic effects of UcnII in vivo, indicating that its actions are independent of β-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.

Corticotropin-releasing factor (CRF), a coordinator of the hypothalamic-pituitary-adrenal axis (1), is one of a family of peptides that includes urocortin (Ucn)I (2), UcnII (also known as stresscopin-related peptide) (3, 4), and UcnIII (also known as stresscopin) (4, 5). These peptides signal through two G protein-coupled receptors, CRF receptors (CRFR)1 and -2, to modulate endocrine, autonomic, and behavioral responses to stress. Although both receptors are found in the central nervous system, CRFR2 is particularly abundant in the periphery, including the heart and systemic vasculature (6-10). UcnII and -III bind selectively to CRFR2, with no appreciable activity at CRFR1 (3, 5).

CRF and UcnI both demonstrate vasodilatory, inotropic, and chronotropic effects on the cardiovascular system via activation of CRFR2 on cardiac myocytes and in the systemic vasculature (2, 11-14). These actions are absent in CRFR2-deficient mice (15, 16). However, both CRF and UcnI also activate CRFR1 in the pituitary and thus stimulate the hypothalamic-pituitary-adrenal axis, complicating the potential use of these peptides for treatment of cardiovascular disorders (14). Therefore, to characterize the cardiovascular physiologic influences of UcnII, wild-type and CRFR2-deficient mice were investigated by using catheter and echocardiographic techniques. Micromanometry and impedance volumetry were used during heart rate control to assess the effect of UcnII administration on left ventricular (LV) myocardial contractility, independent of the force-frequency relation. Effective arterial elastance and systemic vascular resistance were calculated to quantify a vasodilatory effect of UcnII and to further assess the hemodynamic basis of hypertension in CRFR2-deficient mice. We also explored the involvement of β-adrenergic receptors (β-AR) in the myocardial actions of UcnII by examination of CRFR2 activation during β-AR blockade. Finally, the effects of UcnII on myocardial performance and cardiovascular hemodynamics were examined in muscle-specific LIM protein (MLP)-deficient mice, known to develop dilated cardiomyopathy with hypertrophy and heart failure after birth (17-20).

Methods

Animals. CRFR2- and MLP-deficient mice and their wild-type littermates were generated as described (15) and housed in transgenic mouse facilities under a 12-hr light/dark cycle. Mice were studied according to a protocol approved by the Animal Subjects Committee of the University of California at San Diego and research was conducted in accordance with institutional guidelines.

Physiologic Measurements. Transthoracic echocardiography. Echocardiography was performed on anesthetized [2.5% Avertin (Aldrich), 14 μl/g i.p.], spontaneously breathing mice by using a Hewlett-Packard/Phillips 5500 machine and a 15-MHz transducer. Measurements of left ventricle dimensions were made as described (21). LV volume was derived as an ellipse of revolution, assuming that (i) the minor axes are equivalent, and (ii) the major axis of the chamber is twice the measured minor axis (22-24). Cardiac output of wild-type and CRFR2-deficient mice was derived from the product of stroke volume [LV end-diastolic volume (EDV)-end-systolic volume (ESV)] and simultaneous heart rate.

Cardiac catheterization. Hemodynamic evaluation in both CRFR2-deficient and wild-type mice was performed while animals were under general anesthesia [ketamine (100 mg/kg) and xylazine (2.5 mg/kg)] while connected to a ventilator. After bilateral vagotomy, 1.4 French (0.46-mm) micromanometer catheters (Millar Instruments, Houston) were inserted into the right atrium and LV where phasic and mean pressures were continuously monitored (Gould, Cleveland). Systemic vascular resistance was calculated as [(mean aortic pressure - mean right atrial pressure)/cardiac output]. All physiologic signals were acquired by using windaq (Dataq Instruments, Akron, OH). Postprocessing of micromanometer pressure signals for calculation of peak (+) and (-)dP/dt, τ_E, and τ_L (the monoexponential and logistic rate constants of isovolumic pressure fall, respectively) was accomplished by using software developed for our laboratory.

In a subset of wild-type mice, a miniaturized conductance catheter-micromanometer (Millar Instruments) was used to measure simultaneous pressure and volume in the LV before and after i.v. UcnII (Fig. 1) (25). LV volume calibration for the impedance signal was accomplished by digital contrast biplane angiography with the catheter in the LV; the calculation of EDV and ESV used Simpson's rule (26-29). LV ejection fraction was calculated as 1-(ESV/EDV).

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.

E_max (slope of the end-systolic pressure-volume relation), as a specific measure of contractility, and V₀ (the extrapolated ESV at which pressure is zero) were derived from an averaged steady-state pressure-volume loop (n = 7) by using a bilinearly approximated time-varying elastance curve applied to the isovolumic and ejection phases of systole (30). Derived effective arterial elastance (end-systolic pressure/stroke volume) was used as a variable that quantifies in the aggregate the characteristic impedance, resistive, and stiffness properties of the systemic vasculature (31, 32).

Force-frequency analysis. In a subset of wild-type mice (n = 5), the direct effect on myocardial contractility of UcnII, as opposed to a secondary effect through heart rate augmentation (force-frequency relation), was evaluated. In these experiments, the heart rate was first slowed by using zatebradine and thereafter controlled and augmented by using a pacing wire placed in the right atrium (33).

Administration of UcnII. The hemodynamic influences of UcnII were measured before and at specified time points after the i.v. bolus injection of 7.5 μg/kg of the peptide. In a subset of mice (CRFR2-deficient, n = 3; wild-type, n = 4), UcnII was administered 30 min after the initiation of an ongoing infusion of esmalol (150 μg/kg per min).

Statistical analysis. Observations made pre- and post-UcnII administration were tested for significance (P < 0.05) by using a paired two-tail Student t test. Multiple repeated observations were subjected to repeated-measures ANOVA, with analysis of within- and between-group differences by using Student-Newman-Keuls post hoc testing for significance (P < 0.05).

Results

Basal Systemic Arterial Blood Pressure and Peripheral Vascular Resistance. Aortic pressure [peak systolic, mean, mmHg (1 mmHg = 133 Pa)], cardiac output (ml/min), and calculated systemic vascular resistance (mmHg/ml) for CRFR2-deficient and wild-type littermates under general anesthesia are presented in Table 1.

Table 1. Systemic arterial hemodynamic and LV function data in anesthetized, basal state: wild-type and CRFR2-deficient mice.

Group/parameter	Wild type, mean ± SEM	CRFR2-deficient, mean ± SEM
Systemic hemodynamic	n = 6	n = 8
Aortic peak pressure, mmHg	76.7 ± 4.4	95.2 ± 3.3*
Aortic mean pressure, mmHg	61.8 ± 4.1	81.7 ± 3.2*
Right atrial pressure, mmHg	7.4 ± 1.4	6.0 ± 0.7
Cardiac output, ml/min	9.65 ± 1.03	9.70 ± 0.68
Systemic vascular resistance, mmHg/ml	6.06 ± 0.92	8.18 ± 0.83†
Left ventricular micromanometer	n = 17	n = 12
End-diastolic pressure, mmHg	5.8 ± 0.9	6.6 ± 1.2
Peak (+) dP/dt, mmHg/s	7944 ± 554	7123 ± 773
Peak (−) dP/dt, mmHg/s	−6,100 ± 451	−5,553 ± 635
τ, msec	14.8 ± 1.3	17.5 ± 1.7
Left ventricular echocardiography	n = 12	n = 14
End-diastolic diameter, mm	3.73 ± 0.19	3.83 ± 0.17
End-systolic diameter, mm	2.13 ± 0.28	2.14 ± 0.23
Fractional shortening, %	35.5 ± 2.4	35.5 ± 1.2
Posterior wall dimension, mm	0.69 ± 0.01	0.74 ± 0.02†
End-diastolic diameter/posterior wall dimension	5.41 ± 0.29	5.24 ± 0.26
Calculated mass	0.083 ± 0.007	0.092 ± 0.005

^*P ≤ 0.01 vs. wild type.

^†P ≤ 0.05 vs. wild type.

Null deletion of CRFR2 was associated with augmentation of systemic arterial peak systolic and mean blood pressure and systemic vascular resistance. No difference was noted in heart rate, stroke volume, calculated cardiac output, or mean right atrial pressure.

Basal LV Function and Morphology. Using LV micromanometry, basal LV peak (+) dP/dt, peak (-) dP/dt, LV end-diastolic pressure, and τ (monoexponential rate constant of isovolumic relaxation) were normal and not different between wild-type and CRFR2-deficient mice. Echocardiography revealed that the LV end-diastolic diameter, end-systolic diameter, and percentage fractional shortening of the minor axis were normal in both wild-type and CRFR2-deficient groups of mice (Table 1). The posterior wall thickness was found to be slightly higher in the CRFR2-deficient mice; however, when normalized to end-diastolic diameter, this difference was no longer observed. Accordingly, calculated LV mass was not different between the CRFR2-deficient and wild-type groups (Table 1).

Acute Effects of i.v. UcnII on LV Function and Contractility. Acute effects of UcnII on LV function and contractility were analyzed in wild-type and CRFR2-deficient mice. A marked augmentation in peak (+) dP/dt occurred in the wild-type mice despite a significant decline in LV end-diastolic pressure. The augmentation of peak (+) dP/dt began within 2 min after injection, peaked between 5 and 10 min, and was still apparent 20 min after injection. This effect was not detected in the CRFR2-deficient mice (Fig. 2A and Table 2). Comparisons in wild-type mice of equal doses of UcnII and -I revealed that the former caused a more potent enhancement of peak (+) dP/dt (Fig. 2B). Despite ongoing infusion of the β₁-adrenergic receptor antagonist, esmalol, UcnII administration in wild-type mice caused a significant elevation of LV peak (+) dP/dt. This effect was absent in the CRFR2-null mice (Fig. 2C). UcnII administration was associated with a decline in maximum LV pressure (Table 2). LV isovolumic relaxation accelerated in response to UcnII (Table 2). Administration of UcnII to wild-type mice while heart rate was controlled with atrial pacing at 450 beats per min caused a decrease in EDV and ESV, augmentation of stroke volume, a highly significant increase in LV ejection fraction, and an average 27% increase in cardiac output (Table 3). Arterial elastance and resistance both declined significantly, reflecting a potent vasodilatory property of UcnII. Based on a theoretical coupling of effective arterial elastance to end-systolic elastance with prediction of LV ejection fraction (32), reduced E_a (afterload) and enhanced E_es (inotropism) were estimated, on the average, to account for 39.3% and 60.7%, respectively, of the significant improvement in ejection fraction (Fig. 3 and Table 3).

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.

Table 2. Effects of Ucnll on micromanometer-derived LV function parameters: wild-type and CRFR2-deficient mice.

Group/parameter	Wild-type, mean ± SEM, n = 12	CRFR2-deficient, mean ± SEM, n = 4
LV end-diastolic pressure*
Control	6.0 ± 1.1	6.2 ± 1.9
5 min-Ucnll	1.5 ± 0.4†	6.8 ± 2.0
10 min-Ucnll	1.9 ± 0.5†	8.0 ± 3.1
LV peak systolic pressure*
Control	115 ± 6	143 ± 15
5 min-Ucnll	100 ± 6‡	149 ± 8
10 min-Ucnll	100 ± 3‡	144 ± 5
LV peak (+) dp/dt*
Control	8,804 ± 577	11,443 ± 82
5 min-Ucnll	15,199 ± 813†	10,963 ± 110
10 min-Ucnll	15,004 ± 672†	10,728 ± 58
LV peak (−) dp/dt
Control	−7,003 ± 351	−9,344 ± 624
5 min-Ucnll	−6,704 ± 551†	−8,859 ± 487
10 min-Ucnll	−6,306 ± 324‡	−8,611 ± 535
τE
Control	13.0 ± 1.0	11.6 ± 0.7
5 min-Ucnll	10.0 ± 0.8	13.7 ± 1.5
10 min-Ucnll	9.8 ± 0.9	14.3 ± 1.3
τL*
Control	5.4 ± 1.0	5.2 ± 1.3
5 min-Ucnll	4.5 ± 0.7‡	6.6 ± 0.6
10 min-Ucnll	4.4 ± 0.9‡	6.8 ± 0.5
Heart rate*§
Control	367 ± 29	373 ± 17
5 min-Ucnll	523 ± 20†	363 ± 26
10 min-Ucnll	542 ± 22†	360 ± 33

τ_E, monoexponential function; τ_L, logistic function; ANOVA, wild-type vs. CRFR2-deficient: §, P ≤ 0.05; *, P ≤ 0.01; ANOVA-Ucnll vs. control; ‡, P ≤ 0.05; †, P ≤ 0.001.

Table 3. Effects of Ucnll on LV pressure-volume relations and cardiovascular hemodynamics: wild-type and MLP-deficient mice.

	Wild-type, n = 7		MLP-deficient, n = 10
Group/parameter	Control	Ucnll (7.5 μg/kg)	Control	Ucnll (7.5 μg/kg)
Heart rate (beats/min; paced)	450	450	455 ± 34	595 ± 34*
EDV, μl	38.2 ± 1.7	32.4 ± 3.0†	56.8 ± 3.7	39.8 ± 5.8‡
End-diastolic pressure, mmHg	7.9 ± 2.1	3.2 ± 1.6†	10.3 ± 3.7	3.3 ± 0.7‡
ESV, μl	18.1 ± 1.7	7.6 ± 1.7†	48.6 ± 4.2	35.5 ± 4.3‡
Peak (+) dp/dt, mmHg/s	8,966 ± 429	15,480 ± 1,575†	4,758 ± 422	6,730 ± 438*
Ejection fraction	0.51 ± 0.06	0.77 ± 0.05*	0.20 ± 0.03	0.32 ± 0.04*
Emax, mmHg/μl	7.7 ± 1.0	21.8 ± 9.1	4.3 ± 1.1	5.8 ± 1.8‡
Vo, μl	4.8 ± 0.8	1.9 ± 0.9†	30.3 ± 5.3	19.2 ± 4.8
τE, ms	10.2 ± 0.6	7.3 ± 0.5†	27.8 ± 6.2	9.4 ± 1.1†
Stroke volume, μl	21.3 ± 3.4	27.2 ± 3.7†	14.0 ± 2.5	14.7 ± 2.4
Cardiac output, ml/min	9.59 ± 1.53	12.26 ± 1.65†	6.38 ± 0.98	8.46 ± 1.29*
Arterial elastance, mmHg/μl	5.9 ± 0.8	3.1 ± 0.3†	8.6 ± 1.9	6.6 ± 1.7‡
Arterial Resistance (Ea × HR−1) × 103	14.9 ± 1.9	7.8 ± 0.7†	18.9 ± 5.2	11.0 ± 2.7†

E_max, End-systolic elastance; V_o, volume at extrapolated end-systolic pressure of 0 mmHg; E_a, arterial elastance; HR, heart rate.

^*P ≤ 0.001 vs. control.

^†P ≤ 0.01 vs. control.

^‡P ≤ 0.05 vs. control.

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.

Effects of UcnII on Heart Rate and Force-Frequency Relation. UcnII caused elevation of the heart rate above basal levels. This chronotropic effect became notable ≈5 min after administration of the peptide (Table 2). In view of the known influence on contractility of heart rate (the force-frequency relation), we analyzed LV peak (+) dP/dt over a broad range of atrial-paced heart rates, before and after UcnII administration. For any given heart rate, UcnII significantly enhanced peak (+) dP/dt well above that caused by pacing alone (Fig. 4).

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.

Therapeutic Effects of UcnII in a Mouse Model of Myocardial Failure. Treatment of MLP-deficient cardiomyopathic mice with a bolus i.v. injection of 7.5 μg/kg UcnII produced prompt physiologic effects similar to those in noted in wild-type littermates. UcnII caused significant reduction in LV EDV and ESV, with concomitant improvement in LV ejection fraction (Table 3, Fig. 5). Despite the diminution in preload, the stroke volume remained unchanged. Cardiac output increased significantly. Further, MLP-deficient mice showed a significant reduction in end-diastolic pressure, τ, and peak (-) dP/dt (Table 3, Fig. 5).

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.

Discussion

In this investigation, UcnII, signaling through CRFR2 and independently of β-AR, caused a potent enhancement of myocardial inotropy and lusitropy. In examination of the acute effects of UcnII in MLP-deficient mice as a model of dilated cardiomyopathy, UcnII administration caused a dramatic improvement in systolic ventricular-arterial coupling, enhancement of myocardial contractility, and a significant declination in systolic load. After administration of UcnII to the MLP mouse, systemic vascular resistance returned to levels at or below those calculated in wild-type littermates.

CRFR2-deficient mice showed no detectable difference in basal LV or cardiac function compared to littermates. However, these mice exhibited a significant elevation of peak and mean aortic pressure as well as significantly elevated systemic vascular resistance, confirming the previously published observation that systemic arterial pressure is increased in these mice (16). The elevated vascular resistance is likely related to an enhancement of arteriolar and possibly arterial tone. Potent inotropic actions of UcnII signaling specifically through CRFR2 were deduced from its rapid and marked enhancement of LV peak (+) dP/dt in wild-type but not CRFR2-deficient mice. Although affected directly by preload, LV peak (+) dP/dt is very sensitive to changes in contractility while remaining free of the influence of ejection phase load. By echocardiography and impedance catheter measurements, LV minor axis diameter and volume diminished in response to i.v. UcnII. Confirmation of the inotropic effect was further demonstrated by the LV end-systolic pressure-volume relation that manifested as an increased slope (E_max) in response to UcnII administration. Complete pharmacological dose-response and duration of action studies for UcnII are yet to be determined.

Because many of the actions noted with UcnII administration mimicked those associated with β-AR agonists, we analyzed the effects of UcnII during β-AR blockade with esmalol. Previous studies have demonstrated that coronary blood flow and aortic pressure changes during CRF perfusion of isolated rat hearts were not affected by cotreatment with propranolol (34). Our data support these findings in that pretreatment with the β-AR antagonist, esmalol, did not interfere with enhancement of peak (+) dP/dt by UcnII treatment of wild-type mice. This observation may have significant implications for the use of UcnII in both acute and chronic congestive heart failure, prevalent conditions whose pathogenesis and treatment are influenced significantly by attenuation of β-AR signaling (35, 36).

UcnII activation of CRFR2 leads to increased cAMP-dependent PKA activity, phosphorylation of phospholamban, and reduced inhibition of sarcoendoplasmic reticulum calcium-ATPase (13, 37). UcnII is also known to activate the phosphatidylinositol-3 kinase/PKB (Akt) pathway (38). Actions related to inhibition of phosphodiesterases or enhanced calcium release are also possible mechanisms of UcnII. The inotropic effect of UcnII may be partially attributable to the force-frequency relation mediated by the observed chronotropic effect. However, as shown in Fig. 4, UcnII amplified peak (+) dP/dt well above that associated with a pacing-induced increase in heart rate alone. This observed amplification of the force-frequency relation is similar to the influence exerted by dobutamine (33).

UcnII was noted to decrease systemic arterial load as quantified by arterial elastance (ratio of end-systolic pressure to stroke volume) and systemic arterial resistance. Arterial elastance correlates highly with mean arterial resistance and, when lowered, significantly changes ventricular-arterial coupling and allows greater degrees of ventricular shortening (31, 39). Thus, part of the enhancement of ejection fraction by UcnII can be attributed to reduction of arterial load. Our data calculations in the wild-type mouse suggest that the afterload-reduction effect accounts for ≈40% of the observed increase in ejection fraction. This effect may prove even more notable in the failing heart when significant afterload mismatch occurs. UcnII also shortened τ and τ_L, the monoexponential and logistic rate constants for isovolumic pressure decay. LV EDV and end-diastolic pressure were significantly reduced by UcnII treatment.

To assess the potential benefit of UcnII administration on depressed LV function, we used mice deficient in MLP, a Z disk protein, as a model of dilated cardiomyopathy. The Z disk is integral to sarcolemmal membrane integrity, sarcomeric assembly, and organization, mechanical stress sensing, and myofiber force generation. After birth, MLP-deficient mice develop hypertrophy, multichamber dilation, markedly reduced extent of LV shortening, altered diastolic relaxation, and filling, pathophysiologic attributes often seen in heart failure in humans (17-20). Treatment of MLP-deficient mice with UcnII produced significant and dramatic improvement in cardiac output and LV function. Also notable with UcnII treatment in these mice were significant improvements in LV ejection fraction and rate of relaxation. Finally, LV afterload was beneficially affected by the reduction in LV size, aortic impedance, and systemic vascular resistance, all of which are important determinants of wall stress.

Some caution should be exercised regarding the prospective use of a new agent with potent inotropic action for treatment of human myocardial failure. Some clinical drug trials have shown that a beneficial response in hemodynamic variables alone during acute heart failure does not necessarily portend a satisfactory long-term outcome (40). Although not seen in these acute studies, it is possible that chronic UcnII administration could lead to a state of diastolic calcium overload and prove to be proarrhythmic. Further experimental testing and clinical trials are required to resolve these issues.

Conclusion

In summary, we have demonstrated potent inotropic, lusitropic, and systemic arterial load reduction effects of UcnII on the LV myocardium, with attendant enhancement of cardiac output, in mice. We have shown an endogenous role for CRFR2 in modulation of basal pressure. UcnII treatment of mice with dilated cardiomyopathy resulted in significant improvement. These results portend a potential use of UcnII for palliative relief of the abnormal pump performance associated with congestive heart failure.