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Am J Physiol Heart Circ Physiol 293: H1536-H1544, 2007. First published May 25, 2007; doi:10.1152/ajpheart.00377.2007
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Urocortin 1 administration from onset of rapid left ventricular pacing represses progression to overt heart failure

Miriam T. Rademaker, Chris J. Charles, and A. Mark Richards

Christchurch Cardioendocrine Research Group, Department of Medicine, Christchurch School of Medicine, Christchurch, New Zealand

Submitted 26 March 2007 ; accepted in final form 23 May 2007


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
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 µg·kg–1·h–1 iv) and a vehicle control (0.9% saline). Compared with control, Ucn1 attenuated the pacing-induced decline in cardiac output (2.43 ± 0.46 vs. 3.70 ± 0.89 l/min on day 4, P < 0.01) and increases in left atrial pressure (24.9 ± 1.0 vs. 11.9 ± 1.1 mmHg, P < 0.001) and peripheral resistance (38.7 ± 9.4 vs. 25.2 ± 6.1 mmHg·l–1·min, P < 0.001). Ucn1 wholly prevented increases in plasma renin activity (4.02 ± 1.17 vs. 0.87 ± 0.1 nmol·l–1·h–1, P < 0.001), aldosterone (1,313 ± 324 vs. 413 ± 174 pmol/l, P < 0.001), endothelin-1 (3.8 ± 0.5 vs. 2.0 ± 0.1 pmol/l, P < 0.001), and vasopressin (10.8 ± 4.1 vs. 1.8 ± 0.2 pmol/l, P < 0.05) during pacing alone and blunted the progressive increases in plasma epinephrine (2,132 ± 697 vs. 1,250 ± 264 pmol/l, P < 0.05), norepinephrine (3.61 ± 0.73 vs. 2.07 ± 0.52 nmol/l, P < 0.05), and atrial (P < 0.05) and brain (P < 0.01) natriuretic peptide levels. Ucn1 administration also maintained urine sodium excretion (0.75 ± 0.34 vs. 1.59 ± 0.50 mmol/h on day 4, P < 0.05) and suppressed pacing-induced declines in creatinine clearance (P < 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 protein-coupled 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 hypoxia (26) and to protect coronary endothelial function and significantly reduce infarct size, arrhythmias, and oxidative stress in the rat heart after ischemia-reperfusion injury (4, 14, 20).

The nature of Ucn1's cardiovascular actions, together with evidence that ventricular (24, 18) and circulating (23, 32) concentrations of the peptide are significantly elevated in heart failure (HF), invites speculation that Ucn1 might act as a protective counterbalance to preserve cardiac function and circulatory homeostasis in HF. Indeed, we recently showed that Ucn1 administration produces results in considerable hemodynamic, endocrine, and renal benefits in an experimental model of severe congestive HF (32, 33). However, its actions in normal health are greatly attenuated, with a reduced effect on hemodynamics and a negligible influence on vasoactive hormones and kidney function (32). Given these disparate results, the impact of Ucn1 in mild HF or early in the course of the disease is uncertain. We therefore investigated the integrated effects of Ucn1 infusion in sheep from the onset of cardiac overload and during the subsequent development of cardiac decompensation and overt HF induced by rapid left ventricular (LV) pacing.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Surgical preparation. Eight Coopworth ewes (47–60 kg body wt) were instrumented via a left lateral thoracotomy under general anesthesia (induction with 17 mg/kg thiopentone and maintenance with halothane-nitrous oxide) (10). Two polyvinyl chloride catheters were inserted into the left atrium for blood sampling and left atrial pressure (LAP) determination, a Konigsberg pressure-tip transducer was inserted into the aorta for mean arterial pressure (MAP) recording, an electromagnetic flow probe was placed around the ascending aorta for cardiac output (CO) measurement, a Swan-Ganz catheter was inserted into the pulmonary artery for infusions, and a 7-Fr His-bundle electrode was stitched subepicardially to the wall of the LV for pacing. A bladder catheter was inserted into the urethra for urine collections. Animals recovered for 14 days before commencing the study protocol. During the experiments, the animals were held in metabolic cages, fed a standard laboratory diet (500 g of sheep pellets and 250 g of chaff per day, which provided 80 mmol of sodium and 200 mmol of potassium), and had free access to water.

Study protocol. Each animal underwent two separate periods of continuous rapid LV pacing (225 beats/min) for 4 days to allow the development of congestive HF (10, 35). Ten days without pacing between phases allowed all indexes to recover to normal prepacing levels. On initiation of pacing, the animals received a constant 4-day infusion of ovine Ucn1 (0.1 µg·kg–1·h–1 iv; American Peptide) or a vehicle control (50 ml of 0.9% saline per day) in a crossover design.

MAP, LAP, CO, and calculated total peripheral resistance (CTPR = MAP/CO) were recorded at 15-min intervals in the hour preceding pacing/treatment on study day 0 (baseline), at 0.5, 1, 2, 4, and 6 h after commencement of pacing/treatment, and then daily on study days 1–4. Hemodynamic measurements were determined by online computer-assisted analysis using established methods (11). Blood samples were drawn from the left atrium (immediately after hemodynamic measurements) into EDTA-containing tubes on ice, centrifuged at 4°C, and stored at –80°C before assay for Ucn1 (32), cAMP (commercial kit, Biotrak, Amersham, Little Chalfont, UK), AVP (36), cortisol (19), atrial and brain natriuretic peptide (ANP and BNP, respectively) (5, 28), plasma renin activity (PRA) (9), aldosterone (21), endothelin-1 (29), catecholamines (15), and ACTH. ACTH was measured by RIA, as described previously (8), except samples were extracted over Sep-Pak C18 columns before RIA. Extracts were eluted with 80% isopropanol-0.1% trifluoroacetic acid and dried at 37°C and then resuspended in assay buffer. All samples from individual animals were measured in the same assay to avoid interassay variability. Plasma electrolytes and hematocrit were measured each time a blood sample was taken.

Urine volume and samples for measurement of urine cAMP, sodium, potassium, and creatinine excretion were collected over the 2 h before pacing/treatment on study day 0 (baseline), at 2, 4, and 6 h after commencement of pacing/treatment, and then daily on study days 1–4. Water intake was measured as described for urine output. The study protocol was approved by the Animal Ethics Committee of the Christchurch School of Medicine and Health Sciences.

Statistics. Values are means ± SE. Differences between control and Ucn1 baseline data (mean of measurements made within 1 h before pacing/treatment) were compared using paired t-tests. Effects of pacing (development of HF) were assessed by analysis of temporal changes over the control phase using one-way repeated-measures ANOVA. Differences between control and Ucn1 treatments were analyzed by two-way ANOVA (treatment x time interactions). Where significant differences were identified by ANOVA, the level of significance at individual time points was determined by Fisher's protected least significant difference tests.

The Ucn1 treatment arm of the study was also analyzed separately by one-way ANOVA to assess temporal changes (or, rather, lack thereof) in indexes that appeared to change little from baseline over the 4 days of pacing. Significance was assumed at P < 0.05.


   RESULTS
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 METHODS
 RESULTS
DISCUSSION
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Effects of rapid LV pacing. No significant baseline differences were noted between the control and Ucn1 study arms.

Four days of rapid LV pacing during the control phase of the study induced the hemodynamic deterioration, ubiquitous hormonal activation, and sodium-retaining hallmarks of congestive HF. We noted marked, progressive reductions in CO (control baseline vs. day 4: 6.96 ± 1.76 vs. 2.43 ± 0.46 l/min, P < 0.001) and MAP (85.6 ± 2.5 vs. 73.2 ± 3.6 mmHg, P < 0.001) and increases in LAP (3.5 ± 0.4 vs. 24.9 ± 1.0 mmHg, P < 0.001) and CTPR (16.7 ± 3.9 vs. 38.7 ± 9.4 mmHg·l–1·min, P < 0.001; Fig. 1). These changes were associated with significant increases in plasma Ucn1 (16.2 ± 1.3 vs. 19.0 ± 0.7 pmol/l, P < 0.05), cAMP (24.2 ± 2.0 vs. 34.2 ± 4.3 pmol/l, P < 0.01), AVP (1.45 ± 0.11 vs. 10.84 ± 4.08 pmol/l, P < 0.05; Fig. 2), PRA (0.42 ± 0.06 vs. 4.02 ± 1.17 nmol·l–1·h–1, P < 0.001), aldosterone (434 ± 104 vs. 1,313 ± 324 pmol/l, P < 0.001), endothelin-1 (1.9 ± 0.1 vs. 3.8 ± 0.5 pmol/l, P < 0.001; Fig. 3), ANP (27 ± 6 vs. 177 ± 22 pmol/l, P < 0.001), BNP (4 ± 1 vs. 54 ± 8 pmol/l, P < 0.001), epinephrine (436 ± 61 vs. 2,132 ± 697 pmol/l, P < 0.001), norepinephrine (3.44 ± 0.64 vs. 3.611 ± 0.73 pmol/l, P < 0.001; Fig. 4), and creatinine (0.078 ± 0.006 vs. 0.094 ± 0.008 mmol/l, P < 0.001) levels (Table 1).


Figure 1
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  		Fig. 1. Hemodynamic responses to initiation of rapid left ventricular (LV) pacing [beats/min (bpm)] in conjunction with infusions of vehicle (control) and urocortin 1 in 8 sheep. Values are means ± SE. Significantly different from vehicle: *P < 0.05; **P < 0.01; {dagger}P < 0.001.

 

Figure 2
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  		Fig. 2. Plasma urocortin 1, cAMP, arginine vasopressin, ACTH, and cortisol responses to initiation of rapid LV pacing in conjunction with infusions of vehicle and urocortin 1 in 8 sheep. Values are means ± SE. Significantly different from vehicle: *P < 0.05; **P < 0.01; {dagger}P < 0.001.

 

Figure 3
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  		Fig. 3. Plasma renin, aldosterone, and endothelin-1 responses to initiation of rapid LV pacing in conjunction with infusions of vehicle and urocortin 1 in 8 sheep. Values are means ± SE. Significantly different from vehicle: *P < 0.05; **P < 0.01; {dagger}P < 0.001.

 

Figure 4
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  		Fig. 4. Atrial and brain natriuretic peptide, epinephrine, and norepinephrine responses to initiation of rapid LV pacing in conjunction with infusions of vehicle and urocortin 1 in 8 sheep. Values are means ± SE. Significantly different from vehicle: *P < 0.05; **P < 0.01; {dagger}P < 0.001.

 

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  		Table 1. Effects of urocortin 1 on development of pacing-induced heart failure

 
Rapid pacing also reduced creatinine clearance (103 ± 8 vs. 71 ± 7 ml/min, P < 0.001; Table 1) and urine sodium (1.69 ± 0.27 vs. 0.75 ± 0.35 mmol/h, P < 0.05), potassium (9.2 ± 1.5 vs. 4.5 ± 1.0 mmol/h, P < 0.01), and creatinine (0.492 ± 0.024 vs. 0.426 ± 0.015 mmol/h, P < 0.01) excretion (Fig. 5); a similar trend was observed for urine output (52 ± 17 vs. 38 ± 38 ml/h, P = 0.089; Fig. 5) and water intake (144 ± 42 vs. 104 ± 15 ml/h, P = 0.068; Table 1).


Figure 5
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  		Fig. 5. Urine volume and sodium, potassium, creatinine, and cAMP excretory responses to initiation of rapid LV pacing in conjunction with infusions of vehicle and urocortin 1 in 8 sheep. Values are means ± SE. Significantly different from vehicle: *P < 0.05; **P < 0.01; {dagger}P < 0.001.

 
Plasma ACTH levels rose transiently over the first hours of pacing (P < 0.05; Fig. 2), whereas hematocrit and plasma sodium and potassium concentrations were not significantly altered over the 4-day pacing period (Table 1).

Ucn1 treatment. Ucn1 infusion, in conjunction with rapid pacing, noticeably attenuated the decline in CO (2.43 ± 0.46 vs. 3.70 ± 0.89 l/min for control vs. Ucn1 on day 4, P < 0.01) and increases in LAP (24.9 ± 1.0 vs. 11.9 ± 1.1 mmHg, P < 0.001) and CTPR (38.7 ± 9.4 vs. 25.2 ± 6.1 mmHg·l–1·min, P < 0.001; Fig. 1) seen with pacing alone during the control phase. MAP (Fig. 1) and hematocrit (Table 1) responses did not differ significantly between treatments.

Infusion of Ucn1 raised circulating concentrations of the peptide (19 ± 1 vs. 2,856 ± 557 pmol/l, P < 0.001) and repressed pacing-induced elevations in plasma cAMP (34.2 ± 4.3 vs. 25.0 ± 1.3 pmol/l, P < 0.05) and AVP (10.8 ± 4.1 vs. 1.8 ± 0.2 pmol/l, P < 0.05; Fig. 2). Acute increases in plasma ACTH and cortisol in the hours after commencement of Ucn1 treatment (both P < 0.05) were not evident over days 1–4 (Fig. 2).

Ucn1 inhibited the increases in PRA (4.02 ± 1.17 vs. 0.87 ± 0.09 nmol·l–1·h–1, P < 0.001), aldosterone (1,313 ± 324 vs. 413 ± 174 pmol/l, P < 0.001), and endothelin-1 (3.8 ± 0.5 vs. 2.0 ± 0.1 pmol/l, P < 0.001) during pacing alone (Fig. 3) and attenuated the increases in plasma ANP (177 ± 22 vs. 143 ± 22 pmol/l, P < 0.05), BNP (54 ± 8 vs. 39 ± 7 pmol/l, P < 0.01), epinephrine (2,132 ± 697 vs. 1,250 ± 264 pmol/l, P < 0.05), and norepinephrine (3.61 ± 0.73 vs. 2.07 ± 0.52 nmol/l, P < 0.05; Fig. 4).

Analysis of the Ucn1 phase alone (via 1-way ANOVA) established that Ucn1 treatment prevented any significant change in plasma cAMP, AVP, PRA, and endothelin-1 from baseline levels over the 4 days of pacing, whereas aldosterone concentrations actually tended to fall: 505 ± 91 (baseline) vs. 243 ± 40 (day 2) pmol/l (P = 0.0836).

In addition to inducing acute (2–6 h) increases in urine volume (P < 0.05) and sodium (P < 0.05) and creatinine (P < 0.05) output, Ucn1 treatment maintained sodium excretion throughout the study period (0.75 ± 0.34 vs. 1.59 ± 0.50 mmol/h on day 4, P < 0.05) and alleviated the declines in urine creatinine (0.426 ± 0.015 vs. 0.448 ± 0.028 mmol/h, P < 0.05; Fig. 5) and creatinine clearance (70.5 ± 6.8 vs. 84.7 ± 6.3 ml/min, P < 0.05; Table 1) observed over 4 days of pacing alone. A similar trend was evident for urine cAMP excretion (P = 0.089; Fig. 5). Plasma sodium and creatinine concentrations were decreased compared with control (both P < 0.05; Table 1), whereas plasma and urine potassium (Table 1, Fig. 5) and water intake (Table 1) did not differ significantly.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The present study demonstrates that infusion of Ucn1 from the initiation of rapid LV pacing significantly attenuates the hemodynamic deterioration (reductions in CO and elevations in LAP and CTPR) and deleterious hormonal activation (renin-aldosterone, endothelin-1, vasopressin, and catecholamines) associated with the development of congestive HF in untreated animals. Renal function was also protected, as assessed by the maintenance of sodium excretion and blunted decline in creatinine clearance.

In this model of low-output HF, the comparative preservation of CO observed with Ucn1 administration may be due in part to the positive inotropic effects of the peptide, as reported previously in the isolated rat heart (42), since arterial blood pressure (afterload) was matched in both treatment groups (and elevations in LV filling pressure were repressed). Additional actions of Ucn1 to dilate coronary arteries (42) and improve cardiac bioenergetics, including the preservation of highenergy phosphate stores (39), which are depleted in chronic tachycardia (7), may also have contributed to the conservation of heart function. Although MAP might have been expected to decrease less in Ucn1-treated animals given the smaller decline in CO, this was presumably offset by the concomitant attenuated increase in systemic vascular resistance. This latter response likely reflects the direct vasodilator action of Ucn1 (40), which has been reported to be mediated by cAMP and nitric oxide (22), as well as by the absent or blunted activation of a number of vasoconstrictor systems, including endothelin-1, renin-angiotensin, AVP, and sympathetic systems.

Infusion of Ucn1 on initiation of rapid LV pacing also substantially restricted the rise in LAP in control animals, presumably as a result of less reduction in CO, although lusitropic (3) and venodilating (38) effects of the peptide may also have played a part. These results are consistent with the hemodynamic actions of Ucn1 demonstrated in severe HF (32, 33) and indicate that Ucn1 may be particularly useful as an anti-HF therapy when administered early in the course of the disorder.

One of the most striking findings of the present study was the impact of Ucn1 administration on neurohumoral activation during the serial deterioration of cardiovascular function. Although demonstrating a significantly better hemodynamic profile than the control group after 4 days of rapid LV pacing, Ucn1-treated animals still exhibited a 44% reduction in CO and a 17% decline in MAP, together with a 3.8- and a 1.5-fold rise in LAP and CTPR, respectively (65% and 15% decreases in CO and MAP, respectively, and 7.2- and 2.3-fold increases in LAP and CTPR, respectively, in controls). Despite this hemodynamic insult, Ucn1 administration wholly prevented any significant rise in circulating PRA (despite drops in blood pressure and, presumably, renal perfusion pressure equal to that in untreated animals) and actually tended to reduce plasma aldosterone levels relative to prepacing baseline. This contrasted with 10- and 3-fold increases in the respective factors in the untreated animals. Whether the suppression of PRA was due to increased delivery of sodium to the macula densa (evidenced by significant increases in sodium excretion over days 1–3), elevations in plasma concentrations of the natriuretic peptides, a direct inhibitory effect of Ucn1 on renin secretion, or some other PRA-suppressive mechanism is unknown. The trend for aldosterone levels to decline over this same period, where plasma ACTH and potassium were unchanged, might suggest a possible direct inhibitory effect of Ucn1 on the hormone's secretion, especially given the strong immunoreactivity of Ucn1 demonstrated in the medulla of the adrenal gland (13). Alternatively, possible Ucn1-induced reductions in serum angiotensin-converting enzyme activity (45) might explain the decline in aldosterone in the present study via decreased angiotensin II (a prime secretagogue for aldosterone in HF).

Increments in plasma endothelin-1 levels were also fully repressed by Ucn1 administration during rapid LV pacing, in contrast to the doubling of levels observed in the control group. Although a direct effect of Ucn1 on endothelin secretion is yet to be investigated, Ucn1 has been reported to potently oppose the vasoconstricting actions of the peptide (38, 44), and blockade of the urocortin system in experimental HF results in further elevations in circulating endothelin-1 (34). Although it is conceivable that the prominent increases in ANP and BNP may have played a role in repressing endothelin production (16), significantly greater increments of the natriuretic peptides in the control group were not associated with endothelin suppression. Furthermore, reductions in sheer stress (as judged by decreases in MAP), a stimulatory factor for endothelin-1 secretion (16), were comparable in both treatment groups.

The mechanism(s) mediating the complete inhibition of increased AVP secretion with Ucn1 infusion (compared with a 7-fold rise in untreated sheep), which occurred in the face of significant declines in CO and pressure at sinoaortic volume receptors, cannot be determined from the present study.

Although not as striking as the inhibition of the other vasoconstrictor factors (see above), activation of the sympathetic nervous system was still significantly blunted with Ucn1 treatment over the 4-day pacing period. This likely reflects the comparative preservation of heart function demonstrated in this group (2). The actions of Ucn1 to wholly or significantly suppress these deleterious vasoconstrictor systems in the face of persisting substantive deterioration of cardiac and hemodynamic status are truly remarkable and strongly encourage further investigation of Ucn1 as a potential treatment in the early phase of HF, especially given that the maladaptive activation of these systems plays an important role in the downward spiral of this disease.

Elevations in plasma concentrations of the natriuretic peptides were also attenuated with Ucn1 administration. Yet, although the increase in LAP (a major stimulus for ANP secretion) in the Ucn1-treated sheep was half of that in untreated animals, the increase in plasma ANP was 81% of that in the control group. This finding is consistent with reports demonstrating that Ucn1 enhances the production of the natriuretic peptides from cardiac myocytes (24), which is likely to be beneficial in a disease characterized by vasoconstriction and volume retention. Despite major elevations in circulating levels of Ucn1 with infusion of the peptide, plasma concentrations of cAMP, a proposed intracellular second messenger of Ucn1 (40), were largely unaltered and remained significantly lower than plasma cAMP concentrations in the untreated animals (which exhibited only a moderate increase in endogenous Ucn1). However, cAMP is a second messenger utilized by many systems activated in HF, and the failure of levels to rise in the Ucn1-treated animals likely reflects the less severe disease status achieved in this group (25). Nevertheless, cAMP was raised sufficiently at the level of cell signaling to induce the significant effects observed with Ucn1 administration, or, alternatively, other pathways may be involved (22, 37, 42).

Ucn1 prevented the avid sodium retention associated with the development of HF and actually induced a natriuresis over the first 3 days of treatment, with a corresponding relative decrease in plasma sodium levels. Ucn1 further alleviated the marked decline in glomerular filtration rate (as judged by decreases in creatinine clearance) in control animals. Although it is likely that the significant elevation in circulating natriuretic peptides contributed to this effect (where there were no matching increases in antinatriuretic factors such as angiotensin II, aldosterone, AVP, and endothelin-1), it is also possible that Ucn1 has direct tubular actions, given reports of the peptide's expression within the kidney (41) and a trend for urine cAMP excretion to increase in the present study. Although blood pressure and, therefore, presumably renal perfusion pressure were reduced over this period, the effect of Ucn1 to also cause vasodilation of renal blood vessels (37) may have acted to conserve hemodynamic function within the kidney. Whatever the mechanisms, we have shown the relative preservation of renal function by Ucn1 during the development of a disease that is further exacerbated by declining kidney performance.

We previously investigated the acute effects of the three known forms of urocortin (Ucn1, Ucn2, and Ucn3) in overt HF (30–32) and showed that they elicit a very similar range and magnitude of beneficial hemodynamic, neurohormonal, and renal responses, suggesting that it is likely that any one of the urocortin isoforms will act equally successfully in the setting of early cardiac dysfunction or decompensation.

Although rapid LV pacing induces the hemodynamic, hormonal, and renal characteristics of (low-CO) congestive HF, it should be noted that this models only one form of HF and may not reflect some others. A further limitation of this study is the lack of data concerning the direct effect of Ucn1 on ventricular dimensions and function (measured by echocardiography or sonomicrometry). Future investigations into Ucn1's impact on these parameters, especially over more extended treatment periods, are awaited with great interest.

In summary, this study demonstrates that sustained Ucn1 treatment after the onset of rapid LV pacing has the ability to repress the ensuing progressive cardiorenal deterioration, largely prevent the activation of adverse vasoconstrictor/antinatriuretic hormone systems, and augment plasma natriuretic peptide levels, thereby delaying the progression to overt HF. Given the beneficial responses to Ucn1 demonstrated in this model of HF, assessment of the peptide (or its analogs) as a therapeutic option early in the course of episodes of acute clinical HF (such as may occur during acute exacerbation of stable compensated HF or HF induced by myocardial infarction) seems appropriate.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by grants from the Health Research Council and the National Heart Foundation of New Zealand.


   ACKNOWLEDGMENTS
 
We are grateful to the staff of the Endocrine Laboratory for hormone assays and the Christchurch School of Medicine Animal Laboratory for animal care.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. T. Rademaker, Dept. of Medicine, Christchurch School of Medicine, PO Box 4345, Christchurch, New Zealand (e-mail: miriam.rademaker{at}chmeds.ac.nz)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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