Endogenous urocortins reduce vascular tone and renin–aldosterone/endothelin activity in experimental heart failure

Miriam T. Rademaker*, Chris J. Charles, Eric A. Espiner, Chris M. Frampton, John G. Lainchbury and A. Mark Richards

Christchurch Cardioendocrine Research Group, Department of Medicine, The Christchurch School of Medicine, PO Box 4345, Christchurch, New Zealand

Received 11 November 2004; revised 13 February 2005; accepted 17 February 2005; online publish-ahead-of-print 8 April 2005.

* Corresponding author. Tel: +64 3 3640544; fax: +64 3 3640525. E-mail address: miriam.rademaker{at}chmeds.ac.nz


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
Aims To investigate the role of the endogenous urocortin peptides in heart failure (HF) through blockade of the corticotropin-releasing factor receptor 2 (CRF-R2).

Methods and Results Eight sheep were administered the CRF-R2 antagonist CRF(9–41) (1.5 mg bolus) before (Normal) and after development of pacing-induced HF. Compared with controls, CRF(9–41) in HF significantly increased mean arterial pressure (MAP) (71±2 vs. 75±2 mmHg, P=0.0024) and calculated total peripheral resistance (CTPR) (33.3±5.2 vs. 39.4±5.9 mmHg/L/min, P=0.0455). Similar trends were observed in the Normal state (MAP 87±1 vs. 89±2 mmHg, P=0.0689; CTPR 21.9±2.0 vs. 24.4±2.4 mmHg/L/min, P=0.0731). Left atrial pressure was elevated similarly in both states (Normal P=0.0013; HF P=0.0298), whereas cardiac output tended to be reduced (Normal P=0.0614). CRF(9–41) increased plasma urocortin-I (Normal 10.3±0.8 vs. 19.8±1.3 pmol/L, P<0.001; HF 14.4±0.9 vs. 25.3±0.8 pmol/L, P<0.001), renin (Normal 0.34±0.06 vs. 0.41±0.02 nmol/L/hr, P=0.013; HF 1.14±0.29 vs. 1.57±0.36 nmol/L/hr, P=0.0326), aldosterone (Normal 370±62 vs. 563±99 pmol/L, P=0.0813; HF 662±141 vs. 1024±209 pmol/L, P=0.095), and endothelin-1 (HF 3.18±0.18 vs. 4.74±1.04 pmol/L, P=0.0087). MAP, CTPR, renin, and endothelin-1 responses to CRF-R2 antagonism were significantly greater in HF than in the Normal state (P=0.049, 0.0427, 0.0311, and 0.0412, respectively).

Conclusion These data suggest that the endogenous urocortin peptides contribute to the suppression of vascular tone and renin–angiotensin–aldosterone/endothelin activation in HF and thus, play a protective compensatory role in this disorder.

Key Words: CRF(9–41) • Urocortin • Heart failure • Pacing • Blood pressure • Renin • Endothelin


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
Corticotropin-releasing factor (CRF) and the urocortin (Ucn) peptides, Ucn-I, Ucn-II, and Ucn-III, are structurally related ligands of the two CRF receptors, CRF-R1 and CRF-R2. CRF is highly selective for CRF-R1,1 which is expressed primarily in the brain and pituitary (negligible in cardiovascular tissue).2,3 In contrast, the Ucn peptides exhibit strong and comparable binding affinities for CRF-R2,4 and their distribution overlaps with that of the receptor in both the central nervous system and the peripheral tissues, demonstrating strong expression throughout the heart and vasculature (both endothelial and smooth muscle cells).26 Distribution and binding profiles strongly suggest the Ucns are the endogenous ligands of the CRF-R2 receptor. Increasing evidence points to a role for these peptides in the regulation of cardiovascular function. Systemic administration of Ucn-I in normal animals induces vasodilation, positive inotropic and chronotropic activity, and increases in coronary blood flow and conductance.710 Information available on the more recently identified Ucn-II and Ucn-III indicate that both peptides also exhibit significant vasodilator and cardiostimulatory activity.1114 These actions are blocked by CRF-R2 antagonists7,8,1113 and absent in CRF-R2-deficient mice,1415 confirming mediation via the R2 receptor.

A number of recent studies have demonstrated that Ucn-I levels in cardiac tissue16,17 and plasma18,19 are increased in both experimental and human heart failure (HF). Administration of Ucn-I18 and Ucn-II14 in this disease is reported to have beneficial haemodynamic effects, and all three Ucns have been shown to prevent cell death in cultured cardiac myocytes and to reduce infarct size in the intact rat heart following ischaemia/reperfusion injury (mediated via CRF-R2).5,20 Although these findings suggest that the Ucn peptides may have protective actions in states of cardiac injury and dysfunction, the contribution of endogenous Ucns in the pathophysiology of HF remains undefined. The present study investigates for the first time the role of the endogenous Ucn peptides in this disorder by comparing the effects of a selective CRF-R2 antagonist in sheep before and after induction of HF.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
Surgical preparation
Eight Coopworth ewes (40–56 kg) were instrumented via a left lateral thoracotomy21 under general anaesthesia (induced by 17 mg/kg thiopentone, maintained with halothane/nitrous oxide). Two polyvinyl chloride catheters were inserted in the left atrium for blood sampling, left atrial pressure (LAP) determination, and drug administration; a Konigsberg pressure-tip transducer inserted in the aorta to record mean arterial pressure (MAP); an electromagnetic flow probe placed around the ascending aorta to measure cardiac output (CO); and a 7 French His-bundle electrode stitched subepicardially to the wall of the left ventricle for left ventricular pacing. A bladder catheter was inserted into each urethra for urine collections. Animals recovered for 14 days before commencing the study protocol. During the experiments, the animals were held in metabolic cages and had free access to water and food (containing 80 mmol/day sodium; 200 mmol/day potassium).

Study protocol
On two separate days with a rest day between, each sheep received in a randomized, crossover design (four animals to each sequence) a 1.5 mg bolus of the selective CRF-R2 antagonist alpha-helical CRF(9–41)22 and a vehicle control (10 mL 0.9% saline), both before (Normal; study days 1 and 3) and after induction of HF by rapid left ventricular pacing for 7 days at 225 b.p.m. (study days 11 and 13).

Heart rate, MAP, LAP, CO, and calculated total peripheral resistance (CTPR=MAP/CO) were recorded at 15 min intervals in the hour preceding the bolus (baseline) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 h succeeding the bolus. Haemodynamic measurements were determined by on-line computer assisted analysis using established methods.23

Blood samples (20 mL/sample) were drawn from the left atrium following haemodynamic recordings at 30 min and immediately preceding the bolus (baseline) and at 0.5, 1, 2, 3, 4, 5, and 6 h succeeding the bolus. Samples were taken into tubes on ice, centrifuged at 4°C, and stored at either –20 or –80°C before assay for Ucn-I,18 cyclic adenosine monophosphate (cAMP), arginine vasopressin (AVP), adrenocorticotrophic hormone (ACTH), cortisol, plasma renin activity (PRA), aldosterone, endothelin-1, atrial and brain natriuretic peptide (ANP and BNP, respectively), and catecholamines.21,23,24 All samples from individual animals were measured in the same assay to avoid inter-assay variability. Plasma electrolytes and haematocrit were measured with every blood sample taken.

Cross-reactivity in the Ucn-I radioimmunoassay18 to CRF(9–41) (American Peptide Company Inc., Sunnyvale, CA, USA) was <0.0004%; to murine Ucn-II (Peninsula Laboratories Inc., San Carlos, CA, USA) was <0.026%; to human Ucn-II (Peninsula Laboratories) was <0.0034%; to human Ucn-III (Peninsula Laboratories) was <0.07; to human urotensin II (Phoenix Pharmaceuticals Inc., Belmont, CA, USA) was <0.014%; and to ovine and human CRF (Peninsula Laboratories) was <0.001%.

Urine volume and samples for the measurement of urine cAMP, sodium, potassium, and creatinine excretion were collected at 2 h intervals before (baseline) and after the bolus. The study protocol was approved by the local Animal Ethics Committee.

Statistics
A sample size of eight sheep was selected, as previous studies of vasoactive hormones using a similar number of animals in this model of HF18,21,23,24 consistently produce unequivocal results under these carefully controlled experimental conditions and consistently provide >80% power to detect >30% effects (differences between within-subject means) at a two-tailed alpha level of 0.05.

Results are expressed as mean±SEM. Paired t-tests were used to compare Normal and pacing baseline data (mean of measurements made within the hour preceding pre-treatment) to show that the required state of HF had been achieved. CRF(9–41) effects were analysed by repeated measures analysis of variance (ANOVA) (Normal and HF states tested separately) using a random intercept. Differences in the response to CRF(9–41) between Normal and HF states were analysed by covariate repeated measures ANOVA using baseline data as the covariate. The repeated measures analyses included period, sequence, HF, treatment [CRF(9–41)], and within-treatment times all tested as fixed effects (treatment/time interactions quoted in text). The absence of any significant period-by-treatment interactions (which also incorporate carry-over effects) in the present study confirms the adequacy of the wash-out period. Where significant treatment/time interactions were identified by ANOVA, the level of significance at individual time points on Figures 13 was determined by pair-wise least-significant difference (LSD) tests using the appropriate mean-square error term from the ANOVA (Fisher's protected LSD test). The sphericity assumption for the repeated measures analysis was confirmed using Mauchly's test. Statistical significance was assumed when two-tailed P<0.05.



View larger version (34K):
[in this window]
[in a new window]
 
Figure 1 Mean±SEM haemodynamic responses to a 1.5 mg bolus of CRF(9–41) (filled circles) and a vehicle control (open circles) in eight sheep before (Normal) and after induction of HF. Significant differences are shown by: *P<0.05, **P<0.01, {dagger}P<0.001. Note the different y-axis range between Normal and heart failure states.

 


View larger version (23K):
[in this window]
[in a new window]
 
Figure 3 Mean±SEM PRA, aldosterone, and endothelin-1 responses to a 1.5 mg bolus of CRF(9–41) (filled circle) and a vehicle control (open circle) in eight sheep before (Normal) and after induction of HF. Significant differences are shown by: *P<0.05, **P<0.01. Note the different y-axis range between Normal and heart failure states.

 

    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
All eight animals initially included in the preparation phase of the study fully completed the study protocol.

There was no statistical evidence of significant carry-over effects for any of the variables tested (P>0.05 for all sequence by treatment interactions).

Induction of HF
Rapid left ventricular pacing for 7 days induced the haemodynamic, hormonal, and sodium retaining hallmarks of congestive HF,21 with reduced MAP (P<0.001) and CO (P=0.0016) and with increased LAP (P<0.001), CTPR (P=0.0302), and plasma levels of ANP (P<0.001), BNP (P=0.0007), endothelin-1 (P=0.0051), Ucn-1 (P=0.0404), PRA (P=0.037), aldosterone (P=0.0406), AVP (P=0.071) (Figures 14), cAMP (P=0.0021), norepinephrine (P=0.0085), and epinephrine (P=0.0541) (Table 1). These changes occurred in conjunction with attenuated urine sodium excretion (P=0.0217) (Table 2).



View larger version (23K):
[in this window]
[in a new window]
 
Figure 4 Mean±SEM plasma Ucn, AVP, ACTH, and cortisol responses to a 1.5 mg bolus of CRF(9–41) (filled circle) and a vehicle control (open circle) in eight sheep before (Normal) and after induction of HF. Note the different y-axis range between Normal and heart failure states for vasopressin and ACTH.

 

View this table:
[in this window]
[in a new window]
 
Table 1 Responses to CRF(9–41) administration
 

View this table:
[in this window]
[in a new window]
 
Table 2 Renal responses to CRF(9–41) administration
 
Haemodynamics
Compared with time-matched control data, administration of CRF(9–41) significantly increased MAP (peak effect: 71±2 vs. 75±2 mmHg, P=0.0024) and CTPR (33.3±5.2 vs. 39.4±5.9 mmHg/L/min, P=0.0455) in the sheep during the HF phase. Similar but non-significant trends were observed in the Normal state (MAP 87±1 vs. 89±2 mmHg, P=0.0689; CTPR 21.9±2.0 vs. 24.4±2.4 mmHg/L/min, P=0.0731) (Figure 1). These responses were significantly greater in HF than in the Normal state (P=0.049 and P=0.0427, respectively). CRF(9–41) elevated LAP similarly in both states (1–2 mmHg, Normal P=0.0013; HF P=0.0298) and tended to reduce CO (Normal P=0.0614; HF non-significant) (Figure 1).

Peak haemodynamic effects largely occurred within the first 3 h post-bolus. Heart rate also showed a trend to decrease following CRF(9–41) administration in the Normal state (70.5±3.1 vs. 65.6±3.4, P=0.081, Table 1), whereas haematocrit was not affected in either state (Table 1).

Hormones
CRF(9–41) induced significant increases in plasma Ucn-I, with peak increases of ~10 pmol/L occurring 30 min post-bolus in both states (both P<0.001). Levels were still raised at 6 h post-bolus. Plasma ANP concentrations tended to be elevated by CRF(9–41) in the Normal state (P=0.085) and were significantly increased in the sheep during HF (143±9 vs. 189±21 pmol/L, P=0.047). A similar trend was evident for circulating BNP (Normal P=0.065, HF P=0.083) (Figure 2). CRF(9–41) administration also increased PRA (Normal 0.34±0.06 vs. 0.41±0.02 nmol/L/h, P=0.013; HF 1.14±0.29 vs. 1.57±0.36 nmol/L/h, P=0.0326), aldosterone (Normal 370±62 vs. 563±99 pmol/L, P=0.0813; HF 662±141 vs. 1024±209 pmol/L, P=0.095), and endothelin-1 (Normal NS; HF 3.18±0.18 vs. 4.74±1.04 pmol/L, P=0.0087) relative to controls (Figure 3). Plasma ANP, PRA, and endothelin-1 responses were significantly greater in HF than in the Normal state (P=0.0310, 0.0311, and 0.0412, respectively).



View larger version (23K):
[in this window]
[in a new window]
 
Figure 2 Mean±SEM plasma Ucn, ANP, and BNP responses to a 1.5 mg bolus of CRF(9–41) (filled circles) and a vehicle control (open circle) in eight sheep before (Normal) and after induction of HF. Significant differences are shown by: *P<0.05, **P<0.01, {dagger}P<0.001. Note the different y-axis range between Normal and heart failure states for ANP and BNP.

 
Circulating AVP, ACTH, cortisol (Figure 4), cAMP, epinephrine, norepinephrine (Table 1), electrolyte levels (data not shown), and renal parameters (Table 2) were not significantly altered by CRF(9–41) in either state.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
The present study is the first to investigate the extent to which the endogenous Ucn peptides, via CRF-R2, contribute to the regulation of haemodynamic, neurohumoral, and renal function in normal and HF conditions. We found that CRF-R2 antagonism in sheep with HF increased CTPR, MAP, and cardiac pre-load, in conjunction with elevations in plasma renin–aldosterone, endothelin-1, and natriuretic peptide levels. Responses in the normal state were greatly blunted and largely non-significant. These data support a significant role for the endogenous Ucn peptides in blood pressure regulation in HF and suggest that they contribute to the suppression of a number of vasoconstrictor systems in this disease, thus affording some protection to the failing heart.

Haemodynamics
The haemodynamic effects of CRF-R2 antagonism in sheep during HF, increases in CTPR, MAP, and LAP (and tendency to attenuate CO), are mirror images of those produced by administration of the CRF-R2 agonists Ucn-I,7,18 Ucn-II,12,13 and Ucn-III.11 The moderate but significant increment in peripheral resistance (in this already vasoconstricted setting) and associated rise in MAP are presumably due to blockade of the Ucns' direct relaxant action on the vasculature10 and the concomitant and considerable increases in the vasoconstrictor hormones angiotensin II (as assessed by elevations in PRA) and endothelin-1. These data point to the endogenous Ucn peptides as functionally significant vasodilators in HF. The tendency for CO to fall, especially from markedly diminished levels in this HF state, as consistent with blockade of the cardiostimulatory effects of the Ucns.8,14 The rise in cardiac afterload may also have contributed to this effect. CRF(9–41)-induced rises in LAP likely reflect the reduction in CO and possibly an increase in venous tone.9

Although peak haemodynamic effects occurred over the first 2–3 h following the CRF(9–41) bolus, differences from control were still apparent at 6 h. This is in keeping with the long-lasting action of the antagonist as previously reported,7 where pre-treatment with CRF(9–41) prevented the cardiovascular response to subsequent Ucn-I administration for the duration of the 4 h experimental period.

The hypertensive effects of CRF(9–41) treatment in HF were significantly greater than the non-significant responses observed in the normal state. Previous studies in normal animals,12,13 including that by Parkes et al.7 in sheep, reported that although CRF-R2 antagonism prevented the cardiovascular effects of exogenous Ucns (confirming mediation via CRF-R2), there were no significant effects on basal haemodynamic parameters. CRF-R2 blockade in the present study, at a dose three-fold that used by Parkes et al.,7 also failed to produce a significant hypertensive response, suggesting that the endogenous Ucn system does not play a major role in cardiovascular regulation in normal health. However, it should be noted that mice lacking the CRF-R2 exhibit raised basal systemic vascular resistance and blood pressure,14,15 which points to at least some involvement of the receptor (and its agonists) in the regulation of basal vascular tone.

The augmented peripheral resistance and blood pressure response to CRF(9–41) administration observed in the paced compared with the normal phase in the present study may reflect, at least in part, activation of the Ucn system in HF. As observed in previous investigations,18,19 circulating Ucn-I levels were significantly raised in HF compared with the normal state. Although the magnitude of the Ucn-I increment with HF was modest, an ~50% rise (similar to the elevation reported in female HF patients),19 this may not accurately reflect the situation at the tissue level, particularly given the close co-localization of the Ucn peptides and the CRF-R2 receptor within the cardiovascular system, which suggests that the peptide functions largely in a paracrine or autocrine fashion. Indeed, a nearly two-fold increase in immunohistochemical staining for Ucn-I is observed in failing hearts.16 It is possible that enhanced cardiac Ucn-I contributes to the raised plasma concentrations of the peptide in HF. Although there is no information to date regarding plasma or tissue levels of Ucn-II and Ucn-III in this disease, it is plausible to assume that these peptides, like Ucn-I, will also be augmented (although the degree of activation cannot be predicted).

The increased hypertensive effect of CRF(9–41) in the sheep during HF may also be mediated to some extent by the significantly greater enhancement of the vasoconstrictor systems, PRA (angiotensin II) and endothelin-1 in this state (over six-fold and 2.3-fold larger response, respectively, than that observed in the normal state).

Hormones
This study is the first to report plasma levels of any of the CRF-R2 agonists subsequent to receptor-antagonism. In both normal and HF states, plasma Ucn-I levels clearly increased following administration of CRF(9–41). With the cross-reactivity of CRF(9–41) in our Ucn-I assay (<0.0004) too low to account for a 10 pmol rise in plasma concentrations of the peptide, this is presumably a consequence of displacement and/or blockade of endogenous Ucn-I from the CRF-R2 receptor by the antagonist. Indeed, a rise in circulating levels of a peptide following blockade of its receptor is well documented.25 Although the peak Ucn-I effect was evident at the first sampling time-point (30 min), levels were still elevated relative to control at 6 h post-CRF(9–41) bolus, findings again consistent with the long-lasting action of the antagonist7 and the presence of sustained significant haemodynamic and endocrine responses. It is conceivable that plasma Ucn-II and Ucn-III concentrations would also increase with antagonism of the CRF-R2 receptor. Although one might expect a corresponding reduction in plasma cAMP (the Ucns proposed intracellular second messenger) as a biological marker of effective blockade of endogenous Ucn peptide activity, no change in either state was noted. This, however, may not be surprising given that previous acute studies demonstrating substantial changes in circulating Ucn-I following exogenous administration were not associated with rises in plasma cAMP.18 It is assumed that attenuation of cAMP at the tissue level is sufficient to prevent Ucn-induced bioactivity but insufficient to elicit significant changes in plasma concentrations.

CRF-R2 antagonism in HF was associated with marked elevations of the already activated PRA, aldosterone, and endothelin-1 systems compared with controls (by 38, 55, and 50%, respectively). A similar but greatly attenuated response was observed in the normal state. These effects are opposite those induced by administration of Ucn-I,18 whereas the impact of Ucn-II and Ucn-III on these parameters in vivo has not been assessed. Whether the rise in PRA (occurring despite increases in arterial pressure and plasma concentrations of ANP) reflects inhibition by the endogenous Ucns of renin release or is related to some other PRA-stimulatory mechanism/s remains to be seen, although the slow rise in plasma levels may suggest that the effect is a secondary one. Similarly, whether plasma aldosterone augmentation with CRF(9–41) is merely a consequence of increased circulating PRA/angiotensin II or also partly due to the blockade of a direct effect of the Ucns on the adrenal glomerulosa cannot be established from our data. The observed rise in plasma endothelin-1 may be partly due to the haemodynamic changes induced by CRF-R2 blockade. Indeed, haemodynamic forces act as important stimuli for the peptide's secretion, with circulating levels of endothelin-1 shown to specifically correlate with cardiac pre-load in HF.26 Whether the Ucns have a direct effect on endothelin secretion is unknown, although Ucn-I is reported to oppose the vasoconstrictor actions of the peptide9 and thus, is likely to contribute to the attenuation of endothelin-1-mediated hypertension in HF. Clearly, further investigation (in particular, in vitro work) is necessary to determine the relationships between the Ucns and these important vasoconstrictor peptides. Whatever the mechanisms, the present study is the first to demonstrate a significant role of the endogenous Ucn peptides in suppressing the activation of the renin–angiotensin–aldosterone and endothelin systems in HF. A similar pattern of response was observed by Wada et al.,25,27 with prominent increases in plasma PRA, aldosterone, and endothelin in paced (HF) dogs and little effect in normal dogs, following blockade of the endogenous natriuretic peptides, hormones known to directly inhibit secretion of these peptides.

CRF(9–41) treatment also induced significant increases in plasma ANP and BNP levels in HF. As seen with the vasoconstrictor systems mentioned previously, a similar but much blunted response occurred in the normal state. As Ucn-I is reported to enhance natriuretic peptide secretion from rat cardiac myocytes (mediated via CRF-R2),16 this rise is presumably due to elevated cardiac transmural pressures (as evidenced by rises in LAP and MAP) leading to increased secretion. In addition, the concomitant rise in the secretagogue endothelin-1 (and angiotensin II) may have played a contributing role, particularly important at the greatly enhanced intra-cardiac pressures present in HF.28 In keeping with the high specificity of CRF(9–41) for the CRF-R2,22 no ACTH or cortisol effect (mediated via CRF-R1) was noted in either state.

We have previously reported significant and dose-dependent renal augmentation with Ucn-I treatment in sheep with HF.18 Whether this response was due to direct tubular actions of Ucn-I or solely due to indirect effects such as marked reductions in circulating levels of anti-natriuretic/anti-diuretic factors including AVP, angiotensin II, and aldosterone, and increases in glomerular filtration, is unknown. The absence of a converse renal response in the present study following CRF(9–41) administration may reflect insufficient CRF-R2 blockade within the kidney and/or the comparatively minor (or absent) changes in renal haemodynamics and circulating hormone levels.

In conclusion, this study is the first to investigate the role of the endogenous Ucn system in HF. CRF-R2 antagonism in experimental HF significantly increased CTPR, MAP, and cardiac pre-load, in conjunction with elevations in plasma renin–aldosterone and endothelin-1 levels. Responses in the normal state were blunted and largely non-significant. These data suggest that the endogenous Ucn peptides contribute to the suppression of vascular tone and renin–angiotensin–aldosterone and endothelin activation in HF but participate little in cardiovascular regulation in normal health. Thus, augmentation of the endogenous Ucn system in this disorder may play a protective compensatory role.


    Acknowledgement
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
This study was supported by the Health Research Council and National Heart Foundation of New Zealand. We are grateful to the staff of the Endocrine Laboratory, in particular Greg Hammond, for hormone assays and the staff of the Christchurch School of Medicine Animal Laboratory.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 

  1. Vaughan J, Donaldson C, Bittencourt J et al. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 1995;378:287–292.[CrossRef][ISI][Medline]
  2. Baigent SM, Lowry PJ. mRNA expression profiles for corticotrophin-releasing factor (CRF), urocortin, CRF receptors and CRF-binding protein in peripheral rat tissues. J Mol Endocrinol 2000;25:43–52.[Abstract/Free Full Text]
  3. Jain V, Longo M, Ali M et al. Expression of receptors for corticotropin-releasing factor in the vasculature of pregnant rats. J Soc Gynecol Invest 2000;7:153–160.[CrossRef][ISI][Medline]
  4. Lewis K, Li C, Perrin MH et al. Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proc Natl Acad Sci 2001;98:7570–7575.[Abstract/Free Full Text]
  5. Brar BK, Jonassen AK, Egorina EM et al. Urocortin-II and urocortin-III are cardioprotective against ischemia reperfusion injury: an essential endogenous cardioprotective role for corticotropin releasing factor receptor type 2 in the murine heart. Endocrinology 2004;145:24–35.[Abstract/Free Full Text]
  6. Takahashi K, Totsune K, Murakami O et al. Expression of urocortin III/stresscopin in human heart and kidney. J Clin Endocrinol Metab 2004;89:1897–1903.[Abstract/Free Full Text]
  7. Parkes DG, Vaughan J, Rivier J et al. Cardiac inotropic actions of urocortin in conscious sheep. Am J Physiol 1997;272:H2115–H2122.[ISI][Medline]
  8. Terui K, Higashiyama A, Horiba N et al. Coronary vasodilation and positive inotropism by urocortin in the isolated rat heart. J Endocrinol 2001;169:177–183.[Abstract/Free Full Text]
  9. Sanz E, Monge L, Fernandez N et al. Relaxation by urocortin of human saphenous veins. Br J Pharmacol 2002;136:90–94.[CrossRef][ISI][Medline]
  10. Schilling L, Kanzler C, Schmiedek P et al. Characterization of the relaxant action of urocortin, a new peptide related to corticotropin-releasing factor in the rat isolated basilar artery. Br J Pharmacol 1998;125:1164–1171.[CrossRef][ISI][Medline]
  11. Kageyama K, Furukawa K, Miki I et al. Vasodilative effects of urocortin II via protein kinase A and a mitogen-activated protein kinase in rat thoracic aorta. J Cardiovasc Pharmacol 2003;42:561–565.[CrossRef][ISI][Medline]
  12. Chen CY, Doong ML, Rivier JE et al. Intravenous urocortin II decreases blood pressure through CRF(2) receptor in rats. Regul Pept 2003;113:125–130.[CrossRef][ISI][Medline]
  13. Mackay KB, Stiefel TH, Ling N et al. Effects of a selective agonist and antagonist of CRF2 receptors on cardiovascular function in the rat. Eur J Pharmacol 2003;469:111–115.[CrossRef][ISI][Medline]
  14. Bale TL, Hoshijima M, Gu Y et al. The cardiovascular physiologic actions of urocortin II: acute effects in murine heart failure. Proc Natl Acad Sci 2004;101:3697–3702.[Abstract/Free Full Text]
  15. Coste SC, Kesterson RA, Heldwein KA et al. Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotrophin-releasing hormone receptor-2. Nat Genet 2000;24:403–409.
  16. Nishikimi T, Miyata A, Horio T et al. Urocortin, a member of corticotropin-releasing factor family, in normal and diseased hearts. Am J Physiol 2000;279:H3031–H3039.[ISI]
  17. Ikeda K, Tojo K, Sato, S et al. Urocortin, a newly identified corticotropin-releasing factor-related mammalian peptide, stimulates atrial natriuretic peptide and brain natriuretic peptide secretions from neonatal rat cardiomyocytes. Biochem Biophys Res Commun 1998;250:298–304.[CrossRef][ISI][Medline]
  18. Rademaker MT, Charles CJ, Espiner EA et al. Beneficial haemodynamic, endocrine, and renal effects of urocortin in experimental heart failure: comparison with normal sheep. J Am Coll Cardiol 2002;40:1495–1505.[Abstract/Free Full Text]
  19. Ng LL, Loke IW, O'Brien RJ et al. Plasma urocortin in human systolic heart failure. Clin Sci 2004;106:383–388.[CrossRef][ISI][Medline]
  20. Brar BK, Jonassen AK, Stephanou A et al. Urocortin protects against ischemic and reperfusion injury via a MAPK-dependent pathway. J Biol Chem 2000;275:8505–8514.
  21. Fitzpatrick MA, Nicholls MG, Espiner EA et al. Neurohumoral changes during the onset and offset of ovine heart failure: role of ANP. Am J Physiol 1989;256:H1052–H1059.[ISI][Medline]
  22. Brauns O, Liepold T, Radulovic J et al. Pharmacological and chemical properties of astressin, antisauvagine-30 and alpha-helCRF: significance for behavioral experiments. Neuropharmacology 2001;41:507–516.[CrossRef][ISI][Medline]
  23. Fitzpatrick MA, Rademaker MT, Frampton CM et al. Haemodynamic and hormonal effects of renin inhibition in ovine heart failure. Am J Physiol 1990;258:H1625–H1631.[ISI][Medline]
  24. Charles CJ, Rademaker MT, Richards AM et al. Haemodynamic, hormonal, and renal effects of adrenomedullin in conscious sheep. Am J Physiol 1997;272:R2040–R2047.[ISI][Medline]
  25. Wada A, Tsutamoto T, Matsuda Y et al. Cardiorenal and neurohumoral effects of endogenous atrial natriuretic peptide in dogs with severe congestive heart failure using a specific antagonist for guanylate cyclase-coupled receptors. Circulation 1994;89:2232–2240.[Abstract/Free Full Text]
  26. Margulies KB, Hildebrand FL, Lerman A et al. Increased endothelin in experimental heart failure. Circulation 1990;82:2226–2230.[Abstract/Free Full Text]
  27. Wada A, Tsutamato T, Maeda Y et al. Endogenous atrial natriuretic peptide inhibits endothelin-1 secretion in dogs with severe congestive heart failure. Am J Physiol 1996;270:H1819–H1824.[Medline]
  28. Schiebinger RJ, Greening KM. Interaction between stretch and hormonally stimulated atrial natriuretic peptide secretion. Am J Physiol 1992;262:H78–H83.[ISI][Medline]




This Article
Abstract
Full Text (PDF)
All Versions of this Article:
26/19/2046    most recent
ehi227v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (2)
Request Permissions
Google Scholar
Articles by Rademaker, M. T.
Articles by Richards, A. M.
PubMed
PubMed Citation
Articles by Rademaker, M. T.
Articles by Richards, A. M.