Cardiac inotropic actions of urocortin in conscious sheep

Parkes, David G.; Vaughan, Joan; Rivier, J.-L.; Vale, W.; May, Carl

doi:10.1152/ajpheart.1997.272.5.h2115

Cited by 110 publications

(110 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…3 These studies suggest that UCN, unlike CT-1, is a cardioprotective agent that does not induce a hypertrophic response. Moreover, although 100 g of UCN administered to sheep produced changes in cardiac function (18), no hemodynamic changes were observed in response to the lower doses of UCN used in the isolated rat hearts used in these experiments. A previous study on rats revealed that a subcutaneous injection of UCN caused a significant decrease in mean arterial blood pressure; hence, it acts as a hypotensive agent (59).…”

Section: Table II Assessment Of Percent Cell Death Annexin V-positivmentioning

confidence: 76%

See 1 more Smart Citation

Urocortin Protects against Ischemic and Reperfusion Injury via a MAPK-dependent Pathway

Brar

Jonassen

Stephanou

et al. 2000

Journal of Biological Chemistry

233

193

View full text Add to dashboard Cite

Urocortin (UCN) is a peptide related to hypothalamic corticotrophin-releasing hormone and binds with high affinity to corticotrophin-releasing hormone receptor-2␤, which is expressed in the heart. In this study, we report that UCN prevented cell death when administered to primary cardiac myocyte cultures both prior to simulated hypoxia/ischemia and at the point of reoxygenation after simulated hypoxia/ischemia. UCN-mediated cell survival was measured by trypan blue exclusion, 3-OH end labeling of DNA (TUNEL), annexin V, and fluorescence-activated cell sorting. To explore the mechanisms that could be responsible for this effect, we investigated the involvement of MAPK-dependent pathways. UCN caused rapid phosphorylation of ERK1/2-p42/ 44, and PD98059, which blocks the MEK1-ERK1/2-p42/44 cascade, also inhibited the survival-promoting effect of UCN. Most important, UCN reduced damage in isolated rat hearts ex vivo subjected to regional ischemia/reperfusion, with the protective effect being observed when UCN was given either prior to ischemia or at the time of reperfusion after ischemia. This suggests a novel function of UCN as a cardioprotective agent that could act when given after ischemia, at reperfusion. Urocortin (UCN)1 is a peptide related to the hypothalamic hormone corticotrophin-releasing factor (CRF), the central mediator of the hypothalamic-pituitary-adrenal axis and stress response in mammals (1-3). UCN and CRF share 45% homology at the amino acid level, and both are synthesized as precursors, which are subsequently processed to the mature biologically active peptides (in the case of UCN, a 40-amino acid molecule) (4, 5). Although UCN was originally identified in restricted areas of the brain, it has also been found in the placenta, lymphocytes, and heart (6 -9).The CRF family of peptides bind two types of CRF receptors, CRF-R1 and CRF-R2. CRF-R2 exists in three alternative splice variant forms, CRF-R2␣, CRF-R2␤, and CRF-R2␥ (10 -12); and CRF-R2 binds UCN with a higher affinity than CRF both in ligand binding studies (4) and as shown by the effects of ligand on intracellular cAMP (13). In contrast, the R1 receptors show little ligand selectivity for UCN versus CRF. R2 receptors are the only type of CRF receptor found in the heart: the ␣ form in man (14) and the ␤ form in the rat (15). The CRF family of peptides have been shown to stimulate adenylate cyclase activity in cardiac myocytes (16), and changes in CRF-R2 expression have been reported in the hearts of spontaneously hypertensive rats (17).The coincident expression of CRF-R2 receptors with their preferred UCN ligand in the heart suggests that UCN may have physiological cardiac properties. Indeed UCN, but not CRF, induces a dose-dependent increase in heart rate, cardiac output, and coronary blood flow (18). Moreover, cardiac CRF-R2␤ expression is modulated by endotoxin, a potent inducer of cardiovascular dysregulation, further suggesting a possible link between UCN and the cardiovascular response to stress (19). Indeed, in previous studies, we have...

show abstract

Section: Table II Assessment Of Percent Cell Death Annexin V-positivmentioning

confidence: 76%

“…Indeed UCN, but not CRF, induces a dose-dependent increase in heart rate, cardiac output, and coronary blood flow (18). Moreover, cardiac CRF-R2␤ expression is modulated by endotoxin, a potent inducer of cardiovascular dysregulation, further suggesting a possible link between UCN and the cardiovascular response to stress (19).…”

Section: Urocortin (Ucn)mentioning

confidence: 95%

Urocortin Protects against Ischemic and Reperfusion Injury via a MAPK-dependent Pathway

Brar

Jonassen

Stephanou

et al. 2000

Journal of Biological Chemistry

233

193

View full text Add to dashboard Cite

show abstract

“…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)(12)(13)(14). These actions are absent in CRFR2-deficient mice (15, 16).…”

mentioning

confidence: 99%

“…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)(12)(13)(14). These actions are absent in CRFR2-deficient mice (15,16).…”

mentioning

confidence: 99%

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

Bale

Hoshijima

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

120

View full text Add to dashboard Cite

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 pressure͞stroke 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 ␤-adrenergic receptor antagonist, esmalol, had no effect on the inotropic or lusitropic effects of UcnII in vivo, indicating that its actions are independent of ␤-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 receptor 2 ͉ hemodynamics ͉ inotropic agents ͉ lusitropic agents ͉ afterload reduction C orticotropin-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 proteincoupled 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)(12)(13)(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-pituitaryadrenal axis, complicating the potential use of these peptides for treatment of cardiovascular disorders (14). Therefore, to characterize the...

show abstract

“…These effects of urocortins can be summarized as follows; a dose-dependent increase in heart rate, cardiac output, coronary blood flow (8), coronary vasodilatation and positive inotropic effect (9), protection against ischemic and reperfusion injury in ventricular myocytes, a diminution in free radical damage following myocardial infarction (10,11), stimulation of cardiac natriuretic peptide secretion, decrease in left atrial pressure and peripheral vascular resistance (12), decrease in blood pressure, reduction of serum catecholamine levels in hyperadrenergic hypertension (13).…”

Section: Introductionmentioning

confidence: 99%

Relationship of urocortin-2 with systolic and diastolic functions and coronary artery disease: an observational study

Topal¹,

Yağmur²,

Otlu³

et al. 2012

Anadolu Kardiyol Derg

View full text Add to dashboard Cite

Objective: The urocortin (Ucn) hormones have many important roles in the cardiovascular system. Apart from systolic dysfunction (SD), there is no sufficient data on the relationship between serum Ucn-2 and diastolic dysfunction (DD), or coronary artery disease (CAD). We investigated serum Ucn-2 levels in SD, DD, and CAD. Methods: In this observational cross-sectional study, study population was enrolled among outpatients who underwent coronary angiography with the pre-diagnosis of CAD. By examining the echocardiography 86 subjects were selected to study after coronary angiography. The subjects distributed over three groups to investigate the relationship between serum Ucn-2 and SD according to their ejection fraction (EF): subjects with moderate to severe SD (Group A, EF=33.6%), subjects with mild to moderate SD (Group B, EF=46.1%), and those without SD (Group C, EF=64.5%). Apart from these groups, the serum Ucn-2 levels were compared between subjects with and without DD (EF≥45%), and also compared between subjects with and without CAD (EF≥55%). Statistical analyses were performed using one-way ANOVA, Kruskal-Wallis, Chisquare, Mann-Whitney U, Spearman correlation and multiple regression analyses tests. Results: Serum Ucn-2 levels were decreased in Group A and were increased in Group B compared to Group C (9.4±3.4, 12.8±3.6 vs. 10.4±3.9 pg/ mL, respectively, p=0.003). Unlike SD; there was no significant difference in serum Ucn-2 levels between subjects with and without DD (11.4±4.1 vs 11.7±3.9 pg/mL, p=0.8) or CAD (10.7±4.7 vs 10.2±3.2 pg/mL, p=0.7). Conclusion: Ucn-2 is elevated in mild to moderate SD. But, DD (impaired relaxation pattern), or CAD (without myocardial infarction) seems to have no effect on Ucn-2 hormone levels. (Anadolu Kardiyol Derg 2012; 12: 115-20) Key words: Urocortin 2, left ventricular systolic and diastolic dysfunction, coronary artery disease, regression analysis 115 ÖZET Amaç: Urocortin (Ucn) hormonları kardiyovasküler sistemde önemli rol oynamaktadır. Sistolik işlev bozukluğu (SD) dışında, diyastolik işlev bozukluğu (DD) veya koroner arter hastalığının (KAH) serum Ucn-2 ile ilişkisine dair yeterli veri bulunmamaktadır. Bu çalışmamızda SD, DD ve KAH'da serum Ucn-2 düzeyini araştırdık. Yöntemler: Bir gözlemsel enine-kesitli olan bu çalışmanın popülasyonu KAH ön tanısı ile koroner anjiyografi işlemine alınan bireyler arasından belirlendi. Koroner anjiyografi sonrası ekokardiyografi yapılarak 86 kişi seçildi. Ucn-2 ile SD arasındaki ilişkiyi araştırmak için ejeksiyon fraksiyonu (EF) farklı üç grup oluşturuldu: orta-ileri düzey SD olanlar (Grup A, EF=%33.6), hafif-orta SD olanlar (Grup B, EF=%46

show abstract

Cardiac inotropic actions of urocortin in conscious sheep

Cited by 110 publications

References 0 publications

Urocortin Protects against Ischemic and Reperfusion Injury via a MAPK-dependent Pathway

Urocortin Protects against Ischemic and Reperfusion Injury via a MAPK-dependent Pathway

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

Relationship of urocortin-2 with systolic and diastolic functions and coronary artery disease: an observational study

Contact Info

Product

Resources

About