Immediate and Sustained Blood Pressure Lowering by Urocortin 2

Abstract

Abstract-Recently, novel corticotropin-releasing factor-related peptides, named urocortin 1, 2, and 3, and a distinct cardiac and peripheral vascular receptor (corticotropin-releasing factor receptor 2) were described being part of a peripheral corticotropin-releasing factor system modulating cardiovascular function in response to stress. Vasorelaxation and blood pressure lowering have been reported after acute administration of these peptides. No data are available on the acute and chronic effects of urocortin 2 on blood pressure in models of arterial hypertension. To test these effects, hypertensive salt-sensitive and normotensive salt-resistant Dahl rats were randomly assigned to twice-daily applications of urocortin 2 or vehicle for 5 weeks. Blood pressure, heart rate, and left ventricular dimension and function were recorded at baseline, after initial application, and, together with cardiac and aortic expression of urocortin 2 and its receptor, after 5 weeks of treatment. Urocortin 2 significantly reduced blood pressure in hypertensive rats without affecting heart rate. Long-term urocortin 2 treatment in hypertensive rats induced sustained blood pressure reduction and diminished the development of hypertension-induced left ventricular hypertrophy and the deterioration of left ventricular contractile function. Corticotropin-releasing factor receptor 2 expression was preserved despite chronic stimulation by urocortin 2. In conclusion, our study shows that, in an animal model of arterial hypertension, urocortin 2 has immediate and sustained blood pressure-lowering effects. Beneficial effects on blood pressure, left ventricular dimension, and function, together with preserved receptor expression, suggest that corticotropin-releasing factor receptor 2 stimulation by urocortin 2 may represent a novel approach to the treatment of arterial hypertension. A rterial hypertension remains the major risk factor for cardiovascular and related diseases. In its most recent report, the World Health Organization lists high blood pressure (BP) as the leading cause of death worldwide.

Prolonged Urocortin 2 Administration in Experimental Heart Failure

“…Indeed, recent work by Yang et al 19 in spontaneously hypertensive rats (a model also marked by vasoconstriction, as well as an activated renin-angiotensin system) demonstrated that not only does intravenous Ucn1 reduce serum angiotensin-converting enzyme (ACE) and Ang II levels, but a significant positive relationship exists between circulating ACE and systolic blood pressure. In agreement with our study, Dieterle et al 15 have shown sustained blood pressure lowering by Ucn2 in hypertensive salt-sensitive Dahl rats after chronic treatment. This occurred in conjunction with the preservation of left ventricular function (in contrast to the deterioration exhibited in untreated controls) and in the absence of any heart rate increase.…”

“…Despite the observed falls in circulating natriuretic peptide concentrations observed in our study (peptides with a range of beneficial actions in the setting of HF), 24 Ucn2 is reported to stimulate the secretion of ANP and BNP in cardiomyocytes, 25 and ventricular expression of BNP, at least, is reported to be maintained after chronic Ucn2 administration in the rat. 15 Although it is the CRFR1 rather than the CRFR2 subtype responsible for mediating HPA axis activation, 4 the transient rise in plasma cortisol levels seen with chronic infusion of Ucn2 (reportedly selective for CRFR2) was not entirely unexpected given an identical response seen with bolus Ucn2 administration in our previous work. 7 In that earlier study, the concurrent rise in plasma Ucn1 concentrations (and subsequent activation of CRFR1), presumably as a result of competitive inhibition for the CRFR2 by Ucn2, was likely responsible.…”

“…This finding is in keeping with work in rats showing negligible downregulation of CRFR2 mRNA expression in the left ventricle and aorta even after 5 weeks of Ucn2 delivery. 15 The range and the persistence of Ucn2's cardiovascular effects are comparable to those seen in response to 4-day infusion of Ucn1 in experimental HF, 16 although the onset of effect appears to be more rapid with Ucn2. Of note, the magnitude of the effects produced by these 2 peptides by day 4 of treatment were essentially similar despite a Ͼ2-fold higher dose of Ucn2 being used (Ucn2: 0.75 g/kg per hour; Ucn1 0.3 g/kg per hour), 16 indicating, as suggested in earlier acute administration studies, 6 -9 differ- Data show meanϮSEM measurements in sheep before (nonpaced: laboratory normal data; nϭ20) and after induction of heart failure by 7 d of rapid left ventricular pacing at 220 bpm (paced: mean control and Ucn2 baseline data; nϭ12).…”

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

“…Further studies will clarify the role of urocortins in the pathophysiology, diagnosis, and therapeutics of evolving of HF. Ucn-2 may not be as powerful as the natriuretic peptides in the diagnosis of HF for the present, but therapeutic features of Ucn hormone (Ucn-1, Ucn-2 isoforms) (13,(15)(16)(17) are seems to distinctive from the natriuretic peptides.…”

“…In a blood sample practically measurement of such determinants may contribute to the improvement of quick diagnosis of HF and could allow to detect the staging of HF. The published results show that Ucn is a diagnostic marker and a potentially attractive therapeutic target for HF (13,(15)(16)(17). Relatively few studies (18)(19)(20) have been performed related to the role of Ucn hormone in humans HF, and there are no sufficiently investigations regarding relation of serum Ucn levels with diastolic dysfunction (DD) or CAD.…”