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(Hypertension. 2009;53:739.)
© 2009 American Heart Association, Inc.

Original Articles

Immediate and Sustained Blood Pressure Lowering by Urocortin 2

A Novel Approach to Antihypertensive Therapy?

Thomas Dieterle; Silvia Meili-Butz; Katrin Bühler; Christian Morandi; Dietlinde John; Peter T. Buser; Jean Rivier; Wylie W. Vale; Kirk L. Peterson; Marijke Brink

From the Department of Biomedicine (T.D., S.M.-B., K.B., C.M., D.J., M.B.), University of Basel and University Hospital Basel, Basel, Switzerland; Division of Cardiology (T.D., P.T.B.), University Hospital Basel, Basel, Switzerland; Clayton Foundation Laboratories (J.R., W.W.V.), Salk Institute, La Jolla, Calif; and the Institute of Molecular Medicine (K.L.P.), University of California San Diego, La Jolla.

Correspondence to Thomas Dieterle, Division of Cardiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. E-mail dieterlet{at}uhbs.ch

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.

Key Words: CRF receptor • urocortin 2 • Dahl salt-sensitive rat • arterial hypertension • blood pressure • left ventricular hypertrophy • left ventricular function