Immediate and sustained blood pressure lowering by urocortin 2: a novel approach to antihypertensive therapy?
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.
Dieterle
Thomas
T
Division of Cardiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. dieterlet@uhbs.ch
Meili-Butz
Silvia
S
Bühler
Katrin
K
Morandi
Christian
C
John
Dietlinde
D
Buser
Peter T
PT
Rivier
Jean
J
Vale
Wylie W
WW
Peterson
Kirk L
KL
Brink
Marijke
M
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004452:Echocardiography; D015870:Gene Expression / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism*; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051381:Rats; D020303:Rats, Inbred Dahl; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics; D054832:Urocortins / Q000235:genetics / Q000494:pharmacology*
D000959:Antihypertensive Agents; C101531:CRF receptor type 2; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; C514216:urocortin 3, rat; D003346:Corticotropin-Releasing Hormone