QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.068726v1 310/3/1133    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Di Filippo, C. Articles by D'Amico, M. Search for Related Content PubMed PubMed Citation Articles by Di Filippo, C. Articles by D'Amico, M.

CARDIOVASCULAR

The Distinct Alterations Produced in Cardiovascular Functions by Prednisolone and Nitro-prednisolone (NCX-1015) in the Rat Highlight a Causal Role for Endothelin-1

Department of Experimental Medicine, Section of Pharmacology, 2nd University of Naples, Naples, Italy (C.D.F., F.R., M.D.); The William Harvey Research Institute, London, United Kingdom (M.P.); and NicOx Research Institute, Bresso, Italy (P.D.S., E.O.)

Daily administration of prednisolone, but not the derivative NCX-1015 (or prednisolone 21-[4'-nitrooxymethyl]benzoate), to rats resulted in a time- and dose-dependent increase in mean arterial blood pressure (MABP), significant after 1 week for the dose of 6.9 µmol/kg i.p. (n = 10; P < 0.05), and 3 weeks for the lower dose of 1.38 µmol/kg. A similar dichotomy of behavior was observed with respect to myocardial contractility and renal vascular resistance, in either case augmented by 3-week treatment with prednisolone but not NCX-1015. In contrast, both NCX-1015 and prednisolone reduced plasma levels of corticosterone in a dose- (dose range of 0.69-6.9 µmol/kg i.p.) and time-dependent (1-3 weeks) manner. Similar profiles were obtained for plasma nitrate values, although they were increased selectively after NCX-1015 administration. In contrast, prednisolone, but not NCX-1015, augmented plasma endothelin 1 (ET-1) with a profile that mirrored the changes observed in MABP and renal blood flow. Supply in the drinking water of the ET-1 receptor type A (ET_A) antagonist FR139317 [(R-2-[(R)-2-[(S)-2-[[1-(hexahydro-1H-azepinyl)]-carbonyl]amino-4-methylpentanoyl]-amino-3-(2-pyridil)propionic] or mixed ET_A/B, but not of selective ET_B, antagonists prevented the changes produced by a 21-day treatment with prednisolone. In conclusion, this study indicates 1) a lack of occurrence of cardiovascular alterations by nitro-releasing derivative of prednisolone (NCX-1015), and 2) a functional link between prednisolone effects and the endogenous endothelin-1 system.

Address correspondence to: Dr. Mauro Perretti, The William Harvey Research Institute, Queen Mary School of Medicine and Dentistry, University of London, Charterhouse Square, EC1M 6BQ London, UK. E-mail: m.perretti{at}qmul.ac.uk

This article has been cited by other articles:

				G. Leoni, H. B. Patel, A. L. F. Sampaio, F. N. E. Gavins, J. F. Murray, P. Grieco, S. J. Getting, and M. Perretti Inflamed phenotype of the mesenteric microcirculation of melanocortin type 3 receptor-null mice after ischemia-reperfusion FASEB J, December 1, 2008; 22(12): 4228 - 4238. [Abstract] [Full Text] [PDF]