@article {Di Filippo1133, author = {Clara Di Filippo and Francesco Rossi and Ennio Ongini and Piero Del Soldato and Mauro Perretti and Michele D{\textquoteright}Amico}, title = {The Distinct Alterations Produced in Cardiovascular Functions by Prednisolone and Nitro-prednisolone (NCX-1015) in the Rat Highlight a Causal Role for Endothelin-1}, volume = {310}, number = {3}, pages = {1133--1141}, year = {2004}, doi = {10.1124/jpet.104.068726}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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 (ETA) antagonist FR139317 [(R-2-[(R)-2-[(S)-2-[[1-(hexahydro-1H-azepinyl)]-carbonyl]amino-4-methylpentanoyl]-amino-3-(2-pyridil)propionic] or mixed ETA/B, but not of selective ETB, 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. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/310/3/1133}, eprint = {https://jpet.aspetjournals.org/content/310/3/1133.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }