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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 310; no. 3; pp. 1133 - 1141
• Main Authors: Di Filippo, Clara, Rossi, Francesco, Ongini, Ennio, Del Soldato, Piero, Perretti, Mauro, D'Amico, Michele
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.09.2004
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Azepines - pharmacology; Blood Pressure - drug effects; Body Weight - drug effects; Cardiovascular System - drug effects; Endothelin Receptor Antagonists; Endothelin-1 - physiology; Heart Rate - drug effects; Indoles - pharmacology; Kidney - blood supply; Kidney - drug effects; Kidney - physiology; Plasma - chemistry; Prednisolone - analogs & derivatives; Prednisolone - pharmacology; Rats; Rats, Sprague-Dawley; Regional Blood Flow - drug effects; Vascular Resistance - drug effects; Vascular Resistance - physiology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.104.068726

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-1 H -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.