The distinct alterations produced in cardiovascular functions by prednisolone and nitro-prednisolone (NCX-1015) in the rat highlight a causal role for endothelin-1.
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 micromol/kg i.p. (n = 10; P < 0.05), and 3 weeks for the lower dose of 1.38 micromol/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 micromol/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.
Di Filippo
Clara
C
The William Harvey Research Institute, Queen Mary School of Medicine and Dentistry, University of London, Charterhouse Square, EC1M 6BQ London, UK.
Rossi
Francesco
F
Ongini
Ennio
E
Del Soldato
Piero
P
Perretti
Mauro
M
D'Amico
Michele
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000502:physiology; D010949:Plasma / Q000737:chemistry; D011239:Prednisolone / Q000031:analogs & derivatives / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology
D000893:Anti-Inflammatory Agents; D001381:Azepines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007211:Indoles; C418962:prednisolone 21-((4'-nitrooxymethyl)benzoate); C079574:FR 139317; D011239:Prednisolone