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 mumol/kg i.p. (n = 10; P < 0.05), and 3 weeks for the lower dose of 1.38 mu mol/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 mu mol/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.