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.
Footnotes
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M.P. is supported by a Senior Fellowship of the Arthritis Research Campaign UK.
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doi:10.1124/jpet.104.068726.
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ABBREVIATIONS: GC, glucocorticoid; NO, nitric oxide; ET, endothelin; NCX-1015, prednisolone 21-[4′-nitrooxymethyl]benzoate; FR139317, (+)-(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid); SB209670, (R-2-[(R)-2-[(S)-2-[[1-(hexahydro-1H-azepinyl)]-carbonyl]amino-4-methylpentanoyl]-amino-3-(2-pyridil)propionic; BQ-788, N-cis-2,6-dimethylpiperidinocarbonyl-l-γ-metLeu-d-l-methoxy-carbonylTrp-d-Nle; ETA/ETB, ET receptor type A or B; MABP, mean arterial blood pressure; RBF, renal blood flow; RVR, renal vascular resistance.
- Received March 19, 2004.
- Accepted April 27, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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