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Research ArticleCARDIOVASCULAR

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

Clara Di Filippo, Francesco Rossi, Ennio Ongini, Piero Del Soldato, Mauro Perretti and Michele D'Amico
Journal of Pharmacology and Experimental Therapeutics September 2004, 310 (3) 1133-1141; DOI: https://doi.org/10.1124/jpet.104.068726
Clara Di Filippo
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Francesco Rossi
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Ennio Ongini
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Piero Del Soldato
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Mauro Perretti
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Michele D'Amico
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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

  • M.P. is supported by a Senior Fellowship of the Arthritis Research Campaign UK.

  • doi:10.1124/jpet.104.068726.

  • 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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Journal of Pharmacology and Experimental Therapeutics: 310 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 3
1 Sep 2004
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Research ArticleCARDIOVASCULAR

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

Clara Di Filippo, Francesco Rossi, Ennio Ongini, Piero Del Soldato, Mauro Perretti and Michele D'Amico
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 1133-1141; DOI: https://doi.org/10.1124/jpet.104.068726

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Research ArticleCARDIOVASCULAR

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

Clara Di Filippo, Francesco Rossi, Ennio Ongini, Piero Del Soldato, Mauro Perretti and Michele D'Amico
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 1133-1141; DOI: https://doi.org/10.1124/jpet.104.068726
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