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Differential effects of p38 mitogen-activated protein kinase and cyclooxygenase 2 inhibitors in a model of cardiovascular disease.

Abstract
The evidence is compelling for a role of inflammation in cardiovascular diseases; however, the chronic use of anti-inflammatory drugs for these indications has been disappointing. The recent study compares the effects of two anti-inflammatory agents [cyclooxygenase 2 (COX2) and p38 inhibitors] in a model of cardiovascular disease. The vascular, renal, and cardiac effects of 4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one (rofecoxib; a COX2 inhibitor) and 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,2-dimethylpropyl)-3-pyridinecarboxamide [GSK-AHAB, a selective p38 mitogen-activated protein kinase (MAPK) inhibitor], were examined in the spontaneously hypertensive stroke-prone rat (SHR-SP). In SHR-SPs receiving a salt-fat diet (SFD), chronic treatment with GSK-AHAB significantly and dose-dependently improved survival, endothelial-dependent and -independent vascular relaxation, and indices of renal function, and it attenuated dyslipidemia, hypertension, cardiac remodeling, plasma renin activity (PRA), aldosterone, and interleukin-1beta (IL-1beta). In contrast, chronic treatment with a COX2-selective dose of rofecoxib exaggerated the harmful effects of the SFD, i.e., increasing vascular and renal dysfunction, dyslipidemia, hypertension, cardiac hypertrophy, PRA, aldosterone, and IL-1beta. The protective effects of a p38 MAPK inhibitor are clearly distinct from the deleterious effects of a selective COX2 inhibitor in the SHR-SP and suggest that anti-inflammatory agents can have differential effects in cardiovascular disease. The results also suggest a method for evaluating long-term cardiovascular efficacy and safety.
AuthorsRobert N Willette, Marianne E Eybye, Alan R Olzinski, David J Behm, Nambi Aiyar, Kristeen Maniscalco, Ross G Bentley, Robert W Coatney, Shufang Zhao, Timothy D Westfall, Chris P Doe
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 330 Issue 3 Pg. 964-70 (Sep 2009) ISSN: 1521-0103 [Electronic] United States
PMID19556450 (Publication Type: Journal Article)
Chemical References
  • 6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide
  • Cyclooxygenase 2 Inhibitors
  • Cyclopropanes
  • Cytokines
  • Enzyme Inhibitors
  • Interleukin-1beta
  • Lactones
  • Pyridines
  • Sulfones
  • rofecoxib
  • Aldosterone
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • p38 Mitogen-Activated Protein Kinases
  • Renin
Topics
  • Aldosterone (blood)
  • Animals
  • Blood Pressure (drug effects)
  • Cardiovascular Diseases (drug therapy, enzymology)
  • Cyclooxygenase 1 (blood)
  • Cyclooxygenase 2 (blood)
  • Cyclooxygenase 2 Inhibitors (pharmacology)
  • Cyclopropanes (pharmacology)
  • Cytokines (antagonists & inhibitors)
  • Electrocardiography (drug effects)
  • Endothelium, Vascular (drug effects)
  • Enzyme Inhibitors (pharmacology)
  • Interleukin-1beta (blood)
  • Kidney Function Tests
  • Lactones (pharmacology)
  • Lipid Metabolism (drug effects)
  • Male
  • Pyridines (pharmacology)
  • Rats
  • Rats, Inbred SHR
  • Renin (blood)
  • Sulfones (pharmacology)
  • Vasodilation (drug effects)
  • Ventricular Remodeling (drug effects)
  • p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors)

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