Differential Effects of p38 Mitogen-Activated Protein Kinase and Cyclooxygenase 2 Inhibitors in a Model of Cardiovascular Disease

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...

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Published in:The Journal of pharmacology and experimental therapeutics 2009-09, Vol.330 (3), p.964-970
Main Authors: Willette, Robert N, Eybye, Marianne E, Olzinski, Alan R, Behm, David J, Aiyar, Nambi, Maniscalco, Kristeen, Bentley, Ross G, Coatney, Robert W, Zhao, Shufang, Westfall, Timothy D, Doe, Chris P
Format: Article
Language:English
Subjects:
Aldosterone - blood
Animals
Blood Pressure - drug effects
Cardiovascular Diseases - drug therapy
Cardiovascular Diseases - 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
p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors
Pyridines - pharmacology
Rats
Rats, Inbred SHR
Renin - blood
Sulfones - pharmacology
Vasodilation - drug effects
Ventricular Remodeling - drug effects
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Summary: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-5 H -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-1β (IL-1β). 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-1β. 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.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.109.154443