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 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.
Willette
Robert N
RN
Heart Failure Discovery Performance Unit, GlaxoSmithKline Pharmaceutics, 709 Swedeland Rd., King of Prussia, PA 19406, USA. robert.n.willette@gsk.com
Eybye
Marianne E
ME
Olzinski
Alan R
AR
Behm
David J
DJ
Aiyar
Nambi
N
Maniscalco
Kristeen
K
Bentley
Ross G
RG
Coatney
Robert W
RW
Zhao
Shufang
S
Westfall
Timothy D
TD
Doe
Chris P
CP
D000450:Aldosterone / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000201:enzymology; D051545:Cyclooxygenase 1 / Q000097:blood; D051546:Cyclooxygenase 2 / Q000097:blood; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D003521:Cyclopropanes / Q000494:pharmacology*; D016207:Cytokines / Q000037:antagonists & inhibitors; D004562:Electrocardiography / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000097:blood; D007677:Kidney Function Tests; D007783:Lactones / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D012083:Renin / Q000097:blood; D013450:Sulfones / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
C543534:6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide; D052246:Cyclooxygenase 2 Inhibitors; D003521:Cyclopropanes; D016207:Cytokines; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D007783:Lactones; D011725:Pyridines; D013450:Sulfones; C116926:rofecoxib; D000450:Aldosterone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; D012083:Renin