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.
