Objective: Evidence suggests important relationships among chronic inflammatory processes, endothelial dysfunction, hypertension and target organ damage. The present study examined the effects of chronic treatment with an anti-inflammatory p38 mitogen-activated protein kinase (MAPK) inhibitor (SB-239063AN) in the Nω-nitro-l-arginine methyl ester-treated spontaneously hypertensive rat (SHR+l-NAME) model of severe hypertension and accelerated target organ damage. Methods: SHRs were divided into control (n=16), l-NAME (n=26) and l-NAME+SB-239063AN (n=24) groups. l-NAME was delivered by the drinking water ad lib (50 mg/L) and SB-239063AN was administered by the diet (1200 ppm) for 4 weeks. Arterial blood pressure (telemetry) and target organ damage (kidney, heart, and vasculature) were examined. Results: The introduction of l-NAME to the drinking water elicited a severe/sustained increase in blood pressure and significant morbidity and mortality. Chronic treatment with SB-239063AN had no effect on the initial blood pressure response (7 days) to l-NAME but attenuated subsequent increases in diastolic blood pressure and significantly reduced morbidity/mortality (42% vs. 5%, p<0.002). Renal dysfunction characterized by increased total protein and albumin excretion was apparent within 2 weeks in the SHR+l-NAME groups. Treatment with SB-239063AN delayed the onset of proteinuria and albuminuria. SB-239063AN treatment also significantly reduced l-NAME-induced interstitial fibrosis in the kidney and restrictive concentric hypertrophy in the left ventricle (end-diastolic volume 0.24±0.05 vs. 0.41±0.05 ml; p<0.05). Endothelial dysfunction was also not altered by SB-239063AN treatment (Rmax 49±6% vs. 45±9%). Conclusions: The results demonstrate that morbidity/mortality and accelerated target organ damage induced by inhibition of nitric oxide synthase in SHR was attenuated by treatment with a selective p38 MAPK inhibitor, SB-239063AN. The organ protection observed in the heart and kidney was not associated with preservation of endothelial function. © 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Olzinski, A. R., McCafferty, T. A., Zhao, S. Q., Behm, D. J., Eybye, M. E., Maniscalco, K., … Willette, R. N. (2005). Hypertensive target organ damage is attenuated by a p38 MAPK inhibitor: Role of systemic blood pressure and endothelial protection. Cardiovascular Research, 66(1), 170–178. https://doi.org/10.1016/j.cardiores.2004.12.021