Copyright © 2005, European Society of Cardiology
Hypertensive target organ damage is attenuated by a p38 MAPK inhibitor: role of systemic blood pressure and endothelial protection
aDepartment of Investigative and Cardiac Biology, UW2510 GlaxoSmithKline 709 Swedeland Road, PO Box 1539 King of Prussia, PA 19406, USA
bUniversity of Pennsylvania, School of Veterinary Medicine 709 Swedeland Road, PO Box 1539 King of Prussia, PA 19406, USA
cComparative Medicine and Investigative Support, School of Veterinary Medicine 709 Swedeland Road, PO Box 1539 King of Prussia, PA 19406, USA
dSafety Assessment GlaxoSmithKline School of Veterinary Medicine 709 Swedeland Road, PO Box 1539 King of Prussia, PA 19406, USA
* Corresponding author. Tel.: +1 610 270 6052; fax: +1 610 270 5080. Email address: robert.n.willette{at}gsk.com
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 N
-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.
KEYWORDS Hypertension; MAP kinase; p38 MAPK inhibitor; Renal function; Endothelial function; Nitric oxide; Systolic blood pressure
Time for primary review 18 days
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