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Hypertensive target organ damage is attenuated by a p38 MAPK inhibitor: role of systemic blood pressure and endothelial protection.

Abstract：

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(omega)-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.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Olzinski AR,McCafferty TA,Zhao SQ,Behm DJ,Eybye ME,Maniscalco K,Bentley R,Frazier KS,Milliner CM,Mirabile RC,Coatney RW,Willette RN

doi

10.1016/j.cardiores.2004.12.021

subject

Has Abstract

pub_date

2005-04-01 00:00:00

pages

170-8

issue

eissn

0008-6363

issn

1755-3245

pii

S0008-6363(04)00593-0

journal_volume

pub_type

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Hypertensive target organ damage is attenuated by a p38 MAPK inhibitor: role of systemic blood pressure and endothelial protection.