Hypertensive target organ damage is attenuated by a p38 MAPK inhibitor: role of systemic blood pressure and endothelial protection.
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.
Olzinski
Alan R
AR
Department of Investigative and Cardiac Biology, UW2510 GlaxoSmithKline 709 Swedeland Road, PO Box 1539 King of Prussia, PA 19406, USA.
McCafferty
Tara A
TA
Zhao
Shufang Q
SQ
Behm
David J
DJ
Eybye
Marianne E
ME
Maniscalco
Kristeen
K
Bentley
Ross
R
Frazier
Kendall S
KS
Milliner
Chavon M
CM
Mirabile
Rosanna C
RC
Coatney
Robert W
RW
Willette
Robert N
RN
D000818:Animals; D004452:Echocardiography; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007093:Imidazoles / Q000627:therapeutic use*; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D023421:Models, Animal; D009206:Myocardium / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D014655:Vascular Resistance; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D011743:Pyrimidines; C502576:SB-239063AN; D019001:Nitric Oxide Synthase; D048051:p38 Mitogen-Activated Protein Kinases; D019331:NG-Nitroarginine Methyl Ester