title: 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.
authors.affiliation: Department of Investigative and Cardiac Biology, UW2510 GlaxoSmithKline 709 Swedeland Road, PO Box 1539 King of Prussia, PA 19406, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Olzinski
authors.forename: Tara A
authors.initials: TA
authors.lastname: McCafferty
authors.forename: Shufang Q
authors.initials: SQ
authors.lastname: Zhao
authors.forename: David J
authors.initials: DJ
authors.lastname: Behm
authors.forename: Marianne E
authors.initials: ME
authors.lastname: Eybye
authors.forename: Kristeen
authors.initials: K
authors.lastname: Maniscalco
authors.forename: Ross
authors.initials: R
authors.lastname: Bentley
authors.forename: Kendall S
authors.initials: KS
authors.lastname: Frazier
authors.forename: Chavon M
authors.initials: CM
authors.lastname: Milliner
authors.forename: Rosanna C
authors.initials: RC
authors.lastname: Mirabile
authors.forename: Robert W
authors.initials: RW
authors.lastname: Coatney
authors.forename: Robert N
authors.initials: RN
authors.lastname: Willette
mesh_terms: 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*
chemical_list: D007093:Imidazoles; D011743:Pyrimidines; C502576:SB-239063AN; D019001:Nitric Oxide Synthase; D048051:p38 Mitogen-Activated Protein Kinases; D019331:NG-Nitroarginine Methyl Ester