Document Detail

Inhibition of mitogen-activated protein/extracellular signal-regulated kinase improves endothelial function and attenuates Ang II-induced contractility of mesenteric resistance arteries from spontaneously hypertensive rats.
MedLine Citation:
PMID:  12023682     Owner:  NLM     Status:  MEDLINE    
OBJECTIVES: Extracellular signal-regulated kinases (ERK1/2) modulate vascular smooth muscle cell (VSMC) growth and contractility, important factors in blood pressure regulation. In the present in vivo study, we investigated whether short-term inhibition of ERK1/2-dependent signaling pathways influences vascular function and blood pressure (BP) in spontaneously hypertensive rats (SHR).
METHODS: SHR and Wistar-Kyoto (WKY) rats were injected subcutaneously with either PD98059, selective MEK1/2 inhibitor (20 mg/kg), or vehicle. BP was measured by telemetry. Rats were killed 24 h after injection and small mesenteric arteries mounted as pressurized systems for morphometric analysis and assessment of endothelial function and angiotensin II (Ang II)-induced contractility. ERK1/2 phosphorylation was measured by Western blots, using protein extracts from mesenteric arteries, aorta, heart and kidneys.
RESULTS: BP was higher (P < 0.01) in SHR than in WKY rats. PD98059 did not influence BP in either group. Endothelial-dependent relaxation (acetylcholine-induced), which was impaired in SHR, was improved by PD98059 (P < 0.05). Ang II increased contraction, with greater responses in SHR (Emax = 25 +/- 4%) than WKY (Emax = 9 +/- 3%) (P < 0.01). PD98059 reduced Ang II-induced contraction in SHR (Emax = 5.8 +/- 0.4%) and WKY (Emax = 4 +/- 0.4%). Vascular structure was unaltered by PD98059. Vascular and renal ERK1/2 phosphorylation, which was higher in SHR than WKY, was decreased by PD98059 in SHR.
CONCLUSION: Short-term treatment with PD98059 improves endothelial function and vascular contractility without influencing BP in SHR. These findings provide evidence that vascular ERK1/2 activity is upregulated and that MEK1/2-sensitive signaling pathways play an important role in the regulation of vascular function in SHR. Acute inhibition of MEK1/2 does not alter blood pressure despite improved endothelial function and reduced arterial reactivity to Ang II.
Rhian M Touyz; Christian Deschepper; Jeong Bae Park; Gang He; Xin Chen; Mario Fritsch T Neves; Agostino Virdis; Ernesto L Schiffrin
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of hypertension     Volume:  20     ISSN:  0263-6352     ISO Abbreviation:  J. Hypertens.     Publication Date:  2002 Jun 
Date Detail:
Created Date:  2002-05-22     Completed Date:  2002-12-04     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  8306882     Medline TA:  J Hypertens     Country:  England    
Other Details:
Languages:  eng     Pagination:  1127-34     Citation Subset:  IM    
Laboratory of Experimental Hypertension, bLaboratory of Experimental Cardiovascular Biology, Clinical Research Institute of Montreal, University of Montreal, Quebec, Canada.
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MeSH Terms
Angiotensin II / pharmacology
Blood Pressure
Endothelium, Vascular / drug effects*,  physiopathology
Enzyme Inhibitors / pharmacology*
Flavonoids / pharmacology*
Hypertension / pathology,  physiopathology*
Mesenteric Arteries / drug effects*,  pathology,  physiopathology
Mitogen-Activated Protein Kinases / antagonists & inhibitors*,  metabolism
Phosphorylation / drug effects
Rats, Inbred SHR / physiology*
Rats, Inbred WKY
Vascular Resistance
Vasoconstriction / drug effects*
Vasoconstrictor Agents / pharmacology
Reg. No./Substance:
0/2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; 0/Enzyme Inhibitors; 0/Flavonoids; 0/Vasoconstrictor Agents; 11128-99-7/Angiotensin II; EC Protein Kinases
Comment In:
J Hypertens. 2002 Jun;20(6):1053-4   [PMID:  12023665 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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