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PPAR Research
Volume 2012, Article ID 302495, 10 pages
http://dx.doi.org/10.1155/2012/302495
Research Article

PPAR 𝜶 -Independent Arterial Smooth Muscle Relaxant Effects of PPAR 𝜶 Agonists

1Muscle Biology Research Group (MUBIG), Basic Medical Science Department, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA
2Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA

Received 15 June 2012; Accepted 26 July 2012

Academic Editor: Richard P. Phipps

Copyright © 2012 Neerupma Silswal et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

We sought to determine direct vascular effects of peroxisome proliferator-activated receptor alpha (PPARα) agonists using isolated mouse aortas and middle cerebral arteries (MCAs). The PPARα agonists GW7647, WY14643, and gemfibrozil acutely relaxed aortas held under isometric tension and dilated pressurized MCAs with the following order of potency: GW7647≫WY14643>gemfibrozil. Responses were endothelium-independent, and the use of PPARα deficient mice demonstrated that responses were also PPARα-independent. Pretreating arteries with high extracellular K+ attenuated PPARα agonist-mediated relaxations in the aorta, but not in the MCA. In the aorta, the ATP sensitive potassium ( K A T P ) channel blocker glibenclamide also impaired relaxations whereas the other K+ channel inhibitors, 4-aminopyridine and Iberiotoxin, had no effect. In aortas, GW7647 and WY14643 elevated cGMP levels by stimulating soluble guanylyl cyclase (sGC), and inhibition of sGC with ODQ blunted relaxations to PPARα agonists. In the MCA, dilations were inhibited by the protein kinase C (PKC) activator, phorbol 12,13-dibutyrate, and also by ODQ. Our results demonstrated acute, nonreceptor-mediated relaxant effects of PPARα agonists on smooth muscle of mouse arteries. Responses to PPARα agonists in the aorta involved K A T P channels and sGC, whereas in the MCA the PKC and sGC pathways also appeared to contribute to the response.