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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 3, 2006; DOI: 10.1124/jpet.106.111914

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Basil O. Ibe
Adnan Ameer
Ada Mae Portugal
Lissette Renteria
J. Usha Raj
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Received for publication August 3, 2006.
Revised November 1, 2006.
Accepted for publication November 2, 2006.

Platelet Activating Factor Modulates Activity of Cyclic Nucleotides in Fetal Ovine Pulmonary Vascular Smooth Muscle

Basil O. Ibe 1*, Adnan Ameer 1, Ada Mae Portugal 1, Lissette Renteria 1, J. Usha Raj 1

1 Los Angeles Biomedical Research Institute

* Address correspondence to: E-mail: ibe{at}labiomed.org

Abstract

At birth, release of endogenous vasodilators such as nitric oxide and prostacyclin facilitate pulmonary vasodilation via the cyclic nucleotides, cGMP and cAMP. Interaction of cyclic nucleotides and platelet activating factor (PAF) mediated responses in pulmonary vascular smooth muscle is not known. We studied effect of cGMP and cAMP on PAF-mediated responses in ovine fetal intrapulmonary venous smooth muscle cells. Studies were done in hypoxia or normoxia with buffer; with 8-Br-cGMP (BGMP), 8-Br-cAMP (BAMP) as well as PKG and PKA inhibitors. All groups were treated with 1nM PAF and incubated for 30 min for binding assay or 20 min for measurement of inositol phosphate (IP3) production. BGMP and BAMP decreased PAF binding in normoxia by 63% and 14% respectively. Incubations with PKG inhibitor Rp-8-pCPT- cGMPS and PKA inhibitor Rp-cAMPS abrogated the inhibitory effects of BGMP and BAMP. PAF-stimulated IP3 production (DPM/106 cells) was 8565±14 in hypoxia and 5418±118 in normoxia, a 40% decrease. BGMP attenuated PAF- stimulated IP3 production by 67% and 37% in hypoxia and normoxia, the value for BAMP was 44% under both conditions. Pre-treatment with PKG or PKA inhibitor abrogated BGMP and BAMP inhibition of IP3 release. PAF receptor (PAFr) protein expression decreased in normoxia, but pretreatment with 10nM PAF up-regulated PAF-r expression. Pretreatment with PAF decreased expression and activities of PKG or PKA proteins in normoxia and hypoxia. Our data demonstrate existence of cGMP/cAMP-PAF cross-talk in PVSMC, which may be one mechanism by which PAF-r mediated vasoconstriction is down-regulated at birth.


Key words: Hypoxia, PAF receptor, PKA, PKG, Pulmonary hypertension, Smooth muscle cells


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A. M McPeak, S. M. Douglass, B. O. Ibe, and J. U. Raj
Cyclic Nucleotides Down-Regulate Platelet Activating Factor Receptor (PAFr) Protein Expression in Ovine Fetal Pulmonary Arterial Smooth Muscle Cells (SMC-PA)
FASEB J, March 1, 2007; 21(6): LB113 - LB113.



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