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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Division of Neonatology, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California

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 the effects 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) and 8-Br-cAMP (BAMP), as well as cGMP-dependent protein kinase (PKG) and cAMP-dependent protein kinase (PKA) inhibitors. All groups were treated with 1 nM PAF and incubated for 30 min for the binding assay or 20 min for measurement of inositol 1,4,5-phosphate (IP₃) production. BGMP and BAMP decreased PAF binding in normoxia by 63 and 14%, respectively. Incubations with the PKG inhibitor Rp-8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphorothioate sodium and the PKA inhibitor Rp-adenosine-3',5'-cyclic monophosphorothioate abrogated the inhibitory effects of BGMP and BAMP. PAF-stimulated IP₃ production was 8565 ± 314 dpm/10⁶ cells in hypoxia and 5418 ± 118 dpm/10⁶ cells in normoxia, a 40% decrease. BGMP attenuated PAF-stimulated IP₃ production by 67 and 37% in hypoxia and normoxia, respectively; the value for BAMP was 44% under both conditions. Pretreatment with PKG or PKA inhibitor abrogated BGMP and BAMP inhibition of IP₃ release. PAF receptor (PAFr) protein expression decreased in normoxia, but pretreatment with 10 nM PAF up-regulated PAFr expression. Pretreatment with PAF decreased expression and activities of PKG or PKA proteins in normoxia and hypoxia. Our data demonstrate the existence of cGMP/cAMP-PAF cross-talk in pulmonary vascular smooth muscle cells, which may be one mechanism by which PAFr-mediated vasoconstriction is down-regulated at birth.

Address correspondence to: Dr. Basil O. Ibe, Division of Neonatology, Los Angeles Biomedical Research Institute, 1124 W. Carson St., RB-1, Torrance, CA 90502. E-mail: ibe{at}labiomed.org

This article has been cited by other articles:

				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.