Age-Related Differences in Vasoconstrictor Responses to Isoprostanes in Piglet Pulmonary and Mesenteric Vascular Smooth Muscle

Abstract

Isoprostanes are prostaglandin (PG)-like compounds produced nonenzymatically by free radical-catalyzed peroxidation of arachidonic acid. Isoprostanes evoke potent vascular effects but their actions in the neonatal vasculature are poorly known. We aimed to study the effects of 8-iso-PGE 1 , 8-iso-PGE 2 , 8-iso-PGF 1␣ , 8-iso-PGF 1␤ , 8-iso-PGF 2␣ , and 8-iso-PGF 2␤ in pulmonary arteries (PA), pulmonary veins (PV), and mesenteric arteries (MA) from newborn and 2-wk-old piglets. Isoprostanes produced concentrationdependent contractions of PA, PV, and MA (magnitudes up to 1.5-to 2-fold greater than the responses to 62.5 mM KCl) but they were markedly less potent vasoconstrictors than the thromboxane A 2 (TXA 2 ) mimetic U46619. Neonatal PA were more sensitive to 8-iso-PGF 1␣ , 8-iso-PGF 1␤ , and 8-iso-PGF 2␤ than 2-wk-old PA. Neonatal PV were more sensitive to 8-iso-PGE 2 and 8-iso-PGF 1␣, and neonatal MA were more sensitive to 8-iso-PGE 2 , 8-iso-PGF 1␣ , 8-iso-PGF 1␤ , 8-iso-PGF 2␣ , and 8-iso-PGF 2␤ than the corresponding 2-wk-old vessels. The sensitivity to U46619 decreased with postnatal age in MA but did not change in PA and PV. The contractile responses to all the isoprostanes and to U46619 were reverted by the TXA 2 receptor (TP) antagonist SQ 29,548. Moreover, isoprostaneevoked contractions in 2-wk-old PA were reduced by inhibitors of tyrosine kinase (genistein) and Rho kinase (Y 27632 and hydroxyfasudil) but not by inhibitors of protein kinase C (chelerythrine), mitogen-activated protein kinase kinase (PD 98059) or p38-kinase (SB 203580). In conclusion, isoprostanes produced compound-, tissue-, and age-dependent constriction of neonatal porcine pulmonary and mesenteric vascular smooth muscle. Isoprostanes are PG-like compounds formed in vivo by the free radical-catalyzed peroxidation of arachidonic acid, a reaction independent of the COX enzyme (1-3). They are generated initially at the site of a free radical attack of esterified arachidonate in cell membranes from which they are cleaved, presumably by phospholipases (2,3). Isoprostanes are used clinically and experimentally as markers for many disease states in which oxidative stress is a prominent feature, including asthma, myocardial and renal ischemia-reperfusion injury, atherosclerosis, pulmonary hypertension, and hypercholesterolemia (4 -6). However, isoprostanes are much more than inert markers and have been shown to possess biologic activity in whole-animal, isolated tissue, and cell-based systems (6,7). In the vascular system, isoprostanes exert important effects that range from powerful vasoconstriction to complete vasodilatation, depending on the particular isoprostane, tissue, and species studied (7).The neonatal period appears to be particularly interesting for the study of the biologic effects of isoprostanes because the

NADPH oxidases and reactive oxygen species at different stages of chronic hypoxia-induced pulmonary hypertension in newborn piglets

“…In addition to serving as markers of oxidative stress, F 2 -isoprostanes have been proposed to mediate vasoconstriction in different vascular beds and species (5,6,23,30). However, whether changes in vascular responsiveness that occur during exposure to chronic hypoxia in newborn piglets are due to F 2 -isoprostanes is unclear and requires further study.…”

Developmental changes in the effects of prostaglandin E2 in the chicken ductus arteriosus

“…The PGE 2 promiscuous interaction with TP receptors, especially at concentrations higher than 1 M, has also been observed in several vascular tissues including human umbilical arteries (Boersma et al 1999) and veins (Daray et al 2003), human uterine arteries (Baxter et al 1995) and aorta of the spontaneously hypertensive rat (Tang et al 2008). An alternative explanation for the eVects of SQ29,548 on PGE2-induced relaxation might be the blockade of a baseline TxA2-or isoprostaneinduced tone (Gonzalez-Luis et al 2005), allowing greater relaxatory actions of PGE on its dilatory receptors. However, this possibility is unlikely, since SQ29,548 have no eVect on DA mechanical activity, suggesting the lack of basal release of a TP receptor stimulator.…”

Relaxant Effects of the Soluble Guanylate Cyclase Activator and NO Sensitizer YC-1 in Piglet Pulmonary Arteries

“…As previously described, the contraction was measured by an isometric force transducer using data acquisition software and hardware [15] . Arterioles were mounted between an isometric force transducer (Kistler Morce DSC 6, Seattle, Wash., USA) and a displacement device in a myograph (model 610M, Danish Myo Technology, Aarhus, Denmark) using two stainless steel wires (diameter 40 m).…”

“…Endothelium-intact rings were precontracted with the thromboxane A 2 mimetic 9,11-dideoxy-11 ␣ ,9 ␣ -epoxymethano-prostaglandin F 2 ␣ (U46619, 0.1 M ) which induced a submaximal contractile response [15] . In previous experiments, these contractions were equieffective in the two age groups when expressed as a percent of the responses induced by 62.5 m M KCl [15] .…”