Age-related differences in vasoconstrictor responses to isoprostanes in piglet pulmonary and mesenteric vascular smooth muscle

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 alpha), 8-iso-PGF(1 beta), 8-iso-PGF(2 alpha), and 8-iso-PGF(2 beta) in pulmonary arteries (PA), pulmonary veins (PV), and mesenteric arteries (MA) from newborn and 2-wk-old piglets. Isoprostanes produced concentration-dependent 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, (TXA(2)) mimetic U46619. Neonatal PA were more sensitive to 8-iso-PGF(1 alpha), 8-iso-PGF(1 beta), and 8-iso-PGF(2 beta) than 2-wk-old PA. Neonatal PV were more sensitive to 8-iso-PGE(2) and 8-iso-PGF(1 alpha). and neonatal MA were more sensitive to 8-iso-PGE(2), 8-iso-PGF(1 alpha), 8-iso-PGF(1 beta), 8-iso-PGF(2 alpha), and 8-iso-PGF(2 beta) 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, isoprostane-evoked 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. Isoprostane-evoked PA vasoconstriction involved TP receptors and activation of tyrosine kinases and Rho kinases.