Increased Pulmonary Blood Flow Alters Pulmonary Vascular Reactivity in the Lamb. ♦ 143

Congenital heart disease associated with increased pulmonary blood flow frequently produces structural and functional abnormalities of the pulmonary vascular bed, resulting in pulmonary hypertension. The mechanisms producing these changes in vascular reactivity are not well understood. We studied a lamb model of increased pulmonary blood flow with pulmonary hypertension, created by in utero placement of aortopulmonary vascular shunts at 139 days gestation. At four to six weeks of age, 8 shunted lambs and 6 age matched controls were sacrificed and pulmonary arteries (PA) and veins (PV) isolated. Some 4th generation PA were snap frozen, and cGMP content subsequently determined by ¹²⁵I RIA. Other 5th generation vessels were studied in conventional tissue bath systems. Contractility to norepinephrine(NE) was first assessed by full concentration response curves with and without the NO synthase inhibitor LNA. Endothelium intact vessels were then submaximally preconstricted with NE following pretreatment with indomethacin. Full concentration response curves to A23187 (receptor independent stimulus of endothelial NO synthase, ecNOS), SNAP (exogenous NO donor), and atrial natriuretic peptide (ANP, particulate guanylate cyclase agonist) were performed. Results: PV from shunted lambs did not differ from controls in any of the studies. PA from shunted lambs had higher basal cGMP levels than controls (17.6 ± 2.9 vs 8.5 ± 1.7 pm/mg protein, p < 0.05). Contractile responses to NE did not differ between control and shunted lambs. However, LNA enhanced contractile responses to NE in PA from control lambs (57± 22% at maximal NE concentration) but had no effect in PA from shunted lambs. Maximal relaxations to the agonists in PA are tabulated below(*p<0.05 by ANOVA). Table We conclude that while cGMP concentrations are increased in PA from shunted lambs. blunted responses to LNA and A23187 indicate decreased basal and stimulated ecNOS activity. The enhanced relaxations to ANP may indicate increased production of cGMP by particulate guanylate cyclase.

Table 1

Funded by NIH HL#54705 and AHA.