Mechanisms underlying increased reactivity of pulmonary arteries contralateral to a localized high-flow anastomosis

Abstract

Objectives Our model of a systemic-pulmonary shunt exhibits enhanced reactivity of pulmonary arteries contralateral to a localized shunt between the left lower lobe pulmonary artery (LLPA) and aorta relative to those of ipsilateral or control PAs 48 hours after anastomosis. We examined the contribution of nitric oxide (NO), cyclooxygenase (COX), lipoxygenase (LOX), or cytochrome P450 (CYP) production to mediating this enhanced reactivity. Methods We created a surgical end-to-side anastomosis of the left lower lobe PA to the aorta. 48 hours later we tested tension of PA rings from the right and left lower lobes for contraction to the thromboxane mimetic U46619 in the presence of vehicle or inhibitors of NO synthase (S), COX, CYP, or LOX. Western blots of PA homogenates were probed for eNOS or isoforms metabolizing arachidonic acid (AA). Eicosanoid products from intact PAs rings were detected using labeled AA and HPLC separation. Results Enhanced reactivity of unshunted right PAs over that of left PAs from high flow hosts was not eliminated by inhibitors of NOS, COX, or CYP. Treatment with 2 different LOX inhibitors, nordihydroguaiaretic acid and cinnamyl-3,4-dihydroxy-α-cyanocinnamate, closed the difference in contractility of shunted and unshunted PAs. PAs contralateral to shunts metabolized AA to 12-hydroxyeicosatetraenoic acid (HETE) in greater quantities than analogous PAs from the experimental left or control PAs. Conclusions 48 hours after anastomosis enhanced reactivity of contralateral PAs is attributable in part to increased LOX products as opposed to NO or other eicosanoid products. Ultramini-abstract We examined the role of nitric oxide and eicosanoid products in mediating enhanced reactivity of PAs contralateral to a localized aorto-pulmonary shunt 48 hours after creation. Lipoxygense inhibitors eliminated hyperreactivity of unshunted PAs and these arteries produced more 12-HETE, supporting increased synthesis of proconstrictive lipoxygenase products in these vessels.

Effects of a localized high-flow anastomosis between the aorta and left lower lobe pulmonary artery on great vessel flow and pulmonary arterial reactivity in the contralateral lung

“…Further studies to better define mechanisms underlying and biochemical perturbations associated with changes in vascular reactivity induced by subacute changes in flow are needed. In the accompanying paper (16), we explore the contribution of NOS and eicosanoids to vascular reactivity in this model.…”