Abstract 184: Novel Vasoactive Intestinal Peptide-ELP Fusion Protein VPAC-Agonists Trigger Sustained Pulmonary Artery Vaso-Relaxation in Rats with Acute Hypoxia-Induced Pulmonary Hypertension

Abstract

The natural vasoactive intestinal peptide (VIP) triggers potent pulmonary vasodilatation by activating the G-protein-coupled VAPC receptors, and has been suggested as a therapeutic target in pulmonary artery hypertension (PAH); however, VIP’s clinical utility is limited due to its short half-life. A novel ELP fusion technology (PhaseBio’s) permits the creation of long-acting protein-fusion biopolymer-based VPAC-receptor agonists. Here, the pulmonary/systemic hemodynamic effects of two novel ELP-enhanced VIP analogues (ELP-VIP) were evaluated in anesthetized rats with hypoxia-induced PAH. Sprague-Dawley rats (259 ± 5 g, n = 25) were anesthetized (propofol), intubated, mechanically-ventilated (95% FiO2), and instrumented for systemic (arterial) and mean pulmonary-artery pressure monitoring. Following instrumentation PAH was induced by acutely decreasing the inspired FiO2 (to ∼10-11%). Subsequently, the animals were assigned to receive either a novel VPAC agonist (VIP-ELP, n = 18: 3-6 mg/kg) or placebo (VEH, n = 11: 0.9% NaCl). Treatments were delivered as acute single-dose boluses given either intravenously (IV) or intratracheally (IT) at a fixed volume. Reductions in the inspired FiO2 resulted in sustained pulmonary artery pressure increases (+45 ± 3%, 28 ± 1 to 41 ± 1 mmHg; P < 0.05), consistent with hypoxic PAH. Induced-PAH was preserved in the absence of active treatment, as pulmonary pressures remained elevated following placebo administration (VEH: -1 ± 2%, from 40 ± 2 to 40 ± 2 mmHg; n = 11, N.S.). Acute administration of the VIP-ELP analogues resulted in rapid pulmonary artery pressure reductions (-24 ± 3%, from 41 ± 1 to 31 ± 1 mmHg, P < 0.05) with moderate/negligible changes in systemic pressures (MAP: -12 ± 6%) and heart rate (-4 ± 3%). Notably, the pulmonary vaso-relaxation triggered by VIP-ELP agonists was sustained and independent of the route of administration (IV: -17 ± 4%, n = 8; IT: -28 ± 4%, n = 10). The novel ELP-enhanced VIP analogues triggered rapid and sustained reductions in pulmonary-artery pressures in the setting of induced (hypoxic) pulmonary hypertension (PAH). These effects were independent of the route of administration, as both intravenous/intra-tracheal administrations were efficacious.