Abstract 13284: A Novel Formulation of Vasoactive Intestinal Peptide Attenuates both Acute Hypoxic Pulmonary Vasoconstriction and the Development of Pulmonary Hypertension

Abstract

Background: Vasoactive intestinal peptide (VIP) is an endogenous hormone that is known to relax vascular smooth muscle and has established anti-proliferative and immunomodulatory effects in the pulmonary circulation making it an attractive therapeutic target in pulmonary arterial hypertension (PAH). In the current study, a polymer-based nanocarrier (protected graft copolymer - PGC) formulation of VIP, which has been shown to increase the potency and duration of action of VIP, is used to show both acute vasodilatory effects and chronic therapeutic effects in experimental animal models of pulmonary hypertension. Methods: The isolated perfused mouse lung preparation is utilized to test acute hypoxic pulmonary vasoconstriction (HPV) in mice. Two animal models of pulmonary hypertension are used in preventative experiments, chronic hypoxic pulmonary hypertension in mice and monocrotaline-induced pulmonary hypertension in rats. Right ventricular systolic pressure and Fulton’s index (weight ratio of RV/[LV+Septum]) are used for measures of pulmonary hemodynamics and RV hypertrophy respectively. Results: PGC-VIP decreased resting pulmonary artery pressure and attenuated acute HPV elicited by 1% inhaled oxygen tension in a dose dependent manner from 0.1 μM to 1.0 μM. After four weeks of chronic hypoxia, both RVSP measurements and Fulton’s index were significantly decreased in mice receiving 100 mg/kg intraperitoneal PGC-VIP every other day compared to vehicle control. Higher doses were associated with mortality in the treatment group. MCT-PH rats receiving subcutaneous PGC-VIP at a dose of 250 mg/kg failed to show improvement in RVSP or Fulton’s index compared to vehicle control. Conclusion: This novel formulation of VIP demonstrates both acute and chronic vasodilatory effects in the pulmonary circulation. Treatment with PGC-VIP can attenuate the development of hypoxic pulmonary hypertension, yet significant mortality is seen at higher doses. Subcutaneous injection failed to attenuate the development of experimental PH in rats, possibly due to an ineffective dose or route of administration. Further studies are underway to identify the ideal dosing strategy necessary to attenuate and potentially reverse experimental PH in animal models.