Abstract 13022: The Homing Peptide CAR Markedly Enhances the Pulmonary Vasodilator Efficacy and Selectivity of the Rho Kinase Inhibitor Fasudil
Rationale: A major limitation in the systemic treatment of pulmonary arterial hypertension (PAH) with pharmacological agents is the lack of pulmonary vascular selectivity. A recent study has identified a peptide, CARSKNKDC (CAR), which specifically recognizes the neovasculature of wound tissue. We hypothesized CAR would selectively home to injured hypertensive pulmonary arteries, and that co-administration of CAR and the Rho kinase inhibitor fasudil would cause potent pulmonary selective vasodilation in a rat model of severe PAH.
Methods and Results: Rats were injected with a vascular endothelial growth factor receptor blocker, SU5416, and exposed to hypoxia (10% O2) for 3 weeks. They were then returned to normoxia for an additional 2 weeks. Five weeks after SU5416 injection, the rats had severe PAH and were subjected to examinations. Thirty minutes after intravenous administration of fluorescein-labeled CAR, immunohistochemical analysis showed a high intensity signal of CAR in the remodeled pulmonary arteries, while no or low signal was detected in other organs except for the kidney where CAR is excreted. In stark contrast to the non-selective pulmonary and systemic vasodilation by a high dose of fasudil (10 mg/kg) alone, the co-administration of CAR (3 mg/kg) and a low dose of fasudil (1 mg/kg, which has little effect on RVSP in this model when given alone) caused a marked reduction in RVSP with no significant effect on LVSP in catheterized PAH rats. The pulmonary hypotensive effect lasted at least 30 min. (Figure). CAR alone had no significant hemodynamic effect.
Conclusions: The homing peptide CAR may be useful for pulmonary artery selective drug delivery and vasodilation in PAH. The mechanism by which the co-administered CAR enhances the pulmonary vasodilatory effect of fasudil remains to be determined.
- © 2010 by American Heart Association, Inc.