Vascular reactivity of pulmonary artery from PDE9-knockout mice

Introduction PDE9 is a cGMP-selective phosphodiesterase which has recently emerged as a regulator of cardiovascular function: PDE9 deficiency protected from cardiac dysfunction induced by pressure-overload in mice, while a PDE9 inhibitor lowered vascular resistance in a sheep model of heart failure. Still, exact contribution of PDE9 to vascular tone remains elusive. Objective Tone-regulating properties of PDE9 were studied in pulmonary arteries (PA) by using wild-type (WT) and PDE9-knockout (KO) mice, and by investigating the vasoactive properties of PF-04447943 (PF), a selective PDE9 inhibitor. Methods After sacrifice, lungs were harvested from adult male and female KO and WT mice. PDE9 expression was studied by immunoblot. Inner PAs were isolated and mounted on a wire-myograph. Concentration-contractile responses studies were performed for KCl (20-120 mM), U46619 (10-9-3.10-6 M) and phenylephrine (PE, 10-9-3.10-5 M). Vasorelaxant responses to acetylcholine (ACh, 10-5 M) and to PF (10-8-10-5 M) were studied in PA contracted with 60 mM KCl and U46619 (EC80), respectively. Results Among several non-specific bands, anti-PDE9 antibody yielded one signal at ≈65 kD in WT lung which was absent in KO samples. All contractile responses in male were similar in WT and KO mice (n = 6). In female mice, response to PE was less potent in KO (P Conclusion These preliminary data show that PDE9 is expressed in mouse lung. PDE9 deficiency slightly impedes responses to PE in female mice. PF evokes modest relaxation which may be related to selective PDE9 inhibition. Further exploration is needed to delineate contribution of PDE9 to tone regulation in PA.