Sustained therapeutic hypercapnia prevents pulmonary hypertension in experimental animals, but its rescue effects on established disease have not been studied. Therapies which inhibit Rho-kinase (ROCK) and/or augment nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling can reverse or prevent progression of chronic pulmonary hypertension. Our objective in the present study was to determine whether sustained rescue treatment with inhaled CO2 (therapeutic hypercapnia) would improve structural and functional changes of chronic hypoxic pulmonary hypertension. Spontaneously-breathing pups were exposed to air or hypoxia (13% O2) from postnatal days 1-21 with or without 7% CO2 (PaCO2 elevated by ~25 mmHg) or 10% CO2 (PaCO2 elevated by ~40 mmHg) from days 14-21. Compared to hypoxia alone, animals exposed to hypoxia and 10% CO2 had significantly (p < 0.05) decreased pulmonary vascular resistance, right-ventricular systolic pressure, right-ventricular hypertrophy and medial wall thickness of pulmonary resistance arteries as well as decreased lung phosphodiesterase (PDE) V, RhoA and ROCK activity. Rescue treatment with 10% CO2, or treatment with a ROCK inhibitor (Y-27632 15 mg/kg i.p. twice daily from days 14-21) also increased pulmonary arterial endothelial nitric oxide synthase and lung nitric oxide content. In contrast, cGMP content and cGMP-dependent protein kinase (PKG) activity were increased by exposure to 10% CO2, but not by ROCK inhibition with Y-27632. In vitro exposure of pulmonary artery smooth muscle cells to hypercapnia suppressed serum-induced ROCK activity, which was prevented by inhibition of PKG with Rp-8-Br-PET-cGMPS. We conclude that sustained hypercapnia dose-dependently inhibited ROCK activity, augmented NO-cGMP-PKG signaling and led to partial improvements in the hemodynamic and structural abnormalities of chronic hypoxic PHT in juvenile rats. Increased PKG content and activity appears to play a major upstream role in CO2-induced suppression of ROCK activity in pulmonary arterial smooth muscle.
- carbon dioxide
- nitric oxide
- Protein Kinase G
- Copyright © 2011, American Journal of Physiology - Heart and Circulatory Physiology