Rhokinase Blocker Inhibits Development of Hypoxic Pulmonary Hypertension

To evaluate whether Rho/Rho-kinase signaling is involved in the development of HPH, we treated rats exposed to 2 weeks of hypobaric hypoxia (equivalent to -10% 02) with either vehicle or Y-27632 (40 mg/kg/day) via subcutaneous osmotic minipump. Measurements of mean pulmonary artery pressure and right ventricular (RV) weight/left ventricular (LV) plus septal (S) weight (RV/LV+S) showed that treatment with the Rho-kinase inhibitor reduced the severity of pulmonary hypertension (Fig. 5A), without reducing systemic arterial pressure or altering cardiac output (not shown). Y-27632 treatment did not affect the hypoxia-induced polycythemia (hematocrit = 47±1 % in normoxic controls and 67±2 and 70±2%, respectively, in vehicle and Y-27632 hypoxic groups). We have similarly found that treatment with Y-27632 also reduces HPH in mice (16), and preliminary results support the possibility that the attenuation of pulmonary hypertension is associated with increased expression of eNOS (Fig. 5B), and possibly increased NO production, in the hypoxic lung. The inhibition of HPH was only partial in both rats and mice, and it remains to be determined whether or not higher doses of Y-27632, or fasudil, a Rho-kinase inhibitor with possible clinical utility (58), will be more effective. Another consideration is that chronic inhibition of Rho-kinase might enhance the activity of other GTPases such as Rac (64, 67), which could possibly counteract the effects Rho-kinase inhibition on pulmonary vasoconstriction and vascular remodeling. Rho-kinase is involved in many important cellular functions, and near total inhibition of this signaling molecule in vivo may have adverse physiological effects, especially during exposure to hypoxia.

Other investigators have observed that statins also attenuate hypoxic (18) and monocrotaline-induced (22, 44) pulmonary hypertension in rats, and Abe and coworkers have reported that fasudil both markedly prevents and reverses monocrotaline-induced pulmonary hypertension (1). A direct comparison has not been reported, but the impression from the results of these and our studies is that monocrotaline-induced pulmonary hypertension may be more effectively prevented by treatment with Rho-kinase inhibitors than is HPH. If true, it will be interesting to determine why.

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