In mice housed under conditions of reduced oxygen supply rapamycin application partially blocked the thickening of the right ventricular wall The median was reduced by 14% compared to the untreated control group and no significant difference to vehicle or rapamycin injected mice kept at normoxia was detectable. Hypoxia triggered hypertrophy of individual cardiomyocytes done is reduced by rapamycin Untreated or vehicle treated mice kept at hypobaric hypoxia for 3 weeks exhibited a 20% increase in cardio myocyte diameter compared to the normoxic reference groups. Whereas rapamycin had no effect on cardiomyocyte size of mice housed at nor moxia, in hypoxic animals the diameter was significantly reduced. Cardiomyocytes of the left ventricular wall exhibited dis tinctly larger diameters than those of the right ventricular wall.

The size of the cells was affected neither by exposure to hypobaric hypoxia nor by application of rapamycin. Rapamycin reverses hypoxia induced pulmonary vascular remodeling A therapeutic approach was probed Mice were first exposed to hypobaric hypoxia for 3 weeks followed by another 3 weeks of Inhibitors,Modulators,Libraries hypoxia but daily rapamycin treat ment. Age matched controls were held at normoxia and treated for 3 weeks Inhibitors,Modulators,Libraries either with vehicle or with rapamycin. In hypoxic mice proliferative activity within the vascula ture was again determined even below the normoxic con trols Inhibitors,Modulators,Libraries which was not further attenuated by rapamycin treatment. In contrast, 6 weeks of exposure to hypoxia had resulted in a strong 55% increase of muscu larization of the pulmonary arteries.

However, this increase was similar to that observed in animals kept under hypoxic conditions for only 3 weeks indicating that remodeling processes had reached a home ostatic situation within 3 weeks. Despite the lack of appar ent proliferative activity, addition of rapamycin after 3 weeks was able to almost completely reverse vascular muscularization despite ongoing hypoxia. Accordingly, Inhibitors,Modulators,Libraries the index of right ventricular hypertrophy, which had increased twofold during hypoxia, was determined only 131% of normoxic controls when hypoxic animals were treated with rapamycin. Similarly, the increase in cardiomyocyte diameter had significantly declined. In comparison to normoxia, hypoxia had again induced a shift of the relative proportion of arteries with diameters smaller than 20m.

This shift was not affected by rapamy cin treatment of the mice. Discussion The current medical management of PAH is directed at vasodilatation rather than towards inhibition of smooth muscle cell proliferation, Inhibitors,Modulators,Libraries although progression of pulmo nary hypertension is known to be associated with increased proliferation. However, the data of this experimental study imply that AMN-107 targeting vascular remode ling processes may represent a promising therapeutic approach towards hypoxia induced PAH, too.