Reversal of chronic hypoxia-induced alterations in pulmonary artery smooth muscle electromechanical coupling upon air breathing.

Chronic hypoxia (CH) induces selective pulmonary hypertension which is accompanied by structural and functional alterations in the pulmonary vasculature. Little information is available on the regression of CH-induced functional alterations of pulmonary wall. In the present work, we investigated the reversal of CH-induced pulmonary hypertension with a special focus on alterations in the electrophysiological properties of pulmonary artery smooth muscle cells (PAMCs) after normoxia recovery. Rats were exposed to a hypobaric environment for 3 weeks (CH rats) and then subjected to a normoxic environment for 3 weeks (normoxia-recovery group) and compared with rats maintained in a normoxic environment (control rats). Electrophysiological properties of PAMCs were studied using conventional microelectrodes and patch-clamp technique. CH rats exhibited a threefold increase in pulmonary blood pressure compared to control rats and this increase was fully reversed following 3 weeks of normoxia. PAMCs from CH rats were depolarised (about 20 mV), had an elevated calcium concentration and exhibited a hypersensitivity to 4-aminopyridine (4-AP) of membrane potential as well as the tone of arterial rings compared with tissues from control rats. Whole cell patch-clamp recordings indicated that voltage gated potassium channel currents I(Kv) and I(K(N)) were decreased in PAMCs from CH rats with a hyper sensitivity of I(K(N)) to 4-AP. CH-induced alterations in electrophysiological properties of PAMCs were also fully reversed after 3 weeks of normoxia recovery. Both the increase in the pulmonary blood pressure and alterations in electrophysiological properties of PASMCs simultaneously reverse after normoxia recovery. This complete reversibility of all of the CH-induced pulmonary vascular alterations suggests that curative treatments for PAHT may now be designed aimed at targeting the very limited key factors implicated in hypoxia sensing.