Vardenafil Ameliorates Calcium Mobilization in Pulmonary Artery Smooth Muscle Cells from Hypoxic Pulmonary Hypertensive Mice

Background and AimsVardenafil has been found to be potent in pulmonary hypertension; however, the underlying mechanisms remain poorly understood. To address this issue, we investigated the underlying mechanisms of vardenafil in the contribution of Ca2+ signaling and mobilization in modifying vasoconstriction of pulmonary arteries in hypoxic mice.MethodsHemodynamic measurements and morphological studies were performed. Muscle tension was measured by PowerLab system. ICa,L was recorded using a perforated patch-clamp technique. [Ca2+]i was measured using a fluorescence imaging system.ResultsVardenafil greatly inhibited RVSP increases, RV hypertrophy and ameliorated pulmonary artery remodeling in response to chronic hypoxia. Membrane depolarization following 50 mM high K+-caused muscle contraction significantly decreased from 101.7 ± 10.1 in the hypoxia group to 81.8 ± 5.0 mg in hypoxia plus vardenafil arteries. Fifty mM high K+-elicited increase [Ca2+]i was markedly decreased from 610.6 ± 71.8 in hypoxia cells to 400.3 ± 47.2 nM in hypoxia plus vardenafil cells. Application of vardenafil greatly inhibited the density of ICa,L by 37.7% compared with that in the hypoxia group. Administration of 1 μM phenylephrine to stimulate α1-adrenergic receptor resulted in a smaller increase in [Ca2+]i in hypoxia plus vardenafil cells than that in hypoxia cells. One hundred μM ATP-mediated increase in [Ca2+]i was also inhibited in vardenafil-hypoxia group (from 625.8 ± 62.3 to 390.9 ± 38.1 nM), suggesting that internal calcium reserves contribute to neurotransmitter-induced Ca2+ release from the SR through IP3Rs in PASMCs.ConclusionsVardenafil may effectively block Ca2+ influx through L-type Ca2+ channel and inhibit the Ca2+ release from SR through IP3Rs, thus enhancing its vasorelaxation of pulmonary arteries under hypoxia conditions.