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

摘要

Background and Aims: Vardenafil 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 Ca 2+ signaling and mobilization in modifying vasoconstriction of pulmonary arteries in hypoxic mice. Methods: Hemodynamic measurements and morphological studies were performed. Muscle tension was measured by PowerLab system. I Ca,L was recorded using a perforated patch-clamp technique. [Ca 2+] i was measured using a fluorescence imaging system. Results: Vardenafil 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 [Ca 2+] 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 I Ca,L by 37.7% compared with that in the hypoxia group. Administration of 1 μM phenylephrine to stimulate α 1-adrenergic receptor resulted in a smaller increase in [Ca 2+] i in hypoxia plus vardenafil cells than that in hypoxia cells. One hundred μM ATP-mediated increase in [Ca 2+] 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 Ca 2+ release from the SR through IP 3Rs in PASMCs. Conclusions: Vardenafil may effectively block Ca 2+ influx through L-type Ca 2+ channel and inhibit the Ca 2+ release from SR through IP 3Rs, thus enhancing its vasorelaxation of pulmonary arteries under hypoxia conditions.