Vardenafil ameliorates calcium mobilization in pulmonary artery smooth muscle cells from hypoxic pulmonary hypertensive mice.

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+) 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+) 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+) in hypoxia plus vardenafil cells than that in hypoxia cells. One hundred μM ATP-mediated increase in Ca(2+) 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(3)Rs 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(3)Rs, thus enhancing its vasorelaxation of pulmonary arteries under hypoxia conditions.