Vardenafil ameliorates calcium mobilization in pulmonary artery smooth muscle cells from hypoxic pulmonary hypertensive mice.
OBJECTIVE
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(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.
Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Wen-Sheng
WS
Chen
Xiao-Qiang
XQ
Li
Wei
W
Cao
Xiong
X
Xiao
Ling
L
Dong
Jin-Zhou
JZ
Zhang
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002908:Chronic Disease; D004353:Drug Evaluation, Preclinical; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011188:Potassium / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use; D000069058:Vardenafil Dihydrochloride; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
D000316:Adrenergic alpha-Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D007093:Imidazoles; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010879:Piperazines; D013450:Sulfones; D014227:Triazines; D014665:Vasodilator Agents; D010656:Phenylephrine; D000069058:Vardenafil Dihydrochloride; D000255:Adenosine Triphosphate; D011188:Potassium; D002118:Calcium