Therapeutic effects of DCDDP, a calcium channel blocker, on chronic pulmonary hypertension in rat.
To explore the effect of dimethyl 4-(2-chlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (DCDDP) on pulmonary hypertension (PH) induced by monocrotaline (MCT), the parameters of pulmonary hemodynamics, the contents of endothelin-like immunoreactivity, nitric oxide (NO), malondialdehyde, and superoxide dismutase in plasma and pulmonary homogenate were measured. DCDDP was administered in 5, 50, and 500 microg x kg(-1) x day(-1) ip doses, once a day for 28 days. The antiserotonin effect of DCDDP was investigated by using immunohistochemistry, image analysis, and cell culture technique. The results showed that pulmonary arterial pressure was significantly dropped and pulmonary resistance was decreased in DCDDP groups, compared with the MCT group. DCDDP had no influence on endothelin-like immunoreactivity levels in plasma and pulmonary homogenate but reduced the contents of NO, superoxide dismutase, and malondialdehyde in pulmonary homogenate enhanced by MCT. DCDDP also significantly inhibited the increase in numbers of 5-hydroxytryptamine (5-HT) and 5-HT receptor-positive cells in pulmonary tissue of PH rats induced by MCT. The proliferation and contraction of pulmonary arterial smooth muscle cells and the increase in concentration of free Ca(2+) in them evoked by 5-HT were inhibited significantly by DCDDP. The results suggest that DCDDP reduces the production of free radicals and content of 5-HT and 5-HT receptor and the increase in NO in pulmonary tissue, which underlies the mechanisms of DCDDP against MCT-induced PH.
Li
Zhi-Chao
ZC
Department of Pathophysiology, Fourth Military Medical University, Xi'an 710032, China. Lizhic@fmmu.edu.cn
Zhang
Fu-Qin
FQ
Song
Jing-Chun
JC
Mei
Qi-Bing
QB
Zhao
De-Hua
DH
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D003998:Dicarboxylic Acids / Q000627:therapeutic use*; D004095:Dihydropyridines / Q000627:therapeutic use*; D016232:Endothelins / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D009568:Nitrendipine / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects
D002121:Calcium Channel Blockers; D003998:Dicarboxylic Acids; D004095:Dihydropyridines; D016232:Endothelins; C453365:dimethyl-4-(2-chlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate; D009569:Nitric Oxide; D012701:Serotonin; D008315:Malondialdehyde; D016686:Monocrotaline; D009568:Nitrendipine; D013482:Superoxide Dismutase; D002118:Calcium