Pharmacological efficacy of CPU 86017 on hypoxic pulmonary hypertension in rats: mediated by direct inhibition of calcium channels and antioxidant action, but indirect effects on the ET-1 pathway.
Endothelin-1 (ET-1) plays a key role in the pathogenesis of pulmonary hypertension. The present study was conducted to examine the effects of a novel compound p-chlorobenzyltetrahydroberberine (CPU 86017) on endothelin-1 system of hypoxia-induced pulmonary hypertension in rats. SD male rats were divided into control, untreated pulmonary hypertension, nifedipine (10 mg/kg p.o.), and CPU 86017 (80, 40, and 20 mg/kg p.o.) groups. The pulmonary hypertension was established by housing the rats in a hypoxic (10 +/- 0.5% oxygen) chamber 8 hours per day for 4 weeks. Hemodynamic and morphologic assessment exhibited a significant increase in the central vein pressure (CVP), right ventricular systolic pressure (RVSP), and pulmonary arteriole remodeling in the pulmonary hypertensive rats, which were improved by CPU 86017 80 and 40 mg/kg administration (P < 0.01). The elevated pulmonary endothelin-1 level and the over-active preproET-1 and iNOS mRNA expression were also decreased significantly (P < 0.01) in CPU 86017 groups. The maladjustment of redox enzyme system in pulmonary hypertension rats was corrected after treatment. We concluded that CPU 86017 improves pulmonary hypertension mainly to suppress the endothelin-1 pathway at the upstream and downstream via calcium antagonism and antioxidative action, then, resulting in a relief in pathogenesis of the disease.
Zhang
Tian-Tai
TT
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
Cui
Bing
B
Dai
De-Zai
DZ
Tang
Xiao-Yun
XY
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001599:Berberine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy; D000860:Hypoxia / Q000150:complications*; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011651:Pulmonary Artery / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
C400084:4-chlorobenzyltetrahydroberberine; D000975:Antioxidants; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D019332:Endothelin-1; D001599:Berberine; D009569:Nitric Oxide; D008315:Malondialdehyde; D019001:Nitric Oxide Synthase