Effects of U50,488H on hypoxia pulmonary hypertension and its underlying mechanism.
The aim of the present study was to determine whether U50,488H, a selective kappa-opioid receptor agonist, inhibits the remodeling of the pulmonary artery (PA). In addition, changes in the concentrations of nitric oxide (NO), endothelin (ET) and angiotensin II (AngII) in hypoxic pulmonary hypertensive (HPH) rats were investigated to explore the mechanisms underlying the effects of U50, 488H on HPH. We found that intraperitoneal administration of U50,488H (every other day) during hypoxia depressed mean pulmonary arterial pressure (mPAP) and attenuated right ventricular pressure (RVP) and right ventricular hypertrophy, at the same time it inhibited remodeling of the PA compared with hypoxia for 2 wk. Moreover, U50,488H also inhibited proliferation of the pulmonary arterial smooth muscle cells (PASMCs) induced by hypoxia for 48 h in a dose-dependent manner. Compared with the 2 wk hypoxia group, U50,488H increased the concentration of NO and decreased the production of ET and AngII (P<0.01). In addition, acute intravenous administration of U50,488H after hypoxia for 4 wk decreased mPAP. Our results suggest that effects of anti-remodeling of the PA and anti-proliferation of the PASMC, and regulation of the vasomotor factors in both blood and pulmonary tissues of HPH rats may be critical mechanisms underlying the preventive and therapeutic effects of U50,488H in HPH rats.
Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
Juan
J
Li
Peng
P
Zhang
Quan-Yu
QY
Zhang
Shu-Miao
SM
Zhang
Hai-Tao
HT
Guo
Hui
H
Bi
Yue-Min
YM
Wang
Xin
X
Sun
Jin-Cheng
JC
Liu
Liang
L
Cheng
Qin
Q
Cui
Shi-Qiang
SQ
Yu
Alan David
AD
Kaye
Ding-Hua
DH
Yi
Jian-Ming
JM
Pei
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000704:Analysis of Variance; D000804:Angiotensin II / Q000032:analysis / Q000097:blood; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001273:Atmosphere Exposure Chambers; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease / Q000517:prevention & control; D004195:Disease Models, Animal; D016232:Endothelins / Q000032:analysis / Q000097:blood; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000517:prevention & control; D000860:Hypoxia / Q000188:drug therapy* / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D008168:Lung / Q000737:chemistry / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D009569:Nitric Oxide / Q000032:analysis / Q000097:blood; D009929:Organ Size / Q000187:drug effects; D010100:Oxygen / Q000502:physiology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists; D013997:Time Factors
D000959:Antihypertensive Agents; D016232:Endothelins; D017473:Receptors, Opioid, kappa; D000804:Angiotensin II; D009569:Nitric Oxide; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D010100:Oxygen