title: Benefit of combined therapy with nicorandil and colchicine in preventing monocrotaline-induced rat pulmonary arterial hypertension.
abstract: This study tested the hypothesis that combined therapy with nicorandil and colchicine is superior to either alone in attenuating monocrotaline (MCT)-induced rat pulmonary arterial hypertension (PAH). Adult male Sprague-Dawley rats (n=50) were equally randomized into group 1 (sham control), group 2 [MCT (60 mg/kg i.p.)], group 3 [MCT-Nicorandil (5.0 mg/kg/day)], group 4 [MCT-Colchicine (1.0 mg/kg/day)], and group 5 (MCT-Nicorandil-Colchicine). Drugs were given on day 5. All animals were sacrificed on day 90 after MCT administration. Right ventricular systolic blood pressure (RVSBP) and RV weight were increased in group 2 compared to group 1, reduced in groups 3 and 4 compared to group 2, and further reduced in group 5, whereas arterial-oxygen saturation showed an opposite pattern (all p<0.001). Pulmonary damage severity (thickened alveolar septum and pulmonary arteriolar wall, decreased alveolar-sac numbers), number of CD3+ cells, and protein expressions of inflammatory (MMP-9, NF-κB, VCAM-1, angiotensin II-receptor), apoptotic (Bax, caspase 3, cleaved PARP), and fibrotic (TGF-β, Smad3) biomarkers showed an identical pattern compared to that of RVSBP, whereas pulmonary expressions of anti-apoptotic (Bcl-2) and anti-fibrotic (BMP-2, Smad1/5) biomarkers displayed a reverse pattern (all p<0.01). The protein expressions of RV damage markers (BNP, caspase 3) were increased, whereas expression of biomarker for RV functional preservation (Cx43) was reduced in group 2 compared with group 1, elevated in groups 3 and 4 compared to group 2, and further increased in group 5 (all p<0.01). Combined therapy with nicorandil and colchicine is superior to either alone in attenuating MCT-induced PAH in rats.
authors: Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Fan-Yen
authors: FY
authors: Lee
authors: Hung-I
authors: HI
authors: Lu
authors: Yen-Yi
authors: YY
authors: Zhen
authors: Steve
authors: S
authors: Leu
authors: Yung-Lung
authors: YL
authors: Chen
authors: Tzu-Hsien
authors: TH
authors: Tsai
authors: Sheng-Ying
authors: SY
authors: Chung
authors: Sarah
authors: S
authors: Chua
authors: Jiunn-Jye
authors: JJ
authors: Sheu
authors: Shu-Yuan
authors: SY
authors: Hsu
authors: Hsueh-Wen
authors: HW
authors: Chang
authors: Cheuk-Kwan
authors: CK
authors: Sun
authors: Hon-Kan
authors: HK
authors: Yip
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001013:Aorta, Thoracic / Q000166:cytology; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D003078:Colchicine / Q000008:administration & dosage*; D018031:Connexin 43 / Q000378:metabolism; D004359:Drug Therapy, Combination; D065627:Familial Primary Pulmonary Hypertension; D006352:Heart Ventricles / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016686:Monocrotaline; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D020108:Nicorandil / Q000008:administration & dosage*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; C494828:Bax protein, rat; D018031:Connexin 43; C580592:Gja1 protein, rat; D016328:NF-kappa B; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D051028:bcl-2-Associated X Protein; D020108:Nicorandil; D016686:Monocrotaline; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D053148:Caspase 3; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D003078:Colchicine
keywords: Colchicine; Nicorandil; Pulmonary arterial hypertension