Abstract
Aim:
To elucidate the involvement of the endothelin (ET) pathway in the pathogenesis of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and the therapeutic effect of CPU 86017 (p-chlorobenzyltetrahydroberberine chloride) in rats.
Methods:
Rats were injected with a single dose (60 mg/kg, sc) of MCT and given CPU 86017 (20, 40, and 80 mg·kg−1·d−1, po) or saline for 28 d. The hemodynamics, mRNA expression, and vascular activity were evaluated.
Results:
Right ventricular systolic pressure and central venous pressures were elevated markedly in the PAH model and decreased by CPU 86017. In the PAH group, the endothelin-1 (ET-1) in serum and lungs was dramatically increased by 54% (79.9 pg/mL, P<0.01) and 93% (166.2 pg/mL, P<0.01), and mRNA levels of preproET-1, eNOS, and iNOS also increased dramatically compared with control. Compared with PAH group, CPU 86017 decreased the content of ET-1 to the normal level in lung tissue, but was less effective in serum. The level of NO was significantly increased in CPU 86017 at 80 and 40 mg·kg−1·d−1 groups in tissue, whereas the difference in serum was not significant. A significant reduction in MDA production and an increase in the SOD activity in the serum and lungs was observed in all three CPU 86017 groups. CPU 86017 80 mg·kg−1·d−1 po increased the activity of cNOS by 33% (P<0.01). The up-regulation of eNOS and iNOS mRNA levels induced by MCT was significantly reversed in 3 CPU 86017 groups, and preproET-1 mRNA abundance was also reduced notably in CPU 86017 80 mg·kg−1·d−1 group vs the PAH group. The KCl-induced vasoconstrictions in the calcium-free medium decreased markedly in PAH group but recovered partially after CPU 86017 intervention. The constrictions in the presence of Ca2+ was not improved by CPU 86017. The phenylephrine-induced vasoconstrictions in the calcium-free medium decreased markedly in PAH group but not recovered after CPU 86017 intervention. The constrictions in the presence of Ca2+ completely returned to the normal after CPU 86017 intervention.
Conclusion:
CPU 86017 suppressed MCT-induced PAH mainly through an indirect suppression of the ET-1 system, which was involved in the pathogenesis of the disease.
Similar content being viewed by others
Article PDF
References
Jeffery TK, Morrell NW . Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension. Prog Cardiovasc Dis 2002; 45: 173–202.
Tuder RM, Cool CD, Yeager M, Taraseviciene-Stewart L, Bull TM, Voelkel NF . The pathobiology of pulmonary hypertension. Endothelium. Clin Chest Med 2001; 22: 405–18.
Wort SJ, Woods M, Warner TD, Evans TW, Mitchell JA . Endogenously released endothelin-1 from human pulmonary artery smooth muscle promotes cellular proliferation: relevance to pathogenesis of pulmonary hypertension and vascular remodeling. Am J Resp Cell Mol Biol 2001; 25: 104–10.
Michelakis ED . The role of the NO axis and its therapeutic implications in pulmonary arterial hypertension. Heart Fail Rev 2003; 8: 5–21.
Alexandru B, Bogdan MA . Monocrotaline induces pulmonary hypertension in animal models. Pneumologia 2001; 50: 85–9.
Wang HL, Li SB, Dai DZ . Effects of CPU 86017 on L-type calcium current in single guinea pig hypertrophic ventricular myocytes. J China Pharm Univ 2004; 35: 259–62.
Hao JM, Dai DZ, Yu F . The oxidative stress is enhanced after L-thyroxin medication and suppressed by CPU 86017. Prog Pharm Sci 2005; 29: 417–21.
Wang YQ, Shi YP, Dai DZ . The therapeutic effects of CPU 86017 on acute and chronic congestive cardiac failure mediated by reducing ET-1, NOS and oxidative stress in rats. Drug Dev Res 2004; 63: 22–32.
Zhang TT, Dai DZ . Therapeutic effects of nifedipine on pulmonary hypertension and mechanism involved. Prog Pharm Sci 2003, 27: 227–9.
Dai DZ, Feng Y, Li HT . Blockade on sodium, potassium, and calcium channels by a new antiarrhythmic agent CPU 86017. Drug Dev Res 1996; 39: 138–46.
Dai DZ, Jiang JM . p-Chlorobenzyltetrahydroberberine inhibits vascular smooth muscle contractions caused by Ca2+. Acta Pharmacol Sin 1998; 19: 543–7.
Dai DZ, He Y, Huang FH . Comparison of inhibitory activity of berberine derivate CPU 86017 and berberine on vascular contraction. J China Pharm Univ 2000; 31: 447–50.
Dai DZ, Hu HJ, Zhao J, Hao XM, Yang DM, Zhou PA, et al. Blockade of L-type calcium channel in myocardium and calcium-induced contractions of vascular smooth muscle by CPU 86017. Acta Pharmacol Sin 2004; 25: 416–23.
Xu FP, Chen MS, Wang YZ, Yi Q, Lin SB, Chen AF, et al. Leptin induces hypertrophy via endothelin-1-reactive oxygen species pathway in cultured neonatal rat cardiomyocytes. Circulation 2004; 110: 1269–75.
Mazzocchi G, Rossi GP, Malendowicz LK, Champion HC, Nussdorfer GG . Endothelin-1 [1-31], acting as an ETA-receptor selective agonist, stimulates proliferation of cultured rat zona glomerulosa cells. FEBS Lett 2000; 487: 194–8.
Piacentini L, Gray M, Honbo NY, Chentoufi J, Bergman M, Karliner JS . Endothelin-1 stimulates cardiac fibroblast proliferation through activation of protein kinase C. J Mol Cell Cardiol 2000; 32: 565–76.
Herman WH, Simonson MS . Nuclear signaling by endothelin-1: a Ras pathway for the activation of the c-fos serum response element. J Biol Chem 1995; 270: 654–61.
Perazzo J, Eizayaga F, Romay S, Bengochea L, Pavese A, Lemberg A . An experimental model of liver damage and portal hypertension induced by a single dose of monocrotaline. Hepatogastroenterology 1999; 46: 432–5.
Bai XC, Lu D, Liu AL, Zhang ZM, Li XM, Zou ZP, et al. Reactive oxygen species stimulates receptor activator of NF-kappa B ligand expression in osteoblast. J Biol Chem 2005; 280: 17497–506.
Rodriguez JA, Nespereira B, Perez-Ilzarbe M, Eguinoa E, Paramo JA . Vitamins C and E prevent endothelial VEGF and VEGFR-2 overexpression induced by porcine hypercholesterolemic LDL. Cardiovasc Res 2005; 65: 665–73.
Hsu YH, Huang SC . Immunohistochemical localization of endothelin-converting enzyme-1 in neuroendocrine tumors and normal human tissue. Kaohsiung J Med Sci 2003; 19: 555–62.
Resta TC, Chicoine LG, Omdahl JL, Walker BR . Maintained upregulation of pulmonary eNOS gene and protein expression during recovery from chronic hypoxia. Am J Physiol 1999; 276: H699–H708.
Fleming I, Fisslthaler B, Dimmeler S, Kemp BE, Busse R . Phosphorylation of Thr495 regulates Ca2+/calmodulin-dependent endothelial nitric oxide synthase activity. Circ Res 2001; 88: E68–E75.
Murata T, Sato K, Hori M, Ozaki H, Karaki H . Decreased endothelial nitric-oxide synthase (eNOS) activity resulting from abnormal interaction between eNOS and its regulatory proteins in hypoxia-induced pulmonary hypertension. J Biol Chem 2002; 277: 44085–92.
Author information
Authors and Affiliations
Corresponding author
Additional information
Project supported by the National Natural Science Foundation of China (No 30230170).
Rights and permissions
About this article
Cite this article
Zhang, Tt., Cui, B., Dai, Dz. et al. CPU 86017, p-chlorobenzyltetrahydroberberine chloride, attenuates monocrotaline-induced pulmonary hypertension by suppressing endothelin pathway. Acta Pharmacol Sin 26, 1309–1316 (2005). https://doi.org/10.1111/j.1745-7254.2005.00214.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2005.00214.x
Keywords
This article is cited by
-
MicroRNA-27a/b mediates endothelin-1-induced PPARγ reduction and proliferation of pulmonary artery smooth muscle cells
Cell and Tissue Research (2017)
-
CPU86017-RS attenuate hypoxia-induced testicular dysfunction in mice by normalizing androgen biosynthesis genes and pro-inflammatory cytokines
Acta Pharmacologica Sinica (2012)
-
Raisanberine protected pulmonary arterial rings and cardiac myocytes of rats against hypoxia injury by suppressing NADPH oxidase and calcium influx
Acta Pharmacologica Sinica (2012)
-
CPU86017, a berberine derivative, attenuates cardiac failure through normalizing calcium leakage and downregulated phospholamban and exerting antioxidant activity
Acta Pharmacologica Sinica (2010)
-
CPU86017 and its isomers improve hypoxic pulmonary hypertension by attenuating increased ETA receptor expression and extracellular matrix accumulation
Naunyn-Schmiedeberg's Archives of Pharmacology (2008)