© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Serotonin receptor antagonist inhibits monocrotaline-induced pulmonary hypertension and prolongs survival in rats
aDepartment of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
b Department of Cardiovascular Medicine, Shinshu University School of Health Sciences, 3-1-1 Asahi, Matsumoto 390-8621, Japan
cDepartment of Sports Medicine, Shinshu University School of Medicine, Matsumoto, Japan
dFirst Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan
eDepartment of Biomedical Laboratory Sciences, Shinshu University School of Health Sciences, Matsumoto, Japan
fDepartment of Nursing, Shinshu University School of Health Sciences, Matsumoto, Japan
gDepartment of Physiology, Shinshu University School of Health Sciences, Matsumoto, Japan
*Corresponding author. Tel./fax: +81-263-37-2402. Email address: hongo{at}hsp.md.shinshu-u.ac.jp
Objectives: It has been reported that serotonin (5-HT) is involved in the development of pulmonary arterial hypertension (PAH) with pulmonary vascular remodeling. The purpose of the present study was to examine the role of a 5-HT2A receptor antagonist, sarpogrelate hydrochroride, in preventing or reversing monocrotaline (MCT)-induced PAH in rats. Methods: Rats were injected with 40 mg/kg of MCT subcutaneously and randomized to either sarpogrelate (50 mg/kg, intraperitoneally) or placebo for 3 weeks. Animals treated with MCT and survived for 3 weeks were assigned to either sarpogrelate (50 mg/kg, intraperitoneally) or placebo for next 3 weeks. The animals had pressure measurement of the pulmonary artery, and then underwent histologic, immunohistochemical, and Western blot analyses of the lung tissue. Survival rate was also assessed after treatment. Results: Sarpogrelate immediately following MCT injection suppressed PAH with severe pulmonary vascular remodeling and right-sided heart failure. The survival rate was significantly increased in the sarpogrelate-treated group compared with the placebo group (71% vs. 44%, p<0.05). Intense expression of P-selectin was found on the endothelium of the pulmonary arteries in the placebo group, and it was markedly attenuated in the sarpogrelate-treated group. The numbers of the CD45-positive cells and those of the proliferating cell nuclear antigen (PCNA)-positive cells in the lung tissue were significantly increased in the placebo group, and the increases in these cells were prevented by sarpogrelate. Endothelial nitric oxide synthase (eNOS) expression in the lung tissue was markedly decreased in the placebo group, but it was prevented by sarpogrelate (p<0.001). In contrast, late treatment with sarpogrelate failed to reverse established PAH. Conclusions: Specific 5-HT2A receptor blockade with sarpogrelate immediately after MCT inhibited PAH and prolongs survival in rats. These effects were accompanied by anti-inflammatory and anti-proliferative effects in the lung tissue and marked improvement of pulmonary vascular endothelial dysfunction and activation.
KEYWORDS Endothelial function; Pulmonary circulation; Serotonin (5-HT)
* This article was presented in part at the 24th Congress of the European Society of Cardiology held in Berlin, Germany on September 3, 2002.
Time for primary review 15 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. Kugathasan, J. B. Ray, Y. Deng, E. Rezaei, D. J. Dumont, and D. J. Stewart The angiopietin-1-Tie2 pathway prevents rather than promotes pulmonary arterial hypertension in transgenic mice J. Exp. Med., September 28, 2009; 206(10): 2221 - 2234. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Shah, M. Gomberg-Maitland, T. Thenappan, and S. Rich Selective Serotonin Reuptake Inhibitors and the Incidence and Outcome of Pulmonary Hypertension Chest, September 1, 2009; 136(3): 694 - 700. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Kamezaki, H. Tasaki, K. Yamashita, M. Tsutsui, S. Koide, S. Nakata, A. Tanimoto, M. Okazaki, Y. Sasaguri, T. Adachi, et al. Gene Transfer of Extracellular Superoxide Dismutase Ameliorates Pulmonary Hypertension in Rats Am. J. Respir. Crit. Care Med., January 15, 2008; 177(2): 219 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. B. Sehgal and S. Mukhopadhyay Pulmonary arterial hypertension: a disease of tethers, SNAREs and SNAPs? Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H77 - H85. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-F. Jasmin, I. Mercier, J. Dupuis, H. B. Tanowitz, and M. P. Lisanti Short-Term Administration of a Cell-Permeable Caveolin-1 Peptide Prevents the Development of Monocrotaline-Induced Pulmonary Hypertension and Right Ventricular Hypertrophy Circulation, August 29, 2006; 114(9): 912 - 920. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Cogolludo, L. Moreno, F. Lodi, G. Frazziano, L. Cobeno, J. Tamargo, and F. Perez-Vizcaino Serotonin Inhibits Voltage-Gated K+ Currents in Pulmonary Artery Smooth Muscle Cells: Role of 5-HT2A Receptors, Caveolin-1, and KV1.5 Channel Internalization Circ. Res., April 14, 2006; 98(7): 931 - 938. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Guignabert, B. Raffestin, R. Benferhat, W. Raoul, P. Zadigue, D. Rideau, M. Hamon, S. Adnot, and S. Eddahibi Serotonin Transporter Inhibition Prevents and Reverses Monocrotaline-Induced Pulmonary Hypertension in Rats Circulation, May 31, 2005; 111(21): 2812 - 2819. [Abstract] [Full Text] [PDF]
|
|