Combination Therapy With Fasudil and Sildenafil Ameliorates Monocrotaline-Induced Pulmonary Hypertension and Survival in Rats
| Autor: | Yoshihiro Fukumoto, Kimio Satoh, Md. Elias-Al-Mamun, Toru Shimizu, Suvd Nergui, Satoshi Miyata, Hiroaki Shimokawa, Shin-ichi Tanaka |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
Combination therapy Sildenafil Hypertension Pulmonary Pharmacology Piperazines Sildenafil Citrate Muscle hypertrophy Rats Sprague-Dawley chemistry.chemical_compound 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine medicine.artery medicine Animals Sulfones Monocrotaline Lung business.industry Fasudil General Medicine Phosphodiesterase 5 Inhibitors Calcium Channel Blockers medicine.disease Pulmonary hypertension Rats Blood pressure medicine.anatomical_structure chemistry Purines Anesthesia Pulmonary artery Drug Therapy Combination Cardiology and Cardiovascular Medicine business |
| Zdroj: | Circulation Journal. 78:967-976 |
| ISSN: | 1347-4820 1346-9843 |
| DOI: | 10.1253/circj.cj-13-1174 |
| Popis: | Background: Pulmonary hypertension (PH) is a fatal disease characterized by pulmonary artery (PA) remodeling, elevated PA pressure and right ventricular (RV) failure. It has been previously demonstrated that treatment with a Rho-kinase inhibitor, fasudil, ameliorates PH in animal models. Here, whether combination therapy with fasudil and sildenafil further ameliorates PH in rats was examined. Methods and Results: PH was induced in Sprague-Dawley rats by the use of a single subcutaneous monocrotaline (MCT) injection, which caused PA remodeling, elevated RV systolic pressure (RVSP), and RV hypertrophy (RVH). While fasudil and sildenafil monotherapy inhibited the development of MCT-induced PH in the prevention and treatment protocols, their combination therapy further improved RVSP and RVH. Moreover, a histological examination demonstrated significant improvements of PA remodeling in the combination group compared with the monotherapy groups. An echocardiographic examination also revealed significant reduction in RV diameter in the combination group compared with the monotherapy groups. Mechanistic experiments revealed significant inhibition of Rho-kinase activity in PA trunk, lung and RV tissues in the combination group as well as in the monotherapy groups. Finally, the combination therapy markedly improved the long-term survival compared with the monotherapy groups. Conclusions: These results indicate that the combination therapy with fasudil and sildenafil shows the synergistic effects through the inhibition of Rho-kinase activity for the treatment of PH. (Circ J 2014; 78: 967–976) |
| Databáze: | OpenAIRE |
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