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Tadalafil induces antiproliferation, apoptosis, and phosphodiesterase type 5 downregulation in idiopathic pulmonary arterial hypertension in vitro.
Yamamura, Aya; Fujitomi, Eri; Ohara, Naoki; Tsukamoto, Kikuo; Sato, Motohiko; Yamamura, Hisao.
Afiliação
  • Yamamura A; Department of Physiology, Aichi Medical University, 1-1 Yazakokarimata Nagakute, Aichi 480-1195, Japan; Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori Moriyamaku, Nagoya 463-8521, Japan.
  • Fujitomi E; Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori Moriyamaku, Nagoya 463-8521, Japan.
  • Ohara N; Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori Moriyamaku, Nagoya 463-8521, Japan.
  • Tsukamoto K; Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori Moriyamaku, Nagoya 463-8521, Japan.
  • Sato M; Department of Physiology, Aichi Medical University, 1-1 Yazakokarimata Nagakute, Aichi 480-1195, Japan.
  • Yamamura H; Department of Molecular & Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabedori Mizuhoku, Nagoya 467-8603, Japan. Electronic address: yamamura@phar.nagoya-cu.ac.jp.
Eur J Pharmacol ; 810: 44-50, 2017 Sep 05.
Article em En | MEDLINE | ID: mdl-28603047
ABSTRACT
Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease of the pulmonary artery resulting from a currently unidentified etiology. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. Vascular remodeling is mediated by enhanced proliferation and reduced apoptosis in pulmonary arterial smooth muscle cells (PASMCs). Based on its pathological mechanism, specific phosphodiesterase type 5 (PDE5) inhibitors have been used in the treatment of IPAH. In addition to sildenafil, tadalafil has been approved for the treatment of IPAH. However, the effects of tadalafil on excessive proliferation of IPAH-PASMCs currently remain unknown. In the present study, the in vitro pharmacological profiles of tadalafil for cell proliferation and apoptosis were assessed in IPAH-PASMCs using MTT, BrdU incorporation, and caspase 3/7 assays. Expression analyses revealed that PDE5 mRNA and protein expression levels were markedly higher in IPAH-PASMCs than in normal-PASMCs. The treatment with tadalafil inhibited the excessive proliferation of IPAH-PASMCs in a concentration-dependent manner with an IC50 value of 4.5µM. On the other hand, tadalafil (0.03-100µM) did not affect cell growth of PASMCs from normal subjects and patients with chronic thromboembolic pulmonary hypertension (CTEPH). In addition, tadalafil induced apoptosis in IPAH-PASMCs. The antiproliferative and apoptotic effects of tadalafil were markedly stronger than those of sildenafil and vardenafil. The upregulated expression of PDE5 in IPAH-PASMCs was significantly attenuated by a long-term treatment with tadalafil. Taken together, these results indicate that tadalafil attenuates vascular remodeling by inhibiting cell proliferation, promoting apoptosis, and downregulating PDE5 in IPAH-PASMCs, thereby ameliorating IPAH.
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Texto completo: 1 Coleções: 01-internacional Contexto em Saúde: 6_ODS3_enfermedades_notrasmisibles Base de dados: MEDLINE Assunto principal: Regulação para Baixo / Apoptose / Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 / Inibidores da Fosfodiesterase 5 / Hipertensão Pulmonar Primária Familiar / Tadalafila Limite: Humans Idioma: En Revista: Eur J Pharmacol Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Contexto em Saúde: 6_ODS3_enfermedades_notrasmisibles Base de dados: MEDLINE Assunto principal: Regulação para Baixo / Apoptose / Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 / Inibidores da Fosfodiesterase 5 / Hipertensão Pulmonar Primária Familiar / Tadalafila Limite: Humans Idioma: En Revista: Eur J Pharmacol Ano de publicação: 2017 Tipo de documento: Article