title: Calcilytics enhance sildenafil-induced antiproliferation in idiopathic pulmonary arterial hypertension.
abstract: Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal disease of the pulmonary artery resulting from currently unidentified etiology. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. Phosphodiesterase type 5 (PDE5) inhibitors have been clinically used in the treatment of IPAH. Recently, we have shown that Ca(2+)-sensing receptor (CaSR) antagonists, or calcilytics, inhibit excessive cell proliferation of pulmonary arterial smooth muscle cells (PASMCs) from IPAH patients. In this study, the additive or synergistic effect of calcilytics on antiproliferation following PDE5 inhibition was examined in IPAH-PASMCs by MTT assay. Treatment with sildenafil blocked the excessive cell proliferation of IPAH-PASMCs in a concentration-dependent manner with an IC50 value of 16.9μM. However, sildenafil (0.03-100μM) did not affect the cell growth of PASMCs from normal subjects and patients with chronic thromboembolic pulmonary hypertension (CTEPH). Co-treatment with 0.3μM NPS2143, a calcilytic, additively enhanced the antiproliferative effect induced by sildenafil (3 or 30μM) in IPAH-PASMCs. Additionally, the inhibitory effect of calcilytics, NPS2143 or Calhex 231 (1 or 10μM), on excessive cell proliferation of IPAH-PASMCs was synergistic increased in the presence of 1μM sildenafil. Similar results were obtained by BrdU incorporation assay. These findings reveal that calcilytics additively/synergistically enhance the antiproliferative activity mediated by PDE5 inhibition, suggesting that a combination therapy of a PDE5 inhibitor with a calcilytic may be useful as a novel therapeutic approach for IPAH.
authors.affiliation: Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan. Electronic address: yamamura@kinjo-u.ac.jp.
authors.forename: Aya
authors.initials: A
authors.lastname: Yamamura
authors.affiliation: Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Yagi
authors.affiliation: Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ohara
authors.affiliation: Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan.
authors.forename: Kikuo
authors.initials: K
authors.lastname: Tsukamoto
mesh_terms: D001549:Benzamides / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003514:Cyclohexylamines / Q000494:pharmacology*; D004357:Drug Synergism; D065627:Familial Primary Pulmonary Hypertension / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D009281:Naphthalenes / Q000494:pharmacology*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000473:pathology; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors*; D000068677:Sildenafil Citrate / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001549:Benzamides; D003514:Cyclohexylamines; C482333:N(1)-(4-chlorobenzoyl)-N(2)-(1-(1-naphthyl)ethyl)-1,2-diaminocyclohexane; C436740:N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine; D009281:Naphthalenes; D058986:Phosphodiesterase 5 Inhibitors; D044169:Receptors, Calcium-Sensing; D000068677:Sildenafil Citrate
keywords: Calcilytic; Calcium-sensing receptor; NPS2143; Phosphodiesterase 5 inhibitor; Pulmonary hypertension; Sildenafil