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The effect of inflammation on ligand binding and density of L‐type calcium and erg K‐channels in rat myocardium
Author(s) -
Sattari S.,
KarimiBushehri F.,
Weinfeld M.,
Dryden W. F.,
Jamali F.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.179
Subject(s) - inflammation , chemistry , verapamil , dissociation constant , pharmacology , nitrendipine , calcium channel , ligand (biochemistry) , calcium , medicine , endocrinology , receptor , biochemistry
The purpose of this study was to investigate the effect of inflammation on ligand binding and density of L‐type calcium channels (LCC) and erg potassium channels (EKC) in the rat heart. Acute and chronic inflammation were induced, hearts were removed and either their myocytes were isolated or they were homogenized to provide cardiac cell membranes. Equilibrium ligand binding of 3 H‐nitrendipine (NIT) to LCC and 3 H‐dofetilide (DOF) to EKC was performed. Direct effect of TNF on ligand binding was examined using normal rat cardiac membranes. Western blotting of LCC was performed to estimate the density of the target protein. The results indicate that inflammation had no significant effects on dissociation constants (K D ). However, the maximum binding (B max ) for NIT was significantly reduced in chronic (38.7 ± 6.8%) and acute (26.1 ± 8.1%) inflammation. Binding of DOF to EKC in isolated myocytes was not affected by inflammation. The presence of TNF did not affect the binding parameters of NIT to LCC. Western blotting revealed that inflammation had no effect on the density of α1C subunit of LCC. In summary, decrease in efficacy of cardiovascular drug seen in inflamed states could be mainly due to reduced binding to their ligands. Reduced binding may explain, in part, the reduced pharmacological response to calcium channel blockers such as verapamil, in spite of higher plasma concentrations, in the presence of inflammatory diseases such as rheumatoid arthritis. Supported by CIHR. Clinical Pharmacology & Therapeutics (2004) 75 , P48–P48; doi: 10.1016/j.clpt.2003.11.179