Inhibitory effect of fluvastatin on lysophosphatidylcholine-induced nonselective cation current in Guinea pig ventricular myocytes.
Using the whole-cell voltage-clamp method, we investigated the effect of fluvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, on lysophosphatidylcholine (LPC)-induced nonselective cation current (I(NSC)) in guinea pig cardiac ventricular myocytes. External LPC (3 to approximately 50 microM) induced I(NSC) in a dose-dependent manner with a lag. With fluvastatin (5 microM) in the external solution, LPC induced I(NSC), which was significantly smaller and with a longer lag compared with that in the absence of fluvastatin. With mevalonic acid (MVA) (100 microM) in the external solution, fluvastatin did not diminish LPC-induced I(NSC). Geranylgeranylpyrophosphate, an MVA metabolite, in the pipette solution prevented fluvastatin from diminishing LPC-induced I(NSC), suggesting that isoprenylated signaling molecules, such as the small G-protein Rho, might be involved in the LPC effect. Botulinum toxin C3, Rho-kinase inhibitor (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide, 2 HCl (Y-27632), or pertussis toxin in the pipette solution suppressed LPC-induced I(NSC). We conclude that LPC induces I(NSC) via a Gi/Go-coupled receptor and Rho-mediated pathway. The inhibitory effect of fluvastatin on LPC-induced I(NSC) provides a new insight into the signal transduction mechanism and may have important clinical implications.
Department of Pharmacology, and Department of Ecology and Clinical Therapeutics, School of Nursing, Fukushima Medical University, Fukushima, Japan.
Libing
L
Li
Isao
I
Matsuoka
Yuichi
Y
Suzuki
Yasuhide
Y
Watanabe
Toshiyuki
T
Ishibashi
Keiko
K
Yokoyama
Yukio
Y
Maruyama
Junko
J
Kimura
D036002:ADP Ribose Transferases / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001905:Botulinum Toxins; D002412:Cations; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008798:Mevalonic Acid / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D037342:Pertussis Toxin; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016276:Ventricular Function; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D054460:rho-Associated Kinases
D000975:Antioxidants; D002412:Cations; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; D008244:Lysophosphatidylcholines; D011106:Polyisoprenyl Phosphates; D010566:Virulence Factors, Bordetella; D000077340:Fluvastatin; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D037342:Pertussis Toxin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D001905:Botulinum Toxins; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid