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.
Li
Libing
L
Department of Pharmacology, and Department of Ecology and Clinical Therapeutics, School of Nursing, Fukushima Medical University, Fukushima, Japan.
Matsuoka
Isao
I
Suzuki
Yuichi
Y
Watanabe
Yasuhide
Y
Ishibashi
Toshiyuki
T
Yokoyama
Keiko
K
Maruyama
Yukio
Y
Kimura
Junko
J
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