Vol. 62, Issue 3, 602-607, September 2002

Inhibitory Effect of Fluvastatin on Lysophosphatidylcholine-Induced Nonselective Cation Current in Guinea Pig Ventricular Myocytes

Libing Li, Isao Matsuoka, Yuichi Suzuki, Yasuhide Watanabe,¹ Toshiyuki Ishibashi, Keiko Yokoyama, Yukio Maruyama, and Junko Kimura

Department of Pharmacology (L.L., I.M., Y.S., J.K.), First Department of Internal Medicine (T.I., K.Y., Y.M.), School of Medicine, and Department of Ecology and Clinical Therapeutics, School of Nursing (Y.W.), Fukushima Medical University, Fukushima, Japan

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 (3~50 µM) induced I_NSC in a dose-dependent manner with a lag. With fluvastatin (5 µM) 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 µM) 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.