Inhibitory effect of fluvastatin on lysophosphatidylcholine-induced nonselective cation current in Guinea pig ventricular myocytes.

Abstract

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.