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• W2100698524 startingPage "959" @default.
• W2100698524 abstract "Abstract —We recently demonstrated that farnesol, a 15-carbon isoprenoid, blocks L-type Ca 2+ channels in vascular smooth muscle cells. To elucidate farnesol′s mechanism of action, we performed whole-cell and perforated-patch clamp experiments in rat aortic A7r5 cells and in Chinese hamster ovary (CHO) C9 cells expressing smooth muscle Ca 2+ channel α 1C subunits. Farnesol dose-dependently and voltage-independently inhibited Ba 2+ currents in both A7r5 and CHOC9 cells, with similar half-maximal inhibitions at 2.6 and 4.3 mmol/L, respectively ( P =NS). In both cell lines, current inhibition by farnesol was prominent over the whole voltage range without changes in the current-voltage relationship peaks. Neither intracellular infusion of the stable GDP analogue guanosine-5′- O -(2-thiodiphosphate) (100 mmol/L) via the patch pipette nor strong conditioning membrane depolarization prevented the inhibitory effect of farnesol, which indicates G protein–independent inhibition of Ca 2+ channels. In an analysis of the steady-state inactivation curve for voltage dependence, farnesol induced a significant, negative shift (≈10 mV) of the potential causing 50% channel inactivation in both cell lines ( P <0.001). In contrast, the steepness factor characterizing the voltage sensitivity of the channels was unaffected. Unlike pharmacological Ca 2+ channel blockers, farnesol blocked Ca 2+ currents in the resting state: initial block was 63±8% in A7r5 cells and 50±9% in CHOC9 cells at a holding potential of −80 mV. We then gave 500 mg/kg body weight farnesol by gavage to Sabra hypertensive and normotensive rats and found that farnesol reduced blood pressure significantly in the hypertensive strain for at least 48 hours. We conclude that farnesol may represent an endogenous smooth muscle L-type Ca 2+ channel antagonist. Because farnesol is active in cells expressing only the pore-forming α 1 subunit, the data further suggest that this subunit represents the molecular target for farnesol binding and principal action. Finally, farnesol has a blood pressure–lowering action that may be relevant in vivo." @default.
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• W2100698524 date "1999-04-01" @default.
• W2100698524 modified "2023-10-01" @default.
• W2100698524 title "Farnesol Blocks the L-Type Ca ²⁺ Channel by Targeting the α _1C Subunit" @default.
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• W2100698524 doi "https://doi.org/10.1161/01.atv.19.4.959" @default.
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