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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:959-966.)
© 1999 American Heart Association, Inc.

Original Contributions

Farnesol Blocks the L-Type Ca²⁺ Channel by Targeting the _1C Subunit

Ulrich C. Luft; Rostislav Bychkov; Maik Gollasch; Volkmar Gross; Jean-Baptiste Roullet; David A. McCarron; Christian Ried; Franz Hofmann; Yoram Yagil; Chana Yagil; Hermann Haller; Friedrich C. Luft

From the Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Virchow Klinikum-Charité, Humboldt University of Berlin, Berlin, Germany (U.C.L., R.B., M.G., V.G., C.R., H.H., F.C.L.); the Division of Nephrology, Hypertension, and Clinical Pharmacology, Oregon Health Sciences University, Portland (J.-B.R., D.A.M.); the Institute of Pharmacology, Technical University of Munich, Munich, Germany (F.H.); and the Barzilai Medical Center, Faculty of Health Sciences, Ben Gurion University, Ashkelon, Israel (Y.Y., C.Y.).

Correspondence to Friedrich C. Luft, MD, Franz Volhard Clinic, Wiltberg Strasse 50, 13122 Berlin, Germany. E-mail luft{at}fvk-berlin.de

Abstract—We recently demonstrated that farnesol, a 15-carbon isoprenoid, blocks L-type Ca²⁺ 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 Ca²⁺ channel _1C subunits. Farnesol dose-dependently and voltage-independently inhibited Ba²⁺ 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 Ca²⁺ 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 Ca²⁺ channel blockers, farnesol blocked Ca²⁺ 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 Ca²⁺ channel antagonist. Because farnesol is active in cells expressing only the pore-forming 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.

Key Words: smooth muscle cells • farnesol • patch clamp • calcium channel blockers • L-class channels

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