A 3.0 MHz pulsed Doppler echocardiography was used to estimate instantaneous stroke volume (SV) and cardiac output (Q) in eight men during steady-state supine (S) and upright (U) exercise at 300 kpm/min. The mean transients in heart rate (HR), SV, and Q for the first 20 s of exercise in each posture were then determined. Center-line blood velocities were obtained in the ascending aorta with the transducer positioned manually in the suprasternal notch. Mean supine values for SV and Q at rest and exercise were 111 ml and 6.4 1/min and 112 ml and 9.71/min, respectively. The corresponding results for U were 76 ml and 5.61/min and 92 ml and 8.41/min, respectively. These values compare favorably with previous studies utilizing invasive procedures. The transient response of Q following the onset of exercise in U was about twice as fast as in S because of the rapid and almost immediate upsurge in SV. In S, only HR served to augment Q, as SV initially fell. The faster rise in aortic flow in U with exercise represented an additional volume (184 ml) of blood passing through the aorta compared with S in the first 20s. This must be related to the rapid mobilization of pooled venous blood from the leg veins during U.
Farnesol is the dephosphorylated form of farnesyl pyrophosphate, the last precursor common to all branches of the mevalonate pathway (1). The metabolic and biologic importance of farnesol has been recently demonstrated by several reports that identified the isoprenol as a natural nonsterol regulatory component of 3-hydroxy-3-methylglutaryl-CoA reductase activity (2-4) and an inhibitor of neoplastic cell growth (5, 6). Farnesol is catabolized into farnesal, farnesoic acid, and prenyl dicarboxylic acids (7,8). However, it can also be "re-phosphorylated" into farnesyl pyrophosphate and used for protein isoprenylation (9). The observation that shorter (C 10 , geraniol) and longer (C 20 , geranylgeraniol) isoprenols, which are metabolically and structurally related to farnesol, are devoid of biological activity (2, 3) suggest the existence of farnesol-specific cellular targets or binding sites. It has been proposed that farnesol inhibits the cytosol to membrane translocation of protein kinase C (PKC, 1 Ref. 10). An effect on PKC has also been observed with farnesylamine, a closely related structural analogue of farnesol (11). However, a direct effect on PKC is unlikely as farnesol does not affect PKC cellular localization in cell lines derived from normal tissue (12). Other studies have reported the existence of a farnesol-specific, orphan nuclear receptor in vertebrate cells, the farnesoid X-activated receptor, but the role of this receptor in cell signaling pathways still needs to be defined (13,14).We have shown that mevalonate (MVA) availability is an important determinant of vascular tone in animal and human arteries (15,16). Decreased vascular MVA availability following treatment with lovastatin, a 3-hydroxy-3-methylglutarylCoA reductase inhibitor, was associated with an increase in the response to vasoconstrictors, whereas addition of MVA to the arteries inhibited vasoconstriction. These findings, together with the recently characterized metabolic importance of farnesol, led us to hypothesize that farnesol itself has vasoactive properties. In evaluating the functional properties of various farnesyl analogues in the vascular tissue (17), we indeed confirmed this hypothesis and observed that farnesol is a potent inhibitor of vasoconstriction which affects vascular tone in both animals and humans. The effect is rapid, dose-dependent, reversible, and specific of farnesol as geraniol and geranylgeraniol are inactive. The study further indicated that both GTPbinding protein-dependent contractions and those induced by KCl are inhibited by farnesol. We concluded that farnesol inhibits post-receptor and post-GTP-binding protein events and perhaps Ca 2ϩ channels. However, the precise mechanism of action of farnesol on modulating vasoconstriction remained elusive. In the present study, we have explored further the vasoactive properties of farnesol and document that farnesol 1) inhibits Ca 2ϩ signaling in arteries and vascular smooth muscle cells and 2) possesses Ca 2ϩ channel blocker properties. EXPERIMENTAL PROCEDURE...
Abstract-We recently demonstrated that farnesol, a 15-carbon isoprenoid, blocks L-type Ca 2ϩ channels in vascular smooth muscle cells. To elucidate farnesolЈs 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 2ϩ channel ␣ 1C subunits. Farnesol dose-dependently and voltage-independently inhibited Ba 2ϩ currents in both A7r5 and CHOC9 cells, with similar half-maximal inhibitions at 2.6 and 4.3 mmol/L, respectively (PϭNS). 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-5Ј-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 2ϩ channels. In an analysis of the steady-state inactivation curve for voltage dependence, farnesol induced a significant, negative shift (Ϸ10 mV) of the potential causing 50% channel inactivation in both cell lines (PϽ0.001). In contrast, the steepness factor characterizing the voltage sensitivity of the channels was unaffected. Unlike pharmacological Ca 2ϩ channel blockers, farnesol blocked Ca 2ϩ currents in the resting state: initial block was 63Ϯ8% in A7r5 cells and 50Ϯ9% in CHOC9 cells at a holding potential of Ϫ80 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 2ϩ 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. Key Words: smooth muscle cells Ⅲ farnesol Ⅲ patch clamp Ⅲ calcium channel blockers Ⅲ L-class channels F arnesol is 1 of several nonsterol mevalonate derivatives in the cholesterol pathway. 1 Farnesol is derived from farnesyl pyrophosphate, a C 15 isoprenoid lipid implicated in the regulation of G protein activity. 2 Some studies suggest that farnesol participates in the control of cholesterol synthesis by increasing 3-hydroxy-3-methylglutaryl coenzyme A reductase degradation. 3,4 Others suggest that farnesol is implicated in the regulation of cell growth. 5 Roullet et al 6 recently showed that farnesol inhibited contraction in both human and animal arteries. This effect explained earlier reports of a mevalonate-dependent positive regulation of vascular tone. 7,8 These studies featured a series of experiments that showed that farnesol blunted the KCl-induced increase in intracellular Ca 2ϩ concentration in intact arteries and vascular smooth muscle cells (VSMCs) in culture. 9 The patch-clamp technique revealed that micromolar co...
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