Mechanical effects of liriodenine on the left ventricular-arterial coupling in Wistar rats: pressure-stroke volume analysis.
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1. In a recent in vivo study, liriodenine, an aporphine alkaloid, has been identified as a prominent anti-arrhythmic agent that can prevent rats' sudden deaths, even at the dose as low as 10(-7) g kg(-1). The aim of this study was to determine whether liriodenine at its effective anti-arrhythmic dose of 10(-7) g kg(-1) had effects on the left ventricular (LV)-arterial coupling in Wistar rats. 2. LV pressure and ascending aortic flow signals were recorded to construct the ventricular and arterial end-systolic pressure-stroke volume relationships to calculate LV end-systolic elastance (E(es)) and effective arterial volume elastance (E(a)), respectively. The optimal afterload (Q(load)) determined by the ratio of E(a) to E(es) was used to measure the optimality of energy transmission from the left ventricle to the arterial system. 3. Liriodenine at the dose of 10(-7) g kg(-1) showed no significant changes in basal heart rate (HR), cardiac output (CO), LV end-systolic pressure (P(es)), E(a), E(es), and Q(load). 4. By contrast, liriodenine at the dose of 10(-6) g kg(-1) produced a significant fall of 2.0% in HR and a significant rise of 5.8% in CO, but no significant change in P(es). Moreover, liriodenine administration of 10(-6) g kg(-1) to rats significantly decreased E(es) by 8.5% and E(a) by 10.6%, but did not change Q(load). 5. We conclude that liriodenine at the dose of 10(-7) g kg(-1) has no effects on the mechanical properties of the heart and the vasculature and the matching condition for the left ventricle coupled to its vasculature in rats. Even at 10 times the effective anti-arrhythmic dose, liriodenine shows no effects on the efficiency of energy transferred from the left ventricle to the arterial system. (+info)
Interactions between antiarrhythmic drugs and cardiac memory.
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OBJECTIVE: Ventricular pacing or arrhythmias can induce cardiac memory (CM). We hypothesized that clinically administered antiarrhythmic drugs alter the expression of CM, and that the repolarization changes characteristic of CM can modulate the effects of antiarrhythmic drugs. METHODS: We studied conscious, chronically-instrumented dogs paced for two 1-h periods to study the effects of drugs on the evolution of memory (protocol 1) or for 21 days (protocol 2) to observe the effects of steady-state memory on drug actions. Dogs were treated in both settings with quinidine, lidocaine or E4031, in random order, and within therapeutic serum concentration ranges. RESULTS: Pacing, alone, for 2 h significantly prolonged ERP only near the left ventricular pacing site, whereas pacing alone for 21 days prolonged ERP at all sites (P<0.05). Quinidine and E4031, but not lidocaine, prolonged repolarization and ERP and suppressed evolution of CM in protocol 1. However, quinidine's effect in prolonging repolarization was diminished in both protocols, while its effect in prolonging ERP was diminished in the 21-day protocol only. In contrast, the effects of E4031 were additive to those of CM, prolonging repolarization and ERP in both protocols, while lidocaine showed no changes in effect at all. CONCLUSIONS: Pacing to induce CM significantly affects ventricular repolarization and refractoriness, and there are interactions between CM, quinidine and E4031. Depending on the specific drug, these interactions have the potential to be anti- or proarrhythmic, and may impact importantly on the clinical efficacy of drugs as well as on electrophysiologic testing of drug actions. (+info)
In vitro stimulation of warfarin metabolism by quinidine: increases in the formation of 4'- and 10-hydroxywarfarin.
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It has been demonstrated that the activity of cytochrome P450 (CYP)3A4 in certain cases is stimulated by quinidine (positive heterotropic cooperativity). We report herein that the 4'- and 10-hydroxylation of S- and R-warfarin are enhanced in human liver microsomal incubations containing quinidine. These reactions were catalyzed by CYP3A4, based on data derived from immunoinhibitory studies, with 4'-hydroxylation being preferentially associated with S-warfarin and 10-hydroxylation with R-warfarin. The 4'-hydroxylation of S-warfarin and 10-hydroxylation of R-warfarin increased with increasing quinidine concentrations and maximized at ~3- and 5-fold the values of controls, respectively. Stimulatory effects of quinidine also were observed with recombinant CYP3A4, suggesting that increases in warfarin metabolism were due to quinidine-mediated enhancement of CYP3A4 activity. This positive cooperativity of CYP3A4 was characterized by a 2.5-fold increase in V(max) for the 4'-hydroxylation of S-warfarin and a 5-fold increase in V(max) for the 10-hydroxylation of R-warfarin, with little change in K(m) values. Conversely, V(max) for the 3-hydroxylation of quinidine was not influenced by the presence of warfarin. These results are consistent with previous findings suggesting the existence of more than one binding site in CYP3A4 through which interactions may occur between substrate and effector at the active site of the enzyme. Such interactions were subsequently illustrated by a kinetic model containing two binding domains, and a good regression fit was obtained for the experimental data. Finally, stimulation of warfarin metabolism by quinidine was investigated in suspensions of human hepatocytes, and increases in the formation of 4'- and 10-hydroxywarfarin again were observed in the presence of quinidine, indicating that this type of drug-drug interaction occurs in intact cells. (+info)
Effect of P-glycoprotein on flavopiridol sensitivity.
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Flavopiridol is the first potent inhibitor of cyclin-dependent kinases (CDKs) to enter clinical trials. Little is known about mechanisms of resistance to this agent. In order to determine whether P-glycoprotein (Pgp) might play a role in flavopiridol resistance, we examined flavopiridol sensitivity in a pair of Chinese hamster ovary cell lines differing with respect to level of Pgp expression. The IC(50)s of flavopiridol in parental AuxB1 (lower Pgp) and colchicine-selected CH(R)C5 (higher Pgp) cells were 90.2 +/- 6.6 nM and 117 +/- 2.3 nM, respectively (P< 0.01), suggesting that Pgp might have a modest effect on flavopiridol action. Consistent with this hypothesis, pretreatment with either quinidine or verapamil (inhibitors of Pgp-mediated transport) sensitized CH(R)C5 cells to the antiproliferative effects of flavopiridol. Because of concern that colony forming assays might not accurately reflect cytotoxicity, we also examined flavopiridol-treated cells by trypan blue staining and flow cytometry. These assays confirmed that flavopiridol was less toxic to cells expressing higher levels of Pgp. Further experiments revealed that flavopiridol inhibited the binding of [3H]-azidopine to Pgp in isolated membrane vesicles, but only at high concentrations. Collectively, these results identify flavopiridol as a weak substrate for Pgp. (+info)
Effect of capillary efflux transport inhibition on the determination of probe recovery during in vivo microdialysis in the brain.
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Intracerebral microdialysis probe recovery (extraction fraction) may be influenced by several mass transport processes in the brain, including efflux and uptake exchange between brain and blood. Therefore, changes in probe recovery under various experimental conditions can be useful to characterize fundamental drug transport processes. Accordingly, the effect of inhibiting transport on probe recovery was investigated for two capillary efflux transporters with potentially different membrane localization and transport mechanisms, P-glycoprotein and an organic anion transporter. Fluorescein/probenecid and quinidine/LY-335979 were chosen as the substrate/inhibitor combinations for organic anion transport and P-glycoprotein-medicated transport, respectively. Probenecid decreased the probe recovery of fluorescein in frontal cortex, from 0.21 +/- 0.017 to 0.17 +/- 0.020 (p < 0.01). Quantitative microdialysis calculations indicated that probenecid treatment reduced the total brain elimination rate constant by 3-fold from 0.37 to 0.12 (ml/min. ml of extracellular fluid). In contrast, the microdialysis recovery of quinidine, delivered locally to the brain via the probe perfusate, was not sensitive to P-glycoprotein inhibition by systemically administered LY-335979, a potent and specific inhibitor of P-glycoprotein. Recovery of difluorofluorescein, an analog of fluorescein, was also decreased by probenecid in the frontal cortex but not in the ventricle cerebrospinal fluid. These experimental observations are in qualitative agreement with microdialysis theory incorporating mathematical models of transporter kinetics. These studies suggest that only in certain circumstances will efflux inhibition at the blood-brain barrier and blood-cerebrospinal fluid barrier influence the microdialysis probe recovery, and this may depend upon the substrate and inhibitor examined and their routes of administration, the localization and mechanism of the membrane transporter, as well as the microenvironment surrounding the probe. (+info)
Synchronized neural activity in the Drosophila memory centers and its modulation by amnesiac.
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The mushroom bodies are key features of the brain circuitry for insect associative learning, especially when evoked by olfactory cues. Mushroom bodies are also notable for the close-packed parallel architecture of their many intrinsic neuronal elements, known as Kenyon cells. Here, we report that Kenyon cells of adult Drosophila exhibit synchronous oscillation of intracellular calcium concentration, with a mean period of approximately 4 min. Robust oscillation within a dissected brain persists for hours in insect saline and is strongly modulated in amplitude by the product(s) of the memory consolidation gene, amnesiac. It is also sensitive to pharmacological agents specific for several classes of ion channel and for acetylcholine and GABA receptors. A role in memory consolidation involving transcriptionally mediated synaptic strengthening is proposed. (+info)
Independent organic cation transport activity of Na(+)-L-carnitine cotransport system in LLC-PK(1) cells.
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We investigated expression of the Na(+)-L-carnitine cotransport system and its role in transport of tetraethylammonium in a kidney epithelial cell line, LLC-PK(1). L-Carnitine uptake in the LLC-PK(1) cells was markedly stimulated in the presence of Na(+). The uptake was saturable, with Michaelis constant and maximal uptake velocity values of 7.8 microM and 153.7 pmol x mg protein(-1) x 15 min(-1), respectively. Cationic drugs such as tetraethylammonium, cimetidine, and quinidine inhibited L-carnitine uptake. The basolateral-to-apical transport of [(14)C]tetraethylammonium was enhanced markedly in the presence of an H(+) gradient on the apical side at a pH of 5.9. Under the conditions in which Na(+)/L-carnitine cotransport activity was saturable by the addition of 100 microM L-carnitine to the apical-side medium, the basolateral-to-apical transcellular transport of [(14)C]tetraethylammonium was unaffected. These results suggested that the Na(+)-L-carnitine cotransporter is expressed in the apical membranes of LLC-PK(1) cells, and is not responsible for efflux of tetraethylammonium from the cells. Transport of tetraethylammonium appeared to be mediated predominantly by an H(+)/organic cation antiporter in the apical membranes. (+info)
Effect of lidocaine and quinidine on steady-state characteristics and recovery kinetics of (dV/dt)max in guinea pig ventricular myocardium.
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We studied the effects of quinidine and lidocaine on the steady-state relationship between membrane potential and the maximum rate of rise of the action potential, (dV/dt)max, and on the recovery kinetics of (dV/dt)max in guinea pig papillary muscles. The steady-state relationships were determined in fibers stimulated at 0.2/sec and depolarized with KCl. Recovery kinetics were determined at various resting membrane potentials by assessing (dV/dt)max in progressively earlier premature action potentials. Lidocaine caused a dose-dependent decrease in (dV/dt)max, shifted the curve defining the steady-state relationship along the voltage axis in the direction of more negative potentials, and slowed the recovery kinetics of (dV/dt)max. Quinidine caused a dose-dependent decrease in (dV/dt)max but did not alter the shape of the curves defining either the steady-state relationship or the recovery kinetics of (dV/dt)max. Both drugs depressed membrane responsiveness as determined in premature action potentials originating from incompletely repolarized fibers. Our study indicates that the mechanisms whereby quinidine and lidocaine influence (dV/dt)max are different. It is possible that this difference may underlie some of the differences in the clinical effects of these two drugs. (+info)