Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate whether the hydroxylated metabolites of quinidine (Q) and hydroquinidine (HQ): hydroxy-3S-quinidine (OH-Q) and hydroxy-3S-hydroquinidine (OH-HQ), exert electrophysiologic effects and participate in the therapeutic action of the parent drugs, we examined and compared the effects of the metabolites and the parent drugs on the electrical activity of guinea pig ventricular cells recorded by standard microelectrode technique. In addition, we investigated the potential arrhythmogenic properties of these compounds in rabbit Purkinje fibers in low K+ (2.7 mM) Tyrode's solution. The concentration [C]-, frequency-, and voltage-dependent effects of the drugs were investigated. Maximum upstroke velocity of phase 0 (Vmax) was [C]-dependently depressed by both OH-Q and OH-HQ but at a lesser degree than with Q and HQ, respectively: at the [C] of 50 microM, Vmax depression attained 26.7 +/- 2.6% with OH-Q versus 45.9 +/- 1.6% with Q and 32.3 +/- 1.9% with OH-HQ versus 54.6 +/- 1.4% with HQ. This effect was frequency and voltage dependent without significant differences between the four compounds. In the presence of equipotent [C], recovery kinetics of Vmax was significantly slower with metabolites than with respective parent drugs. In contrast, the effects of metabolites on action potential duration at 90% of repolarization (APD90) and effective refractory period (ERP) differed from those observed with parent drugs. With metabolites, APD90 and ERP were increased in a [C]-dependent manner, whereas the Q- and HQ-induced lengthening in APD90 and ERP was observed only at low concentration and low frequency. In addition, the OH-Q- and OH-HQ-induced APD90 lengthening was not altered by increasing pacing rate. In rabbit Purkinje fibers, increase in cycle length and prolonged exposure to either metabolites or parent drug caused early afterdepolarizations (EADs) and triggered activity. With all drugs tested, EADs arose more frequently at the plateau level than at the final repolarization of AP, but the incidence of EADs appeared to be much lower with metabolites than with parent drugs. The present results demonstrate that OH-Q and OH-HQ exert qualitatively similar but quantitatively less potent depressant effects on Vmax than Q and HQ, respectively, but differ in the lengthening effect on APD. We suggest that metabolites may participate in class I antiarrhythmic action of their respective parent drug and contribute to their arrhythmogenicity.
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PMID:Comparative electrophysiologic effects of metabolites of quinidine and hydroquinidine. 137 7

Amiodarone may cause serious complications in patients receiving general anesthetics. Potentially adverse electrophysiologic interactions between amiodarone and halothane were studied with the use of standard microelectrode techniques to record intracellular action potentials (APs) from excised canine Purkinje fibers. A second dog (support dog) was anesthetized and a femoral arteriovenous bypass circuit created in which arterial blood from the support dog superfused the Purkinje fiber in a tissue bath. The applicability of this model was established by first comparing the AP effects of halothane during blood perfusion with those in Tyrode's solution. Halothane reduced AP duration (APD; P less than 0.05) during Tyrode's solution superfusion and blood cross-perfusion. After the blood perfusion-Purkinje fiber model was validated, the interaction between halothane and amiodarone was studied using Purkinje fibers from dogs chronically treated with oral amiodarone, superfused with blood from chronically amiodarone-treated support dogs. Amiodarone reduced resting membrane potential and prolonged APD. Depression of AP amplitude and reduction of the maximum rate of increase of phase 0 of the AP (Vmax) by halothane (both P less than 0.05) suggested risk of conduction defects if halothane is administered to patients receiving chronic amiodarone therapy.
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PMID:The electrophysiologic effects of amiodarone and halothane on canine Purkinje fibers. 206 34

Dauricine (Dau) 1-30 mumol/L produced the concentration-dependent depression of APA, Vmax, MDP, and RP, and prolongations of APD90 of Purkinje fibers (PF) and epicardial ventricular muscles (VM) from both infarcted and non-infarcted zones. The ERP was lengthened only in non-ischemic PF and VM, and APD50 in non-ischemic PF, non- and ischemic VM. The prolonging effects of Dau on APD and ERP of ischemic PF were much less than those of non-ischemic ones, and its depressing effect on the Vmax of ischemic VM was markedly greater than that of non-ischemic VM. The results suggest that Dau exerts its anti-arrhythmic effect through further depressing conduction of ischemic zone.
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PMID:Effects of dauricine on transmembrane potential of ischemic and non-ischemic Purkinje fibers and ventricular muscles from infarcted canine hearts. 213 Jun 14

The use of disopyramide is often limited because of adverse hemodynamic or electrophysiologic side effects. We compared the S(+) and R(-) enantiomers of disopyramide to the clinically used racemic mixture in a canine blood superfusion model. Eighteen support animals (group I) provided extracorporeal blood superfusion of isolated canine cardiac Purkinje fibers. Following administration of 2 mg/kg disopyramide intravenously (i.v.) [S(+), R(-), or racemic] hemodynamic and electrocardiographic parameters were temporally assessed in the support animals while simultaneous cellular electrophysiologic effects were recorded from the blood-superfused Purkinje fibers. An additional 13 animals (group II) underwent extended hemodynamic and pharmacokinetic analysis without the external atrioventricular (AV) shunt required for blood superfusion. Mean peak serum concentrations of racemic disopyramide and its enantiomers were similar (2.7 to 3.1 mg/L), but clearance was stereo-specific [half-life (t1/2) of 1.99 h for S(+) vs. 2.79 h for R(-) disopyramide]. Left ventricular (LV) function was impaired following drug administration, irrespective of optical rotation (cardiac output decreased by 20.8%, LV dP/dtmax decreased by 22.4%). Depression of phase 0 Vmax of the Purkinje fiber action potential was also nonstereo-dependent. S(+) disopyramide prolonged the QTC interval by 11.5% and increased terminal action potential duration (APD75) and effective refractory period (ERP) by 21.2 and 19.0%, respectively. R(-) disopyramide slightly increased the QTC interval (+2.3%) but decreased APD75 and ERP by 8.9 and 6.8%, respectively. The effect of racemic disopyramide on repolarization indexes was intermediate to that of its enantiomers. These data support nonstereodependent depression of both myocardial contractility and sodium channel conductance by disopyramide. Changes in APD and refractoriness were dependent on stereochemical configuration.
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PMID:Hemodynamic and electrophysiologic effects of disopyramide enantiomers in a canine blood superfusion model. 247 Oct 4

The pathophysiological mechanisms of altered transmembrane potentials in diseased human atria were investigated in 20 patients who were divided into group A (normal) and group B (diseased). The electrophysiological data of right atrial tissues measured with glass microelectrodes included maximum diastolic potentials (MDP), action potential amplitudes (APA) and action potential durations at the time required for 50% repolarization (ADP 50%) and 75% repolarization (APD 75%). The sarcolemma isolated from atrial tissues was used for determination of the sarcolemmal Na+-K+ ATPase activities. Anionic molecular sites distributed in the sarcolemmal complex were characterized by cationized ferritins (CF). The electrophysiological data in groups A and B were: MDP -80.74 +/- 1.94 mV and -44.54 +/- 6.24 mV, APA 92.72 +/- 9.25 mV and 57.74 +/- 10.85 mV, APD 50% 42.48 +/- 6.63 msec and 210.34 +/- 36.38 msec and APD 75% 56.47 +/- 8.55 msec and 281.66 +/- 42.18 msec respectively. The difference in the Na+-K+ ATPase activities between groups A (15.37 +/- 0.46 mumole Pi/mg/hr) and B (12.55 +/- 0.4 mumole Pi/mg/hr) was highly significant. CF molecules were frequently seen to be more irregularly and loosely distributed in the sarcolemmal surfaces of group B atrial myocytes. Based on these results we conclude that depression of the sarcolemmal Na+-K+ ATPase activity and derangement of the anionic binding sites in the sarcolemmal surfaces play an important role in altering transmembrane potentials in diseased human atria.
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PMID:Pathophysiological mechanisms of altered transmembrane potentials in diseased human atria. 302 20

As part of a safety-assessment study, doses of 8, 40, and 200 mg/kg per day, 6 days per week, of sodium olpadronate (dimethyl-APD, Me2-APD) were given by gavage to 10-week-old male and female rats during 27 weeks. Only the 200 mg/kg per day dose provoked toxic effects and a meaningful growth depression, regardless of the animal gender. In male animals, doses of 40 or 200 mg/kg per day improved strength, stiffness, and cross-sectional moment of inertia (CSMI) of femur diaphyses despite the toxic effects observed at the highest dose. Changes in bone mechanical properties were a consequence of those induced in CSMI. Regression analyses showed a treatment-induced improvement in bone modeling (as assessed by CSMI) for the same level of bone material stiffness (as expressed by calculated values of elastic modulus). The high dependency of results on body mass bearing suggested that these effects were exerted through an increase in the efficiency of bone mechanostat. Strikingly, they were not evident in female rats. If not related to a lower bone bioavailability of bisphosphonates in female rats as described by others, this phenomenon may have reflected: (1) their a smaller biomass; and/or (2) a less effective mechanostatic regulation of bone architecture derived from a higher bone material stiffness related to male animals. An increase of BMD with a predominance toward the distal region was observed in all femurs studied. This effect, unrelated to the observed changes in mechanical properties, seems to express a lack of remodeling of primary cartilage or bone tissue.
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PMID:Effects of large doses of olpadronate (dimethyl-pamidronate) on mineral density, cross-sectional architecture, and mechanical properties of rat femurs. 762 16

The electrophysiological effects of propafenone, a class Ic antiarrhythmic drug, were studied and compared in isolated sheep Purkinje fibers and ventricular muscles. At concentrations between 10(-7)-10(-6) propafenone decreased the amplitude and maximum of depolarization (Vmax) of the action potential in both the ventricular muscle and Purkinje fibers, without altering the resting potential. At higher concentrations these effects were accompanied by depolarization of the membrane potential, a shift in the membrane responsiveness curve, and a progressive depression of conduction velocity through the Purkinje fiber-ventricular muscle junction leading to conduction block. In addition, propafenone exerted differential effects on the repolarization time course of Purkinje fibers and the ventricular muscle. At concentrations up to 10(-6) M, propafenone shortened the action potential duration at 90% of repolarization (APD90) in Purkinje fibers, while it lengthened the APD90 in the ventricular muscle, which resulted in a more uniform repolarization. However, at higher concentrations, propafenone increased the disparity in APD between Purkinje fibers and the ventricular muscle, which results in an increased inhomogeneity of ventricular repolarization. It is concluded that propafenone may aggravate and/or induce sustained ventricular tachyarrhythmias by increasing the likelihood of incessant reentry, i.e., by slowing conduction with a minor prolongation of refractoriness and producing a nonuniform recovery of excitability.
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PMID:Propafenone slows conduction and produces a nonuniform recovery of excitability between Purkinje and ventricular muscle fibers. 769 58

Effects of extracellular applications of different types of Ca2+ channel blocking agents (Mn2+, verapamil, and nisoldipine) on action-potential duration and membrane currents were studied by the whole-cell patch-clamp technique in guinea pig ventricular myocytes. Low concentrations of Mn2+ (1 mM) and verapamil (1 microM) prolonged action-potential duration at 90% repolarization (APD90) with a suppressed plateau phase. Increases in Mn2+ (5 mM) and verapamil (5 microM) shortened APD90 with a further depression of the plateau. Nisoldipine (0.2-1 microM) shortened APD90 without lengthening it. Applications of Mn2+ and verapamil suppressed amplitudes of the L-type Ca2+ current (ICa), the delayed outward K+ current (IK), and the inward rectifier K+ current (IK1). Furthermore, the ratios of ICa:IK inhibition were similar by low and high concentrations of Mn2+ and verapamil. Nisoldipine selectively suppressed ICa without effect on IK and IK1. A low concentration (1 mM) of Mn2+ not only decreased the peak amplitude of ICa but also delayed its decay time course, which caused an increase in late ICa amplitude at the end of a 200-ms depolarizing pulse. Both verapamil and nisoldipine suppressed peak ICa without affecting its decay. Whereas Mn2+ suppressed IBa without changing its decay time course, verapamil and nisoldipine speeded up the IBa decay with suppressed amplitude of IBa. We conclude that different types of Ca2+ channel blocking agents (Mn2+, verapamil, and nisoldipine) diversely modulate APD because of their multiple modes of actions on ICa and IK.
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PMID:Multiple modulations of action potential duration by different calcium channel blocking agents in guinea pig ventricular myocytes. 933 9

The aim of the study was to determine the in vitro rate-dependent cellular electrophysiological effects of ambasilide (10 and 20 microM/l), a new investigational antiarrhythmic agent, in canine isolated ventricular muscle and Purkinje fibers by applying the standard microelectrode technique. At the cycle length (CL) of 1000 ms, ambasilide significantly prolonged the action potential duration measured at 90% repolarization (APD(90)) in both ventricular muscle and Purkinje fibers. Ambasilide (10 microM/l) produced a more marked prolongation of APD(90) at lower stimulation frequencies in Purkinje fibers (at CL of 2000 ms = 56.0 +/- 16.1%, n = 6, versus CL of 400 ms = 15.1 +/- 3.7%, n = 6; p < 0.05), but, in 20 microM/l, this effect was considerably diminished (15.2 +/- 3.6%, n = 6, versus 7.3 +/- 5.1%, n = 6, p < 0.05). In ventricular muscle, however, both concentrations of the drug induced an almost frequency-independent lengthening of APD(90) in response to a slowing of the stimulation rate (in 20 microM/l at CL of 5000 ms = 19.0 +/- 1.5%, n = 9, versus CL of 400 ms = 16.9 +/- 1.4%, n = 9). Ambasilide induced a marked rate-dependent depression of the maximal rate of rise of the action potential upstroke (V(max)) (in 20 microM/l at CL of 300 ms = -45.1 +/- 3.9%, n = 6, versus CL of 5000 ms = -8.5 +/- 3.9%, n = 6, p < 0. 05, in ventricular muscle) and the corresponding recovery of V(max) time constant was tau = 1082.5 +/- 205.1 ms (n = 6). These data suggest that ambasilide, in addition to its Class III antiarrhythmic action, which is presumably due to its inhibitory effect on the delayed rectifier potassium current, possesses I/B type antiarrhythmic properties as a result of the inhibition of the fast sodium channels at high frequency rate with relatively fast kinetics. This latter effect may play an important role in its known less-pronounced proarrhythmic ("torsadogenic") potential.
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PMID:Analysis of the electrophysiological effects of ambasilide, a new antiarrhythmic agent, in canine isolated ventricular muscle and purkinje fibers. 1097 15

The cellular electrophysiologic effect of GYKI 16638, a new antiarrhythmic compound was studied and compared with that of sotalol and mexiletine in undiseased human right ventricular muscle preparation by applying the conventional microelectrode technique. GYKI 16638 (5 microM), at stimulation cycle length of 1000 ms, lengthened action potential duration (APD(90)) from 338.9 +/- 28.6 ms to 385.4 +/- 24 ms (n = 9, p > 0.05). This APD lengthening effect, unlike that of sotalol (30 microM), was rate-independent. GYKI 16638, contrary to sotalol and like mexiletine (10 microM), exerted a use-dependent depression of the maximal rate of depolarization (V(max)) which amounted to 36.4 +/- 11.7% at cycle length of 400 ms (n = 5, p < 0.05) and was characterised with an offset kinetical time constant of 298.6 +/- 70.2 ms. It was concluded that GYKI 16638 in human ventricular muscle shows combined Class IB and Class III antiarrhythmic properties, resembling the electrophysiological manifestation seen after chronic amiodarone treatment.
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PMID:The cellular electrophysiologic effect of a new amiodarone like antiarrhythmic drug GYKI 16638 in undiseased human ventricular muscle: comparison with sotalol and mexiletine. 1186 Mar 46


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