Potential Duration Research Articles

Suppression of "fast" IPSP, superposed on "slow", as a possible cause of priming in murine hippocampus

Intra- and extracellular response in area CA1 to stimulation of two independent afferent inputs, one a priming or conditioned and the other a test or primed input (C1 and C2, respectively) were recorded in surviving murine hippocampal slices. Duration and amplitude of test field potentials (FP) and of excitatory postsynaptic potentials (EPSP), were measured, as well as amplitude of "fast" and "slow" components of inhibitory postsynaptic potentials or stimulation varying between 0 and 1 sec. Conditioning brought about an increase in the duration of FP, in duration and amplitude of EPSP, and suppression of IPSP at intervals of between 50 and 500 msec peaking at 200 msec (i.e., priming effect). These changes correlated with level of IPSPb in response to conditioned stimuli. The most pronounced effect could be seen in neurons manifesting hyperpolarizing IPSP in response to test stimuli. Suppression of test IPSPa after superposition on IPSPb is thought to bring about the increase in test FP and EPSP seen during priming.

Protein kinase C is not involved in alpha 1-adrenoceptor-mediated positive inotropic effect

This study was performed to determine whether activation of protein kinase C is responsible for the positive inotropic effect of alpha 1-adrenoceptor stimulation in rat papillary muscle. In the presence of 1 microM propranolol, phenylephrine (10 microM) produced triphasic inotropic response that was accompanied by prolongation of action potential duration (APD) and hyperpolarization of membrane potential. Phorbol 12,13-dibutyrate (PDBu, 0.1 microM) abolished the negative inotropic effect of phenylephrine and apparently resulted in enhancement of the positive inotropic effect. PDBu also attenuated the phenylephrine-induced hyperpolarization without affecting the APD prolongation. However, such changes were not observed with 12-O-tetradecanoylphorbol-13-acetate (TPA, 0.1 microM). Neither PDBu nor TPA increased the force of contraction or prolonged APD similar to phenylephrine. The protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H 7, 10 microM) did not suppress the changes induced by PDBu, and more importantly H 7 did not affect the inotropic and electrophysiological effects of phenylephrine. Both TPA and PDBu significantly inhibited the phenylephrine-induced phosphoinositide hydrolysis as measured by [3H]inositol monophosphate, and these inhibitory effects were eliminated in the presence of H 7. Our results provide an argument against a role of protein kinase C activation in the alpha 1-adrenoceptor-mediated inotropic and electrophysiological effects.

Effects of MDL 11,939 on Action Potential and Contractile Force in Cardiac Tissues: A Comparison with Bretylium, Clofilium, and Sotalol

The effect of MDL 11,939 hydrochloride [alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol HCl], a novel antiarrhythmic agent, was studied using microelectrode recording techniques. MDL 11,939 (10(-7) - 10(-6) M increased the action potential (AP) duration in both guinea pig papillary muscle and dog Purkinje fiber with a maximum effective concentration of 10(-6) to 3 x 10(-6) M. MDL 11,939 up to and including 10(-6) M did not alter upstroke velocity (Vmax) of the AP in either tissue but 10(-5) M decreased the Vmax in Purkinje fibers. Compared to the other class III antiarrhythmic agents (bretylium, clofilium, and d-sotalol), MDL 11,939 was among the most potent in increasing AP duration in the papillary muscle, while being relatively less effective in increasing AP duration in Purkinje fiber. Bretylium did not increase the AP duration in papillary muscle unless it was reserpinized. MDL 11,939, clofilium, and d-sotalol all produced negative inotropic effects in papillary muscle, whereas bretylium produced a positive inotropic effect. The positive inotropic effect of bretylium was abolished by reserpinization. In papillary muscle preparations depolarized with 22 mM K+, MDL 11,939 at concentrations greater than or equal to 10(-5) M depressed Vmax of the slow AP, suggesting that it inhibited the inward Ca2+ current, and such an effect may contribute to the negative inotropic effect of this agent. In the depolarized preparations, the slow AP duration was still increased by concentrations of MDL 11,939 greater than or equal to 10(-6) M. In conclusion, MDL 11,939 has cellular electrophysiological properties that suggest a class III antiarrhythmic activity.

Fatal Pulmonary Thromboembolism After Successful Transsphenoidal Hypophysectomy for Cushingʼs Disease

We have reported the case of a 30-year-old woman with Cushing's disease who died of massive pulmonary thromboembolism 5 weeks after successful transsphenoidal hypophysectomy. Glucocorticoid excess appears to cause a hypercoagulable state, and consideration of this thromboembolic propensity and its potential duration after cure is indicated in all patients with Cushing's syndrome during the perioperative period. At the present time, we recommend the routine perioperative use of intermittent pneumatic compression in all patients with Cushing's disease or Cushing's syndrome.

Effects of propranolol on ventricular repolarization in man

The acute effects on monophasic action potentials (MAP), QT interval, and right ventricle effective refractory period (V-ERP) of propranolol 0.2 mg.kg-1 body weight have been studied in 10 patients with coronary artery disease. The median duration of MAP at 90% repolarization (MAP90) was shortened from 238 to 228 ms at a constant paced heart rate of 100 beats.min-1, while V-ERP remained unchanged. The median ratio V-ERP/MAP90 increased from 1.00 to 1.03. The electrical restitution curves of the duration of premature action potentials, normalized to those paced at constant heart rate, were more horizontal after propranolol. Isometric handgrip shortened MAP90 from 217 to 211 ms and after propranolol similar shortening was found (215 to 209 ms), although both values were slightly lower than before beta-blockade.

Regulation of systolic force and control of free energy of ATP-hydrolysis in hypoxic hearts

In isolated isometrically working rat hearts during graded, constant pressure hypoxic saline perfusion (PO2 140-700 mmHg) heart rate was changed experimentally between 80 and 400/min. The following parameters were recorded or estimated: peak systolic pressure, dP/dtmax, dP/tmin, oxygen consumption (VO2), venous PO2, ATP, ADP, phosphocreatine, creatine and inorganic P. Free energy of ATP hydrolysis (dG/d xi) was calculated from cytosolic concentration using CK-equilibrium equation. Two predominant responses of the hearts to hypoxia were observed, pronounced negative force frequency relationship; maintained energetic state (Free energy, dG/d xi) at the respective level of hypoxia if contractile force and beating rate were varied by a factor of 4-5. The enhanced force frequency relationship with a maintained free energy level is interpreted in terms of downregulation of EC-coupling (including duration of action potential) which comprises a possible cardioprotective effect.

F Response Characteristics in Type I Diabetes Mellitus

Ulnar and tibial F response parameters were characterized in 17 healthy controls and 26 subjects with type I diabetes mellitus meeting or exceeding criteria for mild diabetic peripheral neuropathy. The presence of mild diabetic peripheral neuropathy was determined by utilizing conventional nerve conduction studies, the neuropathy symptoms score and a neurologic examination. Ulnar and tibial nerve F response latency, amplitude, duration, chronodispersion and persistence were then compared between populations. The relationship between tibial F response persistence and minimal F response latency was assessed in both populations. In addition, the relationship between tibial F response persistence and tibial nerve conduction velocity and tibial nerve compound action potential characteristics (e.g., latency, amplitude and duration) was assessed in the diabetic population. The results indicate that ulnar F response latency and chronodispersion failed to differentiate the subject and control populations; however, significantly decreased ulnar F response amplitude and duration were noted in the diabetic population. In the tibial nerve, the F response persistence was significantly decreased in the diabetic population but persistence did not correlate with compound muscle action potential latency, amplitude, duration or nerve conduction velocity. Finally, the tibial F response latency, amplitude, duration and chronodispersion failed to differentiate the control and diabetic populations.

Effect of OPC-8490 on the membrane potentials and membrane currents of single guinea-pig myocytes

The direct actions of OPC-8490 on mammalian myocardium were examined by determination of the drug's effects on the action potentials of isolated guinea-pig single ventricular cells and on the underlying ionic currents. OPC-8490 (10(-6) to 10(-4) M) did not alter the resting membrane potential, but rather produced a dose-dependent prolongation of the duration of the action potential. The amplitude of the action-potential plateau was also increased by OPC-8490. Whole-cell voltage clamp experiments revealed that OPC-8490 blocks myocardial delayed outward K+ current (IK), which regulates repolarization of the action potentials. However Ik1, which regulates the resting membrane potential, was not changed by OPC-8490. Ca current (ICa) was increased by OPC-8490 in a dose-dependent and reversible manner. These results suggest that OPC-8490 augments the plateau amplitude and increases the duration of the action potentials by not only increasing ICa, but also by decreasing delayed outward K+ currents. Moreover, OPC-8490 did not affect the intracellular concentration of cyclic AMP in single cells. The OPC-8490 increase in ICa was thus unlikely to be mediated by a process involving cyclic AMP.

Pharmacological modification of mechanical and electrical responses of frog heart to thrombin

The pharmacological modification of the thrombin effect on the mechanical and electrical responses of frog heart was examined in the Straub heart preparation and in single ventricular cells. Associated with the positive inotropic action thrombin increases voltage and duration of action potentials of isolated frog ventricular cells. As found by the patch-clamp technique in the cell-attached mode, thrombin stimulates single L-type Ca2+ channels, presumably mediated by a second messenger. The enhancement of contractility by thrombin depends on the proteolytic activity of the enzyme because enzymatically inactivated thrombin has no effect on frog hearts. The positive inotropic effect of thrombin as well as its stimulation of Ca2+ channel currents were inhibited by the protein kinase C blocker 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine (H7). However, phorbol 12-myristate 13-acetate (PMA), a known stimulator of protein kinase C, was ineffective in stimulating the inotropic action of thrombin. The inhibition of the thrombin-induced enhancement of contractility by indometacin indicates an involvement of arachidonic acid in the action of thrombin on frog heart.

Chloride action potentials and currents in embryonic skeletal muscle of the chick

Chloride-dependent action potentials were elicited from embryonic skeletal muscle fibers of the chick during the last week of in ovo development. The duration of the action potentials was extremely long (greater than 8 sec). The action potentials were reversibly blocked by the stilbene derivative, SITS, a specific blocker of chloride permeability. Using patch clamp pipettes, in which the intracellular chloride concentration was controlled and with other types of ion channels blocked, the membrane potential at the peak of the action potential closely coincided with the chloride equilibrium potential calculated from the Nernst equation. These data indicate that activation of a chloride-selective conductance underlies the long duration action potential. The occurrence of the chloride-dependent action potential was found to increase during embryonic development. The percentage of fibers that displayed the action potential increased from approximately 20% at embryonic day 13 to approximately 70% at hatching. Chloride-dependent action potentials were not found in adult fibers. The voltage and time-dependent currents underlying the action potential were recorded under voltage clamp using the whole-cell version of the patch pipette technique. The reversal potential of the currents was found to shift with the chloride concentration gradient in a manner predicted by the Nernst equation, and the currents were blocked by SITS. These data indicate that chloride ions were the charge carriers. The conductance was activated by depolarization and exhibited very slow activation and deactivation kinetics.

Action potentials and membrane currents of isolated single smooth muscle cells of cat and rabbit colon

Membrane potentials, action potentials and macroscopic currents in enzymatically dispersed, single smooth muscle cells of the circular layer of cat and rabbit colon were investigated. The cells did not exhibit spontaneous depolarizations and repolarizations (slow waves) or spontaneous action potentials. Single action potentials of smooth muscle cells were evoked by depolarizing current pulses of 5 ms to 3 s duration. A repetitive action potential discharge and an increase in the duration of the action potential was observed in cells during long depolarizing current pulses by superfusion with tetraethylammonium (TEA) or 4-aminopyridine (4-AP). Tetrodotoxin (TTX) did not alter the configuration of the action potential. Voltage-clamp experiments revealed two major outward macroscopic currents: a quasi-instantaneous (time-independent) and a time-dependent outward current. Both currents were identified as potassium (K) currents due to their pharmacological sensitivity to K antagonists [TEA, 4-AP and cesium (Cs)] and due to the reversal potential of outward tail currents. Barium selectively blocked the time-independent current. A time-dependent outward K current in colon cells was observed which appeared to be dependent upon entry of calcium ions (Ca2+) through voltage-dependent Ca-channels, since it was blocked by cadmium and low concentrations of nifedipine. The majority of cells did not exhibit transient outward currents. Inward currents were exposed in some of the cells when the K currents were blocked by external TEA and by replacement of K by Cs and TEA in the recording pipette. Inward currents were presumably carried by Ca2+, since they were not altered by TTX, were sensitive to external Ca concentrations and were abolished by the Ca channel antagonist, nifedipine. Carbachol augmented the amplitude of the inward Ca current.

Electrophysiological Effects of AN-132, a New Antiarrhythmic Compound, in Guinea Pig Papillary Muscles

We used electrophysiological techniques to examine the effects of AN-132, a new antiarrhythmic agent, on transmembrane action potentials of isolated papillary muscles of guinea pigs. AN-132 (1-90 microM) produced a dose-dependent decrease in the maximum upstroke velocity of the action potential (Vmax). The resting potential and the amplitude, overshoot, and the duration of the action potential were not affected, even at the highest concentration of the drug used (90 microM). In the presence of AN-132, trains of stimuli at a rate of 0.5, 1, 2, and 4 Hz led to an exponential decline in the Vmax, reaching a new steady state (use-dependent block, UDB). The UDB was augmented by higher stimulation frequencies or lower membrane potentials. In the presence of the drug (60 microM), the time constant and the rate of onset of UDB of Vmax were 13.4-4.5 s and 0.141-0.053 AP-1 at stimulation frequencies of 0.5-4.0 Hz, respectively. The time constant for the recovery of Vmax from the UDB was 81.2 +/- 17.2 s. AN-132 (60 microM) only slightly depressed the Vmax of the first action potential elicited after an 8-min quiescent period (tonic block, TB). In papillary muscles depolarized with 8.4 and 10.4 mM [K+]0, both UDB and TB were augmented, but the augmentation was greater with the former. None of the parameters of the slow response elicited in the presence of 27 mM [K+]0 and 0.2 mM Ba2+ were affected by the drug (30-90 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Electronic Filter Effects on Normal Motor and Sensory Nerve Conduction Tests

Electronic filtering of the recorded signal is a significant aspect of all electro-diagnostic testing, but the filter type and frequency band are infrequently reported. Although the effects of different high- and low-frequency filters have been hypothesized, they have been the subject of little study under actual clinical conditions. This investigation showed clinically and statistically (p less than 0.01) significant alterations in both motor and sensory nerve evoked responses produced by modification of filter settings within the range routinely used for recording. As the low-frequency filter was varied from 3 to 20 Hz; large differences were seen in amplitude, area and duration of the compound muscle action potential. When the high-frequency filter was changed from 10 to 2 kHz, the mean amplitude of the sensory nerve action potential decreased by 12% and the mean latency was increased 0.1 ms. We conclude that filter parameters must remain constant when determining normal values and when performing serial studies on any patient. Filter settings should be reported as part of all electro-diagnostic reports and scientific manuscripts.

Calcium Currents in Rat Myoballs and Their Inhibition by Insulin*

Two Ca2+ currents were found in myoballs prepared from primary culture of hindlimb muscles from rat embryos. One whole cell current, not described previously, was early, fast, and transient. It depended on the presence of Na+ in the bathing solution and was blocked by tetrodotoxin. Despite this behavior suggesting that it might be via a Na+ channel, its reversal potential exceeded 80 mV compared to 46 mV for the Na+ equilibrium potential. It was increased by increased Ca2+ concentration in the bathing solution and eliminated by Co2+ and by diltiazem. The other Ca2+ current resembled the slow inward Ca2+ current ICa(si), described in other cell types. Insulin decreased both Ca2+ currents; even at 64 pM insulin reduced ICa(si). When outward K+ currents were prevented, the myoball action potential was altered greatly, owing to the unopposed effect of ICa(si). Its duration was on the order of seconds. Insulin, in a concentration-dependent manner, beginning at 60 pM, reduced the duration of this action potential more effectively than nimodipine. This is the most sensitive response to insulin observed in skeletal muscle.

Effects of activation of ATP-sensitive K+ channels in mammalian ventricular myocytes.

A cromakalim analogue, SR 44866, is shown to open ATP-sensitive K+ channels in ventricular myocytes. The channels opened by SR 44866 were closed by internal ATP and had the same current-voltage relationship as ATP-sensitive K+ channels; channels closed by ATP could be opened by SR 44866. SR 44866 was effective when applied to either side of excised membrane patches and when included in the pipette during cell-attached membrane recordings. SR 44866 also opened channels in cell-attached membrane patches when it was applied to the cell membrane outside of the pipette. The current evoked by SR 44866 in whole cell recordings was inhibited by tolbutamide. SR 44866 reduced the duration of action potentials and the amplitude and duration of evoked muscle contractions in guinea pig papillary muscle, with dissociation constants of 6.8 microM at 24 degrees C and 1.9 microM at 34 degrees C and Hill coefficients of 1.72 and 1.71, respectively. We conclude that the opening of ATP-sensitive K+ channels has profound inhibitory effects on the electrical and mechanical activity of cardiac muscle.

Age-Related Changes in Electromechanical Properties of Canine Ventricular Muscle: Effect of Ouabain

In this report, alterations between the electrical and mechanical responses of isolated neonatal and adult canine ventricular muscle preparations before and after ouabain exposure are described. No significant differences were observed between the two age groups in the concentration-dependent effects of ouabain on increasing contractile force or decreasing maximum diastolic transmembrane potential. The action potential plateau duration was decreased by high concentrations of ouabain (0.3-1 microM) in both neonatal and adult ventricular muscle. In addition, more adult preparations developed delayed afterdepolarizations associated with aftercontractions after exposure to ouabain than did neonatal preparations. These results suggest that the higher glycoside tolerance in neonatal dogs as compared with adults may be due in part to differences in the mechanisms responsible for development of abnormal ventricular automaticity. The results may also indicate that immature animals do not require higher glycoside levels to produce augmentation of cardiac contractility.

Mechanism of Wenckebach periods: hypothesis based on computer modeling experiments.

Wenckebach periodicity is characterized by progressive lengthening of conduction intervals and by progressive shortening of the intervals between conducted excitations. Although different hypotheses have been suggested to explain the mechanisms of Wenckebach periods, no serious proposition explaining both components of the phenomenon has yet been reported. A computer model simulating detailed mechanisms of excitation transmission and electrotonic interactions between neighboring cardiac cells has been employed to investigate the conduction properties of a one-dimensional cable composed of simulated cells. When introducing gradual prolongation of the recovery phase for the elements in the center of the cable and when incorporating physiologically realistic shapes of premature action potential curves into the simulation experiments, the model was able to reproduce all aspects of Wenckebach periodicity. Systematic evaluation with simulation experiments showed that a shorter duration of premature action potentials (i.e., of action potentials resulting from excitation of a cell before it has been fully repolarized) produced shortening of intervals between conducted excitations during a Wenckebach period.

The effects of vagal stimulation and applied acetylcholine on the sinus venosus of the toad.

1. The effects of vagal stimulation and applied acetylcholine were compared on the isolated sinus venosus preparation of the toad, Bufo marinus. 2. The effects of applied acetylcholine and of low-frequency, or short bursts of high-frequency vagal stimulation were abolished by hyoscine. 3. When intracellular recordings were made from muscle cells of the sinus venosus, it was found that applied acetylcholine caused bradycardia and a cessation of the heart beat which was associated with membrane hyperpolarization and a reduction in the duration of the action potentials. Much of the effect of acetylcholine can be attributed to it causing an increase in potassium conductance, gK. 4. When slowing was produced by low-frequency vagal stimulation, only a small increase in maximum diastolic potential was detected. During vagal arrest the membrane potential settled to a potential positive of the control maximum diastolic potential. 5. In the presence of barium, much of the bradycardia associated with vagal stimulation persisted. Although the bradycardia produced by added acetylcholine also persisted in the presence of barium, the effects of acetylcholine that could be attributed to an increase in gK were abolished. 6. Addition of caesium ions produced bradycardia with membrane potential changes similar to those seen during vagal stimulation. 7. The results are discussed in relation to the idea that neuronally released acetylcholine reduces inward current flow during diastole. In contrast applied acetylcholine as well as reducing inward current flow during diastole also increases outward current flow by increasing gK.

Effects of tolbutamide, glibenclamide and diazoxide upon action potentials recorded from rat ventricular muscle

Drugs which influence the electrical activity of insulin-secreting B cells of mammalian islets of Langerhans by closing (tolbutamide and glibenclamide) or opening (diazoxide) ATP-sensitive potassium channels were applied to the ventricular muscle of the rat. Action potentials were recorded from ventricular epicardium of perfused intact rat hearts. Tolbutamide (0.5-2.0 mM), glibenclamide (0.01-0.1 mM) and diazoxide (0.5 mM) each evoked a dose-dependent increase (7-33%) in the duration of the ventricular action potential measured at 50% of repolarization. These drugs were without effect upon the resting membrane potential or the peak of the action potential. Single-channel recordings of ATP-sensitive K+ channels were obtained from excised membrane patches of enzymatically isolated rat ventricular myocytes. Tolbutamide and diazoxide inhibited openings of ATP-sensitive K+ channels. Diazoxide inhibited ATP-sensitive K+ channel openings in the presence of ATP. Diazoxide did not evoke opening of ATP-sensitive K+ channels. It is concluded that these drugs could act to increase the duration of the cardiac action potential by inhibiting openings of ATP-sensitive K+ channels.

Possible inhibition of canine ventricular sarcoplasmic reticulum by BAY K 8644

The calcium-channel agonist-antagonist racemic mixture of BAY K 8644 as well as the pure calcium-channel agonist enantiomer, converted rest potentiation in canine ventricular muscle to rest depression. The depressed postrest beats had increased action potential plateau heights and durations, suggesting that extracellular calcium entry was enhanced. BAY K 8644 did not alter the time to peak tension of either steady-state or postrest beats. Although BAY K 8644 slightly increased the amplitude of rapid-cooling contractures (RCC) immediately after an electrically evoked steady-state contraction (RCCss), the RCC amplitude rapidly decreased with increasing durations of rest. These results suggest that increased calcium influx because of BAY K 8644 increases the pool of releasable calcium during steady-state stimulation. However, they also indicate that BAY K 8644 causes acceleration of diastolic loss of calcium from the sarcoplasmic reticulum (SR). Scattered light intensity fluctuation measurements showed that the negative inotropic effect of BAY K 8644 on postrest contraction was not caused by calcium overloading of the SR, since BAY K 8644 reduced asynchronous myofilament motion. A negative relationship found between extracellular calcium and BAY K 8644-induced postrest depression also rules out the possibility that the latter effect is caused by intracellular calcium overload. BAY K 8644 seems to accelerate the loss of calcium from the SR during diastole by a pathway that does not appear to pass through the myofilaments.