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Biomedical subjects

D H Singer

Publications and source records attributed to D H Singer.

At least 19 recordsLinked to original sources
PubMed1992

Effects of intravenous amiodarone on electrical dispersion in normal and ischaemic tissues and on arrhythmia inducibility: monophasic action potential studies.

OBJECTIVE: The aim was to study the effects of intravenous amiodarone on: (1) repolarisation and other monophasic action potential characteristics of normal and ischaemic tissues, and (2) vulnerability to pacing induced repetitive ventricular firing following acute left anterior descending coronary artery ligation. METHODS: Epicardial monophasic action potentials were continuously and simultaneously recorded from ischaemic and non-ischaemic regions of the hearts of 24 pentobarbitone anaesthetised dogs. Monophasic action potential duration, rise time, and amplitude, as well as the degree of dispersion of repolarisation between normal and ischaemic areas and vulnerability to electrical induction of repetitive ventricular firing, were determined using hand held silver-silver chloride "contact pressure" electrodes, before and 15 min after coronary ligation; and 15 min after exposure to low (10 mg.kg-1) doses of amiodarone. Similar determinations were made in drug free controls. RESULTS: Under control conditions, monophasic action potentials from both the (potentially) ischaemic and non-ischaemic regions were comparable, dispersion of repolarisation was minimal, and repetitive ventricular firing could not be induced. Coronary ligation significantly decreased monophasic action potential duration and increased rise time in the ischaemic, but not in the non-ischaemic, regions. Dispersion of repolarisation increased markedly. Repetitive ventricular firing could be induced in all dogs. "Low dose" amiodarone caused a much greater prolongation of repolarisation duration at ischaemic than at non-ischaemic sites. Dispersion of repolarisation decreased virtually to control levels and repetitive firing could no longer be induced in six of seven dogs. "High dose" amiodarone increased ischaemic region repolarisation duration and rise time relative to the non-ischaemic region to an even greater extent than the "low" dose, with the result that dispersion of repolarisation increased rather than decreased and repetitive ventricular firing again became inducible. CONCLUSIONS: The data indicate that: (1) intravenous amiodarone prolongs repolarisation of ischaemic tissues to a greater extent than that of normal tissues; (2) "low" dose amiodarone resulted in an overall decrease in dispersion of repolarisation, with little or no change in dispersion of rise time; (3) the "high" dose increased dispersion of both repolarisation and rise time. These changes were paralleled by changes in vulnerability to induction of repetitive ventricular firing by programmed ventricular pacing, the "low" dose being associated with decreases, and the "high" dose with further increases, in vulnerability, respectively.

Action Potentials↗
PubMed1992

Characterization of the sodium current in single human atrial myocytes.

Patch-clamp recording techniques have permitted measurement of the fast Na+ current (INa) in isolated cardiac cells from a number of species in recent years. However, there is still only very little information concerning human cardiac INa. The purpose of this study was to describe the kinetics of INa in normal-appearing, Ca(2+)-tolerant, enzymatically isolated human atrial myocytes using whole-cell voltage-clamp techniques. Atrial specimens were obtained from 46 patients undergoing open heart surgery. Cs+ was substituted for K+ in both pipette and external solutions and F- was added to the former. The reversal potential of the rapid inward current varied approximately 57 mV at 17 +/- 1 degrees C with a 10-fold change in [Na+]o, and the current was completely blocked by 100 microM tetrodotoxin, findings typical of the fast cardiac Na+ current. The tetrodotoxin dose-response curve was best fitted by an equation describing binding to high- and low-affinity sites. INa was activated at a voltage threshold of -70 to -60 mV, and peak inward current was obtained at approximately -30 mV (holding potential, -140 mV). The inactivation time course was voltage dependent and was fitted best by the sum of two exponentials. The relation between voltage and steady-state availability (h infinity) was sigmoidal with the half-inactivation at -95.8 +/- 0.9 mV and a slope factor of 5.3 +/- 0.1 mV (n = 46), and we did not observe a significant difference with disease and age. The overlap of the h infinity and activation curves suggested the presence of a Na+ "window" current. Recovery from inactivation also was voltage dependent and best fitted by a model describing the sum of two exponentials. Recovery occurred after an initial delay at potentials positive to -140 mV, suggesting that inactivation of human atrial INa is a multistate process. We conclude that INa of normal-appearing, Ca(2+)-tolerant human atrial myocytes is similar to that of other mammalian cardiac cells with the possible exception of having two tetrodotoxin binding sites.

Adolescent↗
PubMed1992

Heart rate variability. Frequency domain analysis.

Experience with frequency domain analysis over the past two decades strongly suggests that it represents a unique, noninvasive tool for achieving a more precise assessment of autonomic function in both the experimental and clinical settings. Available studies indicate that the significance of the HF component is far better understood than that of the lower frequency components. In general, it is considered to reflect vagal activity, and because it is readily manipulated pharmacologically, is used as a an index of that activity. However, some caution is required because this parameter also is strongly influenced by the degree of coupling between respiration and heart rate, which, in turn, reflects the intensity of the respiratory effort as well as of parasympathetic activity. Respiratory pattern also can significantly influence HF power. The use of controlled breathing minimizes these problems, improves reproducibility of test findings, and also facilitates quantitative comparisons. The situation with respect to LF power is more complicated because it is modulated by both sympathetic and parasympathetic outflows (see previous discussion) as well as by other factors, including baroreceptor activity. Therefore, LF analysis per se cannot afford a precise delineation of the state of sympathetic activation. Determinations of the LF/HF ratio, an index of sympathovagal balance both under control conditions and in conjunction with interventions that maximize sympathetic and parasympathetic activity, provide additional insights, as do correlations between spectral activity and direct nerve recordings, plasma norepinephrine concentrations, and radionuclide imaging of adrenergic nerves. Renewed interest has recently been evinced in frequencies lower than 0.04 Hz in view of reports that the VLF portion of the spectrum (0.01-0.04 Hz) reflects a purer form of sympathetic activity than does the LF band. Despite the potential applicability to clinical problems, only very little is known about the physiologic basis of the VLF and ULF bands. Further study is required. However, it is important to note that meaningful determinations of VLF and ULF power may be difficult because decreases in frequency to such low levels are associated with an increasing propensity to violate the rules governing power spectral determinations (see previous discussion and appendix), violations that diminish reliability despite the most sophisticated preprocessing. It is also noteworthy that the reliability of spectral power determinations diminishes with decreases in the power of the signal and of the signal-to-noise ratio.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1991

Reproducibility and relation to mean heart rate of heart rate variability in normal subjects and in patients with congestive heart failure secondary to coronary artery disease.

Before heart rate (HR) variability can be used for predictive purposes in the clinical setting, day-to-day variation and reproducibility need to be defined as do relations to mean HR. HR variability and mean HR were therefore determined in 2 successive 24-hour ambulatory electrocardiograms obtained from 33 normal subjects (age 34 +/- 7 years, group I), and 22 patients with coronary disease and stable congestive heart failure (CHF) (age 59 +/- 7 years, group II). Three measures were used: (1) SDANN (standard deviation of all mean 5-minute normal sinus RR intervals in successive 5-minute recording periods over 24 hours); (2) SD (the mean of the standard deviation of all normal sinus RR intervals in successive 5-minute recording periods over 24 hours); and (3) CV (coefficient of variation of the SD measure), a new measure that compensates for HR effects. Group mean HR was higher and HR variability lower in group II than in group I (80 +/- 10 vs 74 +/- 9 beats/min, p less than 0.04). Mean group values for HR and HR variability showed good correlations between days 1 and 2 (mean RR, r = 0.89, 0.97; SDANN, r = 0.87, 0.87; SD, r = 0.93, 0.97; CV, r = 0.95, 0.97 in groups I and II, respectively). In contrast, considerable individual day-to-day variation occurred (group I, 0 to 46%; group II, 0 to 51%). Low HR variability values were more consistent than high values. SDANN and SD correlated moderately with HR in both groups (r = 0.50 to 0.64). The CV measure minimizes HR effects on HR variability.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Negative inotropic effects of amiodarone on isolated guinea pig papillary muscle.

STUDY OBJECTIVE: The aim of the study was to investigate the inotropic effects on isolated papillary muscle of acute and chronic exposure to amiodarone. DESIGN: Papillary muscles were obtained from untreated and amiodarone pretreated guinea pigs, and tension recording and conventional glass microelectrode techniques were used to assess the effects of amiodarone. SUBJECTS: Guinea pigs of either sex weighing 300-500 g were used: 65 untreated and 18 amiodarone pretreated (20 mg.kg-1.d-1 for 3 1/2 weeks). MEASUREMENTS AND RESULTS: Acute amiodarone exposure (4.4 X 10(-6)-1.1 X 10(-3) mol.litre-1) caused a concentration dependent negative inotropic effect, which was also frequency dependent (0.1-5 Hz), with greater effect at higher stimulation frequencies. Time to peak tension and resting tension increased, while rate of development and relaxation of twitch contraction were slower. Amiodarone caused a dose dependent depression or abolition of slow response action potentials and of contraction in both untreated and amiodarone pretreated specimens. In amiodarone pretreated muscle, contractile forces did not differ significantly from control preparations. Chronic exposure to amiodarone attenuated the negative inotropic effects of acute amiodarone superfusion. CONCLUSIONS: The negative inotropic action of amiodarone may reflect a decrease in Na+ influx via Na+ channels and/or Ca2+ influx via Ca2+ channels, and/or an impairment of Ca2+ sequestration, alone or in combination. The differences in contractile response in relation to acute and chronic amiodarone exposure may be relevant to clinical actions of amiodarone.

Action Potentials↗
PubMed1990

Dependence of Na-K pump current on internal Na+ in mammalian cardiac myocytes.

Na-K pump current (Ipump) is a function of the intracellular Na+ concentration [( Na+]i). We examined the quantitative relationship between Ipump and [Na+]i in isolated guinea pig ventricular myocytes under steady-state conditions. [Na+]i was controlled and "clamped" at several selected concentrations using wide-tipped pipette microelectrodes, and membrane current was measured using the whole cell patch voltage-clamp technique. Ipump generated at a holding potential of -40 mV was determined by measuring the change in steady-state holding current before and during exposure to dihydroouabain (1 mM); Ipump was measured at 11 levels of [Na+]i ranging from 0 to 80 mM (n = 63) with only one measurement per cell and normalized to cell capacitance to account for differences between myocytes in sarcolemmal surface area. Ipump exhibited a nonlinear dependence on [Na+]i; a Hill analysis of the relationship yielded a half-maximal [Na+]i for pump stimulation of 43.2 mM and a Hill coefficient of 1.53. An alternative analysis of the experimental data was performed assuming that occupation of three internal binding sites by Na+ is required for enzyme turnover. Regression analysis gave the best fit when only two different binding affinities (KD) are postulated. The values are KD1 = 1 mM, KD2 = KD3 = 29 mM. From the analysis using the latter model, the level of [Na+]i at which Ipump saturated closely approximated the theoretical saturation level calculated from published estimates of pump turnover rate and density. The maximal sensitivity of the Na-K pump to changes in [Na+]i occurs when internal [Na+] is within the range for the normal resting physiological level.

Animals↗
PubMed1990

Acetylcholine-sensitive potassium channels in human atrial myocytes.

Single channel recording techniques were used to study acetylcholine (ACh)-sensitive K+ channel activity in human atrial myocytes isolated from specimens obtained during corrective cardiac surgery. Under conditions of cell-attached patch, the presence of ACh in the patch pipette activated K+ channels. Single channel activity occurred in periodic bursts. The channels exhibited a slope conductance of 46 +/- 2 pS inwardly (means +/- SD, n = 4). During a burst, both open and closed time histograms were fitted by a single exponential curve, suggesting the existence of one open and one closed state during a burst. Open probability increased directly with ACh concentration without affecting open time. The channel could be activated by GTP and guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) (in the presence and absence of ACh in the pipette, respectively). Slope conductance, the response to GTP and GTP gamma S, and the independence of activation from Ca2+ were similar to those for other species. In contrast, sensitivity to ACh appeared diminished compared with frog atrial myocytes.

Acetylcholine↗
PubMed1990

Two stable levels of diastolic potential at physiological K+ concentrations in human ventricular myocardial cells.

Cells in many specimens of human ventricle can exhibit either of two stable levels of diastolic potential (DP) when exposed to 4 mM K+ in vitro (i.e., -78 +/- 4 mV or -45 +/- 5 mV, mean +/- SEM). In this report we show that the DP of some partially depolarized human ventricular cells developed a sustained 25-35 mV hyperpolarization (n = 28) when bath K+ concentration (K+b) was raised from 4 to 7 mM. On return of K+b to 4 mM, the DP of most, but not all, of these cells returned to the original depolarized levels. In other cells, the transition between the two levels of DP occurred at variable K+b ranging from 1 to 20 mM. We investigated the ionic mechanism(s) underlying the shifts between the two levels of potential by studying the K+ dependence of the DP in partially depolarized cells in 22 specimens of human ventricle. DP hyperpolarized an average of 25.6 mV (from -44.4 +/- 1.3 to -70.0 +/- 1.3 mV; n = 25) when K+b was increased from 4 to 7 mM. Intracellular K+ activity, determined by K+-selective microelectrodes, was within the range of normal reported for other mammalian species (106.7 +/- 4.4 mM in 4 mM K+; n = 22) and was unaffected by increasing K+b to 7 mM (111.7 +/- 6.6 mM; n = 6). Ba2+ (0.05 mM), a blocker of the inward rectifying K+ current, reversibly prevented the hyperpolarization, whereas acetylstrophanthidin (9 microM) failed to inhibit it. These results suggest that the hyperpolarization was due to a K+-dependent increase in K+ permeability and that electrogenic sodium pumping did not contribute significantly to the process. The ionic basis of the depolarization from a hyperpolarized level of DP also was investigated. Decreasing bath Na+ concentration and exposure to 30 microM tetrodotoxin did not prevent the depolarization. However, the depolarization could be inhibited by 2 mM Mn2+. These findings suggest that the depolarization may have been due to a Mn2+-sensitive inward current.

Diastole↗
PubMed1989

Ionic diffusion in voltage-clamped isolated cardiac myocytes. Implications for Na,K-pump studies.

The whole-cell voltage-clamp technique employing electrolyte-filled micro-pipette suction electrodes is widely used to investigate questions requiring an electrophysiological approach. With this technique, the ionic composition of the cytosol is assumed to be strongly influenced (as result of diffusion) by the ionic composition of the solution contained in the electrode. If this assumption is valid for isolated cardiac myocytes, the technique would be particularly powerful for studying the dependence of their Na,K-pump on the intracellular [Na+]. However, the relationship between the concentrations of ions in the solution filling the electrode and those in the cytosol has not been established. The relationship was investigated to determine in particular whether the [Na+] at the intracellular cation ligand binding sites for the Na-pump ([ Na+]ps) can be set and clamped by [Na+] in the pipette electrode ([ Na+]pip). If [Na+]pip can set and clamp [Na+]ps, this would provide a means for defining the dependence of the Na,K-pump on intracellular [Na+]. The relationship between [Na+]pip and [Na+]ps was analyzed using two approaches. First, a mathematical model of three-dimensional ionic diffusion within a whole-cell patch-clamped myocyte was developed and the effects of experimental parameters on mean [Na+]ps were investigated. When typical experimental values were simulated, the time course to achieve steady state mean [Na+]ps was found to be most sensitive to variations in electrode pore size, cell length and the Na+ pumping rate, but at steady state, mean [Na+]ps varies from [Na+]pip by 5% or less depending on pump rate. Second, to provide experimental support for the validity of the simulations, isolated ventricular myocytes were voltage-clamped and the reversal potential for the Na current was determined in order to estimate steady state intracellular [Na+]. The results of the mathematical and experimental analyses suggest that steady state [Na+]ps can be regulated by the [Na+] in suction pipette electrodes. These findings, while also having a broader significance, indicate for isolated cardiac myocytes that whole-cell suction micro-electrodes can provide a means to assess the dependence of the Na,K-pump on [Na+]ps.

Algorithms↗
PubMed1989

Inhibition of Na-K pump current in guinea pig ventricular myocytes by dihydroouabain occurs at high- and low-affinity sites.

Binding of cardiac glycosides to the Na+,K+-dependent ATPase has been shown to occur at both high- and low-affinity sites. However, recent reports suggest that glycoside-induced inhibition of electrogenic Na-K pump current occurs with simple first-order binding kinetics at relatively low-affinity sites. This implies that high-affinity binding sites have little to do with Na-K pump inhibition during exposure to cardiac glycosides. To better understand the role of the high-affinity site, we investigated the concentration dependence of Ipump inhibition by dihydroouabain (DHO) in guinea pig ventricular myocytes through use of wide-pore patch pipettes to "fix" internal Na+ activity at approximately 30 mM and to voltage clamp at -40 mV (T = 34 degrees C). DHO was found to have no effect on membrane conductance at a holding potential of -40 mV. Holding current was monitored and the difference between steady-state holding current before and during external exposure to nine concentrations (range, 0.01-1,000 microM) of DHO was measured and normalized to cellular membrane capacitance. The concentration dependence of the inhibition of Na-K pump current was biphasic and well fitted to a two-binding site model with inhibitory KD values of 0.05 microM and 64.5 microM. This is consistent with previously reported 3H-ouabain binding studies in guinea pig myocardium. These findings indicate that the electrogenic properties of the Na-K pump can be inhibited by glycoside binding to both high- and low-affinity sites.

Animals↗
PubMed1989

Amiodarone blocks calcium current in single guinea pig ventricular myocytes.

Ca++ current (lca) block by amiodarone and the underlying mechanisms thereof were investigated in guinea pig single ventricular myocytes using the single suction pipette whole cell voltage clamp method. The dose-response curve revealed a 1:1 stoichiometry for binding of amiodarone to its receptor with an apparent dissociation constant of 5.8 microM in the resting state. Amiodarone, 5 microM did not significantly alter the time course of ICa decay, but did shift the steady-state inactivation curve for lca in the hyperpolarizing direction by 9.2 +/- 3.1 mV. Development of block at depolarized potentials was voltage-dependent between -20 and 10 mV with time constants of 112 +/- 33 and 755 +/- 212 msec at 10 mV. In the presence of 0.2 microM amiodarone, recovery from inactivation was fitted by a double exponential most likely indicating rapid recovery of the drug-free Ca++ channels and slow recovery of the drug-associated Ca++ channels with time constants of 44 +/- 12 and 108 +/- 403 msec, respectively, at -80 mV. The proportion of the current recovering via the slow phase was 36 +/- 7%. By using this value, we estimated the dissociation constant in the inactivated state to be 0.36 microM. Amiodarone's marked use-dependent block of lca is explicable in terms of its high affinity for, and slow dissociation from, Ca++ channels in the inactivated state. These results suggest that amiodarone blocks lca in both the resting and inactivated states.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗
PubMed1988

Low heart rate variability and sudden cardiac death.

Our results indicate the following. 1. HRV is markedly depressed in inducible SCD survivors, a group at high risk of a subsequent episode of SCD. 2. Studies on patients who developed SCD during Holter monitoring indicate that HRV is depressed prior to SCD. 3. HRV is markedly depressed in inducible "asymptomatic ventricular ectopy" patients, with the degree of reduction paralleling that observed in inducible SCD survivors. In contrast, HRV of noninducible "asymptomatic ventricular ectopy" patients did not differ statistically from normal. 4. The findings provide additional evidence that cardiac parasympathetic function is depressed in patients prone to development of SCD and that altered autonomic function contributes to the development of electrical instability in such individuals. This accords with findings that such risk factors for sudden death as coronary artery disease, myocardial infarction, congestive failure, and hypertension all have been associated with reduced parasympathetic activity or attenuation of parasympathetically mediated reflexes. It is tempting to believe that diminished cardiac parasympathetic activity, perhaps by failing to counter excess sympathetic activity, contributes to SCD. 5. It may be inferred that HRV measurements have potential for serving as an independent predictor of inducibility in response to programmed ventricular stimulation and that they could represent a noninvasive screen for patients referred for evaluation of risk of SCD because of asymptomatic ventricular ectopy or other causes. In a larger sense, the data suggest that HRV measurements may provide information pertinent to the identification of individuals at increased risk of SCD that is independent of that provided by other risk factors. Given the human and economic stakes, further study is clearly warranted.

Death, Sudden↗
PubMed1987

Amiodarone-induced block of sodium current in isolated cardiac cells.

Sodium current (INa) block by amiodarone (AMI) was investigated in isolated single Purkinje and ventricular myocardial cells using the single suction-pipette voltage-clamp technique. AMI produced marked resting block that was enhanced at low holding potentials, findings consistent with a shift in the steady-state INa availability curve to more negative potentials (-16 +/- 3 mV). Resting block was not associated with any change in the time course of INa decay during a depolarizing clamp step. AMI also produced use-dependent block in conjunction with increases in rate (0.5-5.0 Hz) and pulse duration (2-200 msec). These changes are consistent with a slowing of the recovery from inactivation of the sodium channel. Brief depolarizing pulses produced little use-dependent block, suggesting that the onset of drug-induced block is slow. Thus, AMI blocks INa and shifts the availability curve in isolated myocytes, both of which contribute to the net tonic block. The results suggest that both rested state and inactivated state sodium channel block are factors in AMI's antiarrhythmic efficacy.

Amiodarone↗
PubMed1986

Characterization of a sodium pump-induced hyperpolarization in isolated human atrium.

Specimens of right atrial appendage from 106 patients were incubated in cold Tyrode solution, and transmembrane resting potentials (Em) were recorded during rewarming at selected temperatures. Rewarming caused a transient hyperpolarization to develop. The hyperpolarization had a temperature threshold between 17 and 22 degrees C and was inhibited by acetylstrophanthidin. Acetylcholine (ACh) induced a depolarization during early rewarming in 7, 10, 20, and 40 mM K+, indicating that Em hyperpolarized to a potential negative to the equilibrium potential for K+. ACh had no effect after some decline of Em, and hyperpolarization was induced by ACh when Em had reached steady state. The relationship between [K+] in the bulk phase of the superfusate [( K]b) and the "reversal potentials" for the ACh effect was log linear and had a slope of 61.7 mV per tenfold change in [K]b. The relationship between [K]b and hyperpolarization was studied in the presence of 0.5 mM Ba2+. The apparent [K]b resulting in half-maximal pump-induced hyperpolarization was 1.3 mM. The data indicate that human atrium can pump Na+ electrogenically and that the characteristics of the Na+ pump-induced hyperpolarization resemble those described for cardiac tissue from several other mammalian species.

Aged↗
PubMed1979

Pseudo atrioventricular block.

Pseudo first- and second-degree atrioventricular (AV) block can occur due to depressive effects of concealed junctional discharges on AV conduction of sinus impulses. Pseudo AV block is not indicative of a primary impairment of AV conduction and is reversible by interventions that suppress ectopy.

Electrocardiography↗