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Biomedical subjects

K R Courtney

Publications and source records attributed to K R Courtney.

At least 19 recordsLinked to original sources
PubMed1992

d-Sotalol has opposite effects from encainide and propafenone on the proportion of episodes of ventricular tachycardia that are sustained in an experimental substrate for reentry.

Conversion of sustained ventricular tachycardia (VT) to nonsustained VT may be a potent mode of antiarrhythmic drug action, whereas a drug's conversion of nonsustained VT to sustained VT could produce serious clinical complications. We tested the effects of two class Ic drugs [encainide (1, 2, and 4 microM) and propafenone (0.1, 0.3, and 0.6 microM)) and a class III drug (d-sotalol (25, 50, and 100 microM)] on the proportion of VT episodes that were sustained (duration greater than 1 min) in an acute in vitro model of reentrant VT in left ventricular (LV) epicardium: a Langendorff-perfused rabbit heart whose LV endocardial and midwall cells have been killed by a selective freezing procedure. Multiple VT episodes were generated by increasing the stimulation rate until self-sustained activity occurred. Some episodes spontaneously terminated in less than 1 min; others lasted longer and were terminated by transient cooling of the heart. Both encainide and propafenone increased the fraction of episodes of sustained VT in all preparations; the increase was significant in 4 of the 5 encainide preparations (p less than 0.02) and 4 of the 5 propafenone preparations (p less than 0.003). d-Sotalol, on the other hand, decreased the fraction of sustained VT in all preparations; the decrease was significant (p less than 0.002) in 4 of the 5 preparations. All 3 drugs increased the basic cycle length of pacing at which VT was induced and the cycle time of the resulting VT. These results of this new assay of drug action may be related to the drugs' different mechanisms of prolonging refractoriness.

Animals↗
PubMed1992

Gate-dependent blockade of sodium channels by phenothiazine derivatives: structure-activity relationships.

Voltage-clamp studies of myelinated nerve fibers that are designed to determine structural criteria regarding selective drug blocking of open and inactive states of the sodium channel are described. A series of phenothiazines were studied. It was shown that two of these drugs (ethmozine and ethacizine, at 5 microM) require open channels for blocking action and the other two (chlorpromazine and chloracizine, at 5 microM) can effectively block inactive channels. A size criterion, which looks at the spanning width at the aromatic end of these molecules, can explain this qualitative difference in drug action. Other important differences in the action of these four drugs are described, including their rates of development of drug block and removal of drug block. Relevant critiques of proposed structure-activity hypotheses are given.

Animals↗
PubMed1990

Reentrant tachycardia in a thin layer of ventricular subepicardium: effects of d-sotalol and lidocaine.

Ventricular tachycardia (VT) was induced by premature stimulation or fast pacing in 14 Langendorff-perfused rabbit hearts whose left ventricular endocardial and intramural cells had been selectively killed by freezing. VTs were caused by apparent reentrant excitation in the surviving thin (1 mm thick) subepicardial layer of anisotropically oriented cells having ostensibly normal membrane characteristics. During VT, 100 microM d-sotalol (seven hearts) or 30 microM lidocaine (seven hearts) was added to the perfusate. Electrophysiological variables were measured before and during drug exposure at both slow (S1 = 300 ms) and fast (S1 = 150-180 ms) pacing rates. Sotalol prevented VT reinduction in six of seven preparations, compared to only two of seven with lidocaine. Lidocaine prolonged the functional refractory period (FRP) and slowed conduction velocity (CV). Lidocaine prolonged the wavelength of the cardiac impulse (= FRP x CV) by 18% at slow rates but reduced it by 21% at fast rates. Sotalol, however, since it increased the FRP without reducing CV, caused wavelength prolongation at both rates (43% at slow rates, 26% at fast rates). Thus, this VT model may provide an important contrast of class I and class III drug action, with the drug effects on wavelength predicting susceptibility to VT induction.

Action Potentials↗
PubMed1990

Sodium channel blockers: the size/solubility hypothesis revisited.

The influence that drug size has on the rate of recovery of sodium channels in heart tissue has been reexamined. A drug dimension that looks at the end-on view of the molecule provides a substantially better explanation for the size dependence of repriming kinetics than does molecular weight. A quantitative model for the recovery time is provided that couples proton exchange kinetics with a drug size-dependent process that is related to recovery from inactivation. Drugs having a wider span at their aromatic end produce more slowing of the rate of recovery from inactivation.

Adrenergic beta-Antagonists↗
PubMed1989

Use-dependent block of single sodium channels by lidocaine in guinea pig ventricular myocytes.

Single sodium channel openings have been recorded from cell-attached patches of isolated guinea pig ventricular myocytes. A paired pulse protocol was used to test the hypothesis that channel openings are required for lidocaine block. While the averaged ensemble current during the test pulse was much reduced, there was no correlation between the appearance of channel openings during the conditioning pulse and the subsequent test pulse. Analysis of single channel records demonstrated that the unit conductance of open channels was not changed by lidocaine. The block of ensemble INa was explained by roughly equal reductions in number of open channel events, and in the average duration of opening for each event. These results suggest that lidocaine binding to Na+ channels is dependent upon voltage, but may occur before channel opening. A lidocaine-modified channel can still open, but will be less likely to remain open than a drug-free channel. These results are consistent with block of a pre-open state of the channel.

Animals↗
PubMed1988

Bupivacaine is an effective potassium channel blocker in heart.

The local anesthetic agent bupivacaine increases action potential duration in isolated frog atrial myocytes, and blocks two potassium conductances, IK and IK1. The effective concentrations, particularly for IK, are similar to those which depress the sodium conductance. Potassium channel block may thus contribute to bupivacaine's reported cardiotoxicity.

Action Potentials↗
PubMed1988

Why do some drugs preferentially block open sodium channels?

It has been known for some time now that many antiarrhythmics and local anesthetics block sodium channels especially when they are depolarized. Two major phases of channel blocking occur, one "transient" and one "maintained" during the depolarization. Open channel blocking is thought to occur when intracellular forms of drug access the open channel via an aqueous pathway. This early phase of drug access is transient in the sense that opening of channels occurs for only a brief period of time (a few ms) after a depolarizing stimulus. There is also drug access to the receptor during maintained depolarizations, such as during the plateau phase of cardiac action potentials. New results provided by Kodama et al. regarding these two phases of drug blocking, transient and maintained, have prompted the structural analysis presented here. A surprisingly simple size criterion is developed that explains why certain drugs cannot use the pathway that is available during maintained depolarizations.

Anti-Arrhythmia Agents↗
PubMed1988

Local anesthetics.

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Anesthetics, Local↗
PubMed1988

pH and voltage dependence of INa recovery kinetics in atrial cells exposed to lidocaine.

Lidocaine blocks sodium channels during depolarizations. The rate of recovery (repriming) of drug-blocked channels between depolarizations is slowed by both membrane depolarization and by acidification. This modulation of recovery kinetics was studied using a single-electrode voltage clamp on atrial cells isolated from the bullfrog. The pH dependence of recovery from inactivation, in drug-free conditions, is opposite to that observed in myelinated nerves; recovery occurs faster at higher pH levels in these cardiac preparations. The combined pH dependence and voltage dependence of repriming kinetics during lidocaine treatment can be explained by assuming that channels occupied by neutral drug can reactivate most readily at a rate that appears to be coupled to recovery from channel inactivation.

Animals↗
PubMed1987

Progress and prospects for optimum antiarrhythmic drug design.

Different class I drugs slow down to differing degrees the rate at which sodium channel availability, hence excitability, recovers after action potentials. Drugs that produce longer recovery half-times generally produce greater proarrhythmic side effects. Increased lipid solubility may improve a drug's "potency" for blocking channels yet with implications for adverse effects. Drug action may be potentiated in depolarized and acidotic tissue via modulation of the recovery process. A knowledge of molecular properties of antiarrhythmic drugs helps to define these modes of interaction with the sodium channels and, hence, will help in future drug design. Prospects for improving our understanding of ionic events involved in the repolarization phase of cardiac action potentials are also outlined. The development of successful strategies for controlling reentrant arrhythmias will probably require a thorough understanding of both class I and class III drug actions at the level of the membrane ion channel.

Animals↗
PubMed1987

Design of a multi-point laser scanned optical monitor of cardiac action potential propagation: application to microreentry in guinea pig atrium.

A system is described that uses a scanned laser beam to excite voltage-dependent fluorescence in cardiac muscle and thereby monitors propagation of the action potential. Details of the optical and electronic design are presented along with descriptions of the system performance. The scanner can monitor membrane voltage activity from 64 points simultaneously at a sample rate of 1000 samples/sec. Results are presented from a laser scan of arrhythmic guinea pig left atrium showing the complete evolution, from initiation to termination, of a functional microreentry induced by a premature stimulus.

Action Potentials↗
PubMed1987

Quantitative structure/activity relations based on use-dependent block and repriming kinetics in myocardium.

Different class 1 antiarrhythmic drugs have differing capabilities for producing a rate-dependent modulation of cardiac excitability. Structural hypotheses regarding these drug actions, both in terms of their widely differing abilities for blocking myocardial sodium channels during individual action potentials and their associated repriming kinetics, have been proposed. Recent studies on the channel blocking actions of these drugs, assessed using maximum upstroke velocities of intracellularly recorded actions potentials (APs), are reviewed in order to test these hypotheses. The size/solubility hypothesis, which says that smaller antiarrhythmic drugs with good lipid distribution capabilities provide more rapid repriming kinetics, is supported by results on 36 of 40 drugs having molecular weights up to 350. Blocking abilities during individual APs are also examined, with lipid distribution coefficients describing this blocking capability within selected classes of drug structures. However overall "potency" must include consideration of drug repriming kinetics which allows for accumulation of excitability block. Evidence which suggests that the kinetically slower drugs may be more cardiotoxic (arrhythmogenic) is presented. A model for the steep size dependence of drug recovery times is provided by a cylindrical pore having a radius of 4.1 Angstroms. Finally the different drug pools that drive the hypothesized hydrophilic and hydrophobic pathways to the receptor are considered in order to explain why drug lipid distribution characteristics might play a role in recovery kinetics.

Action Potentials↗
PubMed1986

Modeling ion channel blockade at guarded binding sites: application to tertiary drugs.

Excitable membranes exposed to sodium channel blocking agents (D; local anesthetics and antiarrhythmic drugs) show a progressive reduction of peak sodium current when repetitively depolarized (use dependence). Thus, with repetitive excitation, use dependence reflects a net rightward shift in the balance between unblocked channels (U) and blocked channels (B): U + D in equilibrium with B. The modulated receptor hypothesis (a 7-parameter model) has been proposed to account for this shift and is based on a channel lumen binding site whose affinity varies with channel state and where drug-complexed channels exhibit modified inactivation gate kinetics. Alternatively, we consider use-dependent binding as the result of transient access to a constant-affinity binding site. In this setting, the channel gate conformation is viewed as controlling the flux of drug as it diffuses between drug pools and the binding site. Apparent variation in binding rates is therefore considered the result of variations in the fraction of accessible sites. This guarded receptor hypothesis, with three fewer parameters, is able to predict apparent changes in channel binding and apparent shifts in channel inactivation without incorporating modified gating parameters in drug-complexed channels. Furthermore, with this model one is able to characterize both relaxation kinetics and channel blockade associated with tertiary amines as well as hydrophobic and hydrophilic agents. The pH dependence of repriming rates is utilized to estimate several of the important parameters associated with this simplified hypothesis.

Amines↗