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Biomedical subjects

K R Courtney

Publications and source records attributed to K R Courtney.

At least 37 records · Page 2Linked to original sources
PubMed1983

Modulated anticonvulsant block of sodium channels in nerve and muscle.

We have looked at several anticonvulsant drugs regarding their potency for basal block of sodium channels in both skeletal muscle and myelinated nerve preparations under voltage clamp conditions. There is an inverse relationship observed between the half-blocking concentration of each drug and its lipid distribution coefficient. Furthermore the anticonvulsants which are cyclic amides show a systematically weaker potency for blocking channels than do local anesthetics (linear amides) of comparable solubility. Additional kinetic characterizations of drug block are described that may contribute to accumulation of frequency-dependent block and to the appearance of 'inactivation shift' phenomena. Finally, evidence is provided showing that phenytoin and carbamazepine (as well as phenobarbital) selectively block the inactive form of closed sodium channels, thus giving these anticonvulsants a capability for selective action in depolarized tissue.

Anesthetics, Local↗
PubMed1983

Quantifying antiarrhythmic drug blocking during action potentials in guinea-pig papillary muscle.

This report examines the blocking effects that several antiarrhythmic drugs have on rapid upstroke velocities of action potentials recorded from guinea-pig papillary muscle. A mathematical analysis is developed, that measures an effective "blocking rate' that acts during the action potential with the purpose being to compare these blocking rates for different drug structures. There is a systematic, inverse relationship observed between the concentration of amide-linked drug that must be applied in order to produce a given blocking effect and the lipid distribution capability of each drug. Ether-linked drug structures are relatively more potent than amide-linked drugs in this context.

Action Potentials↗
PubMed1982

Voltage-sensitive dyes. Discerning contraction and electrical signals in myocardium.

Muscle contraction can introduce artifact in attempted optical measurements of the action potential in heart tissue stained with voltage-sensitive dyes. Using rabbit sinus node and atrial tissue in vitro, we found that the voltage-sensitive part of the optical signal remains relatively unchanged by variations in the rate of external stimulation or by the application of transmural stimulation (TS), while the contraction-related component can be significantly increased by these same interventions. The relative contributions of membrane voltage and contraction to the optical signal can thus be determined. In particular, the rapid upstroke component of the action potential can be easily identified using this technique.

Animals↗
PubMed1981

Comparative actions of mexiletine on sodium channels in nerve, skeletal and cardiac muscle.

Mexiletine's actions on voltage-clamped sodium channels of frog myelinated nerve and skeletal muscle are described. Mexiletine blocks half the sodium channels (infrequent depolarizations) of single myelinated nerves at a 83 micro M concentration while only 26 micro M is required to do the same in skeletal muscle preparations where similar vaseline-gap techniques are utilized. Mexiletine's potency for block of sodium current in nerve is clearly related to its lipid distribution characteristics given proper consideration of the drug class to which it belongs. Hyperpolarizing prepulses, which are typically used to remove normal sodium inactivation, appear to reduce drug blocking potency suggesting that noninactive channels have a considerably lower affinity for the drug than do inactive channels. Direct evidence supporting selective drug block of inactive channels is also given. In addition the effects of this drug on sodium channels of guinea pig papillary muscle have been studied using measurements of maximum upstroke velocity of intracellularly recorded action potentials. In these myocardial studies 5 to 20 micro M mexiletine depressed upstroke velocity of papillary muscle action potentials in a frequency-dependent fashion. No basal (nonfrequency-dependent) block was observed in heart at these therapeutic concentrations of mexiletine. comparisons are made between skeletal and cardiac muscle effects of mexiletine, especially relating to the important role played by sodium channel inactivation.

Action Potentials↗
PubMed1980

Structure-activity relations for frequency-dependent sodium channel block in nerve by local anesthetics.

Different local anesthetic drug structures differ significantly in their capabilities for producing frequency (f)-dependent sodium channel block. Voltage-clamped frog myelinated nerve preparations have been utilized in order to investigate structure-activity relations for several modes of local anesthetic drug action, including the kinetics of f-dependent excitability block. Lipid solubility has been shown to be an important determinant of closed channel blocking potency, at least within the amide-linked series of local anesthetics. The ester-linked (beta blockers) and ester-linked local anesthetics appear to be relatively more potent at closed channel block than drugs of the amide-linked series. In addition, f-dependent block increments are greater for drugs of lower lipid solubility, supporting the "modulated drug receptor" hypothesis that intracellular drug forms participate in the open channel binding involved in f-dependent blocking. Finally, molecular size has been shown to be a very important determinant of closed channel block escape rates with smaller drug structures showing faster escape rates from f-dependent increments in channel block.

Anesthetics, Local↗
PubMed1979

Extracellular pH selectively modulates recovery from sodium inactivation in frog myelinated nerve.

The Hodgkin-Huxley kinetic parameters, alpha h and beta h, which govern the rate of recovery from and development of sodium channel inactivation, respectively, have been measured as a function of membrane potential and external pH using a three-pulse protocol. alpha h but not beta h is substantially accelerated by reducing external pH from 7.4 to 6.4. The alpha h vs. voltage curve appears to be selectively shifted in the depolarizing direction by approximately 12 mV for this pH change, giving an apparent, h infinity curve shift of approximately 6 mV in the same direction (less inactivation).

Animals↗
PubMed1979

Imipramine affects autonomic control of sinoatrial rate in isolated right atrial preparations.

The effects of imipramine on sinoatrial rate and chronotropic responses to transmural stimulation (TS) were studied in the isolated guinea-pig right atrial preparation. The negative chronotropic response (cholinergically mediated rate decrease) to TS was progressively inhibited by imipramine (5 x 10(-6) M). This inhibition can be attributed directly to an "atropine-like" effect of this drug. The positive chronotropic response (adrenergically mediated rate increase) to TS was markedly potentiated by imipramine at similar therapeutic doses; higher doses (5 x 10(-5) M) substantially depressed this rate response. This depression of the adrenergic response to TS does not appear to be the result of a blockade of beta adrenergic receptors since imipramine still potentiated the rate increase in response to exogenous norepinephrine at doses where no TS response remained. Basal spontaneous rate was also depressed by imipramine at high doses (5 x 10(-5) M), both in the absence and presence of autonomic blockers.

Acetylcholine↗