PubMed Health⌕ Search

Biomedical subjects

J Weirich

Publications and source records attributed to J Weirich.

31 records · Page 2Linked to original sources
PubMed1989

Modelling frequency- and voltage-dependent effects of a class I antiarrhythmic drug (nicainoprol) on Vmax of the cardiac action potential from guinea-pig papillary muscle.

Frequency- and voltage-dependent effects of a class I antiarrhythmic agent (nicainoprol) on the maximal upstroke velocity (Vmax) of the action potential of guinea-pig papillary muscle are compared with the effects predicted by a kinetic model of frequency- and voltage-dependent block of fast sodium channels. The model is based on the guarded-receptor hypothesis, which assumes a constant affinity binding site with the drug access to and egress from the binding site being controlled by the channel conformational state. At normal resting membrane potential (RMP approximately -86 mV) nicainoprol (3.3 x 10(-6) mol/l and 10(-5) mol/l) causes no Vmax-reduction after a resting period (i.e. no resting block) but a frequency-dependent decrease of Vmax (frequency-dependent block), which saturates at above 2.0 Hz. Both, resting and frequency-dependent block strongly depend on the RMP in a way that the frequency-dependent block decreases with depolarizing RMP while the resting block increases. Development of and recovery from frequency-dependent block is faster at depolarized RMP. These results can be interpreted in terms of the guarded-receptor hypothesis with nicainoprol preferentially binding to inactivated sodium channels. All its effects on Vmax can be fully described by only three model parameters: a binding rate coefficient (kB = 8.49 x 10(3) mol-1.1.s-1), an unbinding rate coefficient (k-B = 6.24 x 10(-2).S-1), and a parameter with the meaning of an electrical location of the binding site (about 35% on the way through the membrane field from the extracellular surface).

Action Potentials↗
PubMed1988

Evaluation and interpretation of voltage- and frequency-dependent electrophysiologic effects of a new class I antiarrhythmic agent (nicainoprol) on guinea pig papillary muscle and isolated heart.

Frequency- and voltage-dependent electrophysiologic effects of a chemically novel compound, nicainoprol, were evaluated by recording transmembrane action potentials (APs) from papillary muscles and electrograms (EGs) from isolated perfused hearts of guinea pigs. At 0.2 Hz stimulation, nicainoprol (3.3 x 10(-6) M and 10(-5) M) significantly reduces the maximal upstroke velocity (Vmax) of APs without significant change in resting membrane potential (RMP), functional refractory period (FRP), and action potential duration. Nicainoprol prolongs the spread of excitation but has little effect on the duration of the ventricular EG. The Vmax depression is frequency dependent in the range of 0.02-2.5 Hz, showing saturation at higher frequencies. Under resting conditions, nicainoprol (3.3 x 10(-6) M and 10(-5) M) has no effect on Vmax. The onset of frequency-dependent Vmax reduction follows monoexponential time courses with rate constants of 0.053 +/- 0.007 AP-1 (3.3 x 10(-6) M) and of 0.066 +/- 0.005 AP-1 (10(-5) M) at 1 Hz. Vmax recovers from frequency-dependent depression with time constants of 45.4 +/- 3.2 s (3.3 x 10(-6) M) and 48.4 +/- 3.5 s (10(-5) M). Nicainoprol significantly shifts the Vmax-RMP relation in hyperpolarizing direction by 2.6 +/- 1.1 mV (3.3 x 10(-6) M) and 5.4 +/- 1.3 mV (10(-5) M) at membrane potentials where Vmax is half maximal. It is concluded that nicainoprol can be classified as a class 1C drug and does preferentially bind to inactivated sodium channels with a dissociation constant of about 10(-5) M.

Action Potentials↗
PubMed1988

Effects of polidocanol as a constituent of a venous sclerosing agent on cardiac electrical activity. Studies on the isolated perfused heart and papillary muscle of the guinea pig and on the isolated sinus node of the rabbit.

The effects of a frequently used sclerosing agent (Sotravarix 6%, main constituent polidocanol 60 mg/ml = 0.1 mol/l) on the electrical activity of the isolated perfused guinea pig heart and on transmembrane potential of isolated papillary muscle and sinus node were studied. Application of the sclerosing agent in a dilution of 1:40,000 (corresponding to polidocanol 2.6 x 10(-6) mol/l) caused a significant decrease in frequency (-27%) and (at constant frequency) a significant delay of the atrioventricular as well as of the intraventricular conduction (+105% or + 210%, resp. n = 4). These effects were only slightly reversible in a 30 min wash-out period. In the isolated papillary muscle, the sclerosing agent (dilution 1:10,000; polidocanol 1 x 10(-5) mol/l) decreased the maximum rate of rise of the action potential and shortened its duration, both by about 10%. In the isolated sinus node the same dilution decreased the spontaneous rate by about 8% mainly by reducing the diastolic depolarization rate (-18%). The effects of the sclerosing agent are attributable to the influence of polidocanol and consist in a blockade of the fast sodium channels (local anesthesia) and in additional inhibitory effects on calcium and/or potassium conductance.

Action Potentials↗
PubMed1982

Electrophysiological studies on effects of AQ-A 39 in the isolated guinea pig heart and myocardial preparations.

An isolated perfused hearts as well as in papillary muscles and in Purkinje fibres, the influence of 5,6-dimethoxy-2(3[alpha-(3,4-dimethoxy)phenylethyl)-methylamino]propyl)phthalimidine hydrochloride (AQ-A 39) on the electrical activity was examined (concentration range of AQ-A 39 2.15--10.7 x 10-(5) mol/l). In the isolated heart AQ-A 39 (2.15 x 10(-5) mol/l) reduced the sinus frequency by about 50%. Higher concentrations (up to 10.7 x 10(-5) mol/l) exerted only little additional influence. Similar effects of AQ-A 39 were observed in Ba2+ induced pacemakers in the ventricular myocardium. In Purkinje fibres (K+e 2.7 x 10(-3) mol/l) AQ-A 39 (2.15 x 10(-5) mol/l) reduced the rate of spontaneous discharge to a considerable extent. In papillary muscles as well as in Purkinje fibres the terminal phase of repolarization of the action potential was markedly prolonged without a detectable influence on the resting potential or the maximal rate of rise (Vmax). In the Ba2+ treated depolarized myocardium Vmax was considerably reduced by AQ-A 39. The effects of AQ-A 39 are discussed in view of their ionic mechanisms as well as of the therapeutic application of the drug.

Action Potentials↗
PubMedDate not supplied

Frequency-dependent action of antiarrhythmic drugs: the useful concept of periodical ligand binding.

The action of most antiarrhythmic drugs which block cardiac ionic channels depends on heart rate, which is established as use- or frequency-dependence. This property is consistent with periodical drug (ligand) binding to channel binding sites which are transiently available during the excitation sequence of cardiac tissue. Antiarrhythmic drugs differ with respect to their binding and unbinding kinetics, i.e., with respect to their blocking and unblocking kinetics. This gives rise to different block-frequency relations and onset-kinetics of frequency-dependent ion channel blockade. Antiarrhythmic drugs have never been systematically compared with regard to their block-frequency relations. However, both the onset-kinetics as well as the block-frequency relation are essential in characterizing the frequency-dependent drug action, since both may be predictors of the anti- and pro-arrhythmic potential of antiarrhythmic drugs.

Animals↗
PubMedDate not supplied

Factors determining the susceptibility of the isolated guinea pig heart to ventricular fibrillation induced by sinusoidal alternating current at frequencies from 1 to 1000 Hz.

We determined the threshold for ventricular fibrillation by means of sinusoidal alternating current (AC) from 1 to 1000 Hz on isolated perfused guinea pig hearts. Current was applied via electrodes located in the aorta and at the apex of the heart. The duration of current flow was kept constant at 1 s. Electrical activity was recorded with epicardial electrodes attached to the ventricles. Additional experiments were performed in isolated papillary muscles with intracellular microelectrodes. The fibrillation threshold, expressed as peak-to-peak current strength, attains a minimum at about 30 Hz and rises by a factor of 5 at 1 Hz, and by a factor of 14 at 1000 Hz. In the frequency range from 30 to 1000 Hz the rise of the fibrillation threshold can be attributed to the increase of the threshold for stimulation due to the progressive shortening of the AC periods. Thus no change of the fibrillation threshold occurs if DC pulses of constant duration are used in the same range of frequencies. Below 30 Hz there is only a slight increase of the threshold for stimulation, which cannot entirely account for the rise of the threshold for fibrillation. A likely cause of the reduced susceptibility of the heart to fibrillation at the lower frequencies is the reduced number of extrasystoles preceding the onset of fibrillation, which results in a less pronounced state of inhomogeneous excitability.

Acoustics↗
PubMedDate not supplied

Influence of direct current on the electrical activity of the heart and on its susceptibility to ventricular fibrillation.

Isolated perfused guinea pig hearts (Langendorff preparation) were used to study the influence of direct current (DC) on the shape of the electrogram and to determine the thresholds for extrasystoles and for fibrillation. DC impulse durations ranged between 30 ms and 5 s. During DC flow through the heart, marked deformations of the electrogram occur mainly concerning the repolarization phase and increasing with growing current strength. At an intensity of twice the diastolic threshold for stimulation, constant DC induces extrasystoles, which are suggested to result from an enhancement of the intrinsic automatic activity by cathodal polarization. Compared with the diastolic threshold for stimulation, the threshold for fibrillation is higher by a factor of about 15. The curve relating the threshold for fibrillation to the impulse duration shows a marked decline between 30 ms and 60 ms, followed by a slight increase and adjustment to a constant level beyond about 80 ms. In the used setup, the threshold for fibrillation is independent on the reversal of polarity of the electrodes. Long-lasting DC pulses are able to induce fibrillation even if they are switched on in the absolute refractory period of a normal beat. Application of 50-Hz alternating current revealed a higher threshold for stimulation and a three times lower fibrillation threshold compared with the effects of DC in the same heart.

Animals↗
PubMedDate not supplied

Effects of mexiletine on steady-state characteristics and recovery kinetics of V max and conduction velocity in guinea pig myocardium.

We studied the effect of the antiarrhythmic compound mexiletine on the maximal rate of rise (V max) on the action potential and on conduction velocity in isolated papillary muscles of guinea pigs. Action potentials and V max were measured by means of conventional microelectrodes. The conduction velocity was determined from extracellular recordings Mexiletine (concentrations, 4.6 x 10(-5) and 1.15 x 10(-4) mol/L) caused a depression of V max that depended on the condition examined. The h infinity curve relating V max of the action potential to the resting membrane potential was shifted along the voltage axis to more negative membrane potentials. Qualitatively equal effects were observed on the curve of membrane responsiveness relating V max to the membrane potential during the phase of repolarization of the preceding action potential. Eventually, marked prolongation of the recovery kinetics of V max by mexiletine, as well as frequency-dependent reduction of V max, could be demonstrated. The action of mexiletine on conduction velocity was very similar to its influence on V max. Thus, prolongation of the recovery kinetics was found of about the same magnitude as that measured in V max. Similarly, in experiments with K + -induced depolarizations, a dependence on the membrane potential of the action of mexiletine on the conduction velocity could be demonstrated. The results suggest that mexiletine may exert antiarrhythmic effects mainly in damaged cardiac cells exhibiting a moderately reduced resting potential.

Action Potentials↗