The blockade of $$\dot V_{\max }$$ of the atrioventricular action potential produced by the slow channel inhibitors verapamil and nifedipine

Kohlhardt, M.; Haap, K.

doi:10.1007/bf00505314

Cited by 23 publications

(7 citation statements)

References 24 publications

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“…However, heart rate and sympathetic, parasympathetic, and intrinsic baroreflex activity each influence atrioventricular conduction as well. The inhibitory effects of verapamil on the slow inward calcium current in cardi-ac tissues have been shown to be both use and frequency dependent (52,53). The use-dependent properties dictate that more depression of atrioventricular nodal transmission is produced by calcium channel blockade as the stimulation rate is increased (52,53).…”

Section: Discussionmentioning

confidence: 99%

Verapamil Pharmacodynamics and Disposition in Young and Elderly Hypertensive Patients

Abernethy¹,

et al. 1986

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We studied verapamil pharmacodynamics and disposition in seven young, ten elderly, and seven very elderly hypertensive males. Maximal decrease in mean (+/- SD) blood pressure tended to be greater in the elderly (-13.5 +/- 5.9 mm Hg) and the very elderly patients (-15.9 +/- 9.6 mm Hg) compared with that in young patients (-7.3 +/- 4.2 mm Hg). Disparate effects on heart rate responses were noted with reflex tachycardia in young patients compared with decreases in heart rate among the elderly and very elderly. Sensitivity to verapamil-induced prolongation in electrocardiographic P-R interval was less in the very elderly, and maximal prolongation in P-R interval induced by verapamil was less in the elderly and very elderly. Verapamil disposition was also age related. Total verapamil clearance was decreased in elderly (10.5 +/- 3.5 mL/min X kg; p less than 0.05) and very elderly (8.0 +/- 4.1 mL/min X kg; p less than 0.01) when compared with that in young patients (15.5 +/- 4.5 mL/min X kg). Elimination half-life was prolonged in the elderly (7.4 +/- 3.3 h; p less than 0.01) and very elderly (8.0 +/- 1.2 h; p less than 0.01) compared with that in young patients (3.8 +/- 1.1 h). Our data indicate age- and hypertension-related physiologic changes result in predictable pharmacokinetic changes. However, the complex alterations in verapamil pharmacodynamic responses indicate an interaction between direct drug effects and age- and disease-related changes in hemodynamic and autonomic nervous system function.

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Section: Discussionmentioning

confidence: 99%

Verapamil Pharmacodynamics and Disposition in Young and Elderly Hypertensive Patients

Abernethy¹,

et al. 1986

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“…The inhibition of calcium channels in smooth muscle cells by phenylalkylamines is crucially dependent on the frequency of membrane depolarization (Klockner and Isenberg, 1986;Hering et al, 1989). In this respect, the mechanism of action of the phenylalkylamines appears to be similar in all excitable cells which have been studied (Ehara and Kaufmann, 1978;Kohlhardt and Haap, 1981;Lee andTsien, 1983, McDonald et al, 1984;Oyama et al, 1987). In a recent study in smooth muscle cells of the rabbit ear artery, we have shown that the amount of calcium channel block produced by D600 is determined by the channel open time rather than by the change in membrane voltage or channel inactivation (Hering et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

A method for estimation of drug affinity constants to the open conformational state of calcium channels

Timin

Hering

1992

Biophysical Journal

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The affinity of D600 to calcium channels in the open state has been examined in isolated smooth muscle cells of the rabbit ear artery. Calcium channel currents were measured in high external barium solution by means of the patch-clamp technique. The current inhibition in various D600 concentrations (3-100 microM) on application of trains of short test pulses (20-80 ms) has been studied in nonmodified calcium channels and in cells where the calcium channels were modified by the agonist dihydropyridine (+) 202,791 (100 nM). The kinetics of the peak current decay has been analyzed with a mathematical model which is based on the experimental finding that D600 interacts primarily with calcium channels in the open conformational state. The model approach allows the estimation of drug affinity constants of D600 to the calcium channel in the open conformation. An association rate constant to the open conformational state of D600 of 6.16 x 10(4) M-1 s-1 was estimated. The association rate of the drug was not significantly changed after the calcium channels have been modified with 100 nM (+) 202,791. A method for correction of rate constants for possible drug trapping is discussed.

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“…However, nifedipine does inhibit the maximum upstroke velocity of action potentials recorded from AV-nodal cells in a frequency-dependent fashion (Kohlhardt and Haap, 1981).…”

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confidence: 99%

Voltage-dependent block of calcium channel current in the calf cardiac Purkinje fiber by dihydropyridine calcium channel antagonists.

Sanguinetti

Kass

1984

Circulation Research

532

256

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SUMMARY. We have investigated the mechanisms of blockade of calcium channel current by the dihydropyridines, e.g. nisoldipine, nitrendipine, and nicardipine. Membrane current was recorded in isolated calf Purkinje fibers using a two-microelectrode voltage-clamp technique, and voltage protocols were designed to identify voltage-and use-dependent block by these compounds systematically. Our results show that calcium channel blockade by dihydropyridine derivatives is strongly modulated by membrane potential. Block is more pronounced when current is measured from depolarized holding potentials, but in contrast to verapamil, this voltage-dependent block occurs in the absence of repetitive depolarizations. Use-dependent block by dihydropyridines is observed at pulse frequencies greater than 1 Hz. Our results suggest that dihydropyridines bind preferentially to the inactivated state of the calcium channel, and that the development of usedependent block is related to the ionization constants of the compounds. Furthermore, binding is approximately one thousand times stronger to inactivated channels than to resting channels. This state-dependent difference in binding affinities may account for the previously reported contrast between electrophysiological and binding data for these compounds. (Circ Res 55: 336-348, 1984)

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The blockade of $$\dot V_{\max }$$ of the atrioventricular action potential produced by the slow channel inhibitors verapamil and nifedipine

Cited by 23 publications

References 24 publications

Verapamil Pharmacodynamics and Disposition in Young and Elderly Hypertensive Patients

Verapamil Pharmacodynamics and Disposition in Young and Elderly Hypertensive Patients

A method for estimation of drug affinity constants to the open conformational state of calcium channels

Voltage-dependent block of calcium channel current in the calf cardiac Purkinje fiber by dihydropyridine calcium channel antagonists.

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