Swynghedauw, Bernard. Molecular Mechanisms of Myocardial Remodeling. Physiol. Rev. 79: 215–262, 1999. — “Remodeling” implies changes that result in rearrangement of normally existing structures. Th...

Molecular Mechanisms of Myocardial Remodeling

Synopsis: Verapamil is a novel antiarrhythmic and antianginal agent which, although introduced in 1962, has only recently gained prominence not only as a significant agent in cardiovascular therapeutics but also as a powerful tool to examine the nature of some of the biophysical phenomena at the membrane of cardiac and other excitable tissues. Verapamil is the prototype of those agents which selectively inhibit membrane transport of calcium, an action which accounts for the drug’s peripheral and coronary vasodilator properties, its effect on excitation-contraction coupling and hence its negative inotropic propensity, as well as its depressant effects on the sinus node and atrioventricular conduction. Its pharmacological effects are largely independent of the autonomic nervous system. The main therapeutic uses of the drug are in the management of atrial tachyarrhythmias, angina, and possibly hypertension. The overall experimental and clinical data suggest that verapamil will become an important and safe addition to existing drug regimens, especially as an agent of choice for the short-term treatment of most cases of paroxysmal supraventricular tachycardias. The initial experience in other arrhythmias, angina and hypertension, is also sufficiently encouraging to justify further detailed clinical trials to define its potential role in cardiovascular therapeutics.

Verapamil: A Review of its Pharmacological Properties and Therapeutic Use

https://www.cell.com/biophysj/pdf/S0006-3495(92)81615-6.pdf

Theory of excitation-contraction coupling in cardiac muscle

MORE than 80 years ago, Sir James MacKenzie1 noted: "The more I study the symptoms of heart failure, and the more I reflect on the part played by the heart muscle, the more convinced I am that... heart failure is due to the exhaustion of the reserve force of the heart muscle." Except for the cardiac glycosides, however, therapy for congestive heart failure generally has focused on the systemic signs and symptoms that appear when the failing heart becomes unable to meet the hemodynamic demands of the body, rather than on abnormalities in the heart muscle itself, which both cause . . .

Cardiomyopathy of overload. A major determinant of prognosis in congestive heart failure.

Hypertension and sudden death: Increased ventricular ectopic activity in left ventricular hypertrophy☆

Calcium-movement controlling cardiac contractility. II. Analog computation of cardiac excitation-contraction coupling on the basis of calcium kinetics in a multi-compartment model ☆ ☆☆

Right ventricular hypertrophy in the cat--an electrophysiological and anatomical study.

Ca-movements controlling mammalian myocardial contractility. II. Analogue computation of contractile behaviour assuming a multicompartment model.

1.

Tension development and membrane currents have been measured in cat ventricular fibres applying a double sucrose-gap voltage clamp technique.




2.

A well defined mechanical threshold was found at which a considerable all-or-non response occurred. This threshold obviously coincided with the threshold potential of the fast inward current (INa). Changes in [Cae] (0.8–7.5 mM) did not separate the two thresholds. Ramp clamps of decreasing steepness shifted the threshold of bothINa and that of tension development towards less negative potentials. Ramp clamps ineffective in elicitingINa did not produce phasic tension development. This suggests that a fast inward current normally triggers the internal Ca release.




3.

In rhythmically activated preparations the steady state voltage-tension relationship rose roughly in parallel toICa in a S-shaped manner up to about zero potential. With further depolarizations the steady-state tension development tended to decline again. It was concluded that this voltage dependent gain of contractile activation reflects the time integral of transmembrane Ca supply provided from the extracellular space.




4.

Under steady state conditions peak tension produced by square clamps of a given suprathreshold voltage rose with prolongation of the clamp duration up to a maximum at 500–700 msec. This maximum in turn depended on the clamp potential applied. From the results obtained, a tension-time-voltage relationship has been drawn. Even under very long lasting depolarizations (up to 10 sec) usually no tonic responses occurred.




5.

A muscle once activated by a suprathreshold square clamp did not respond to a second depolarization unless the membrane had been repolarized to a given level and for a given duration. The amplitude of contractile response to second clamp steps depended in a characteristic manner on both the voltage and the duration of the recovery period.




6.

Mechanical transients typically observed when either the voltage or the duration of clamp steps had been changed were analyzed in order to obtain information about the kinetics of intracellular Ca movements assumed to take place in a multicompartment model derived from structural and functional observations.

Ca-movement controlling myocardial contractility. I. Voltage-, current- and time-dependence of mechanical activity under voltage clamp conditions (cat papillary muscles and trabeculae).

[A new group of competitive divalent Ca-antagonists (iproveratril, D 600, prenylamine) with potent inhibitory effects on electromechanical coupling in mammalian myocardium].

H. Tritthart

Papers

Calcium-movement controlling cardiac contractility. II. Analog computation of cardiac excitation-contraction coupling on the basis of calcium kinetics in a multi-compartment model ☆ ☆☆

Right ventricular hypertrophy in the cat--an electrophysiological and anatomical study.

Ca-movements controlling mammalian myocardial contractility. II. Analogue computation of contractile behaviour assuming a multicompartment model.

Ca-movement controlling myocardial contractility. I. Voltage-, current- and time-dependence of mechanical activity under voltage clamp conditions (cat papillary muscles and trabeculae).

[A new group of competitive divalent Ca-antagonists (iproveratril, D 600, prenylamine) with potent inhibitory effects on electromechanical coupling in mammalian myocardium].