14th International Congress
THE "NEW FRONTIERS"
OF ARRHYTHMIAS 2000

Jan. 29 - Feb. 5, 2000
Marilleva, Trento, Italy

RT-199

The antiarrhythmic properties of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers

Pablo I. Altieri, María Crespo, Nelson Escobales, José F. Rodríguez, Héctor Banch.
Departments of Medicine, Physiology and Biochemistry, Medical Sciences Campus, University of Puerto Rico

Mechanisms

Refractoriness⁶

A reduction in refractoriness will increase the incidence of ventricular arrhythmias increasing the incidence of sudden death. The effect of enalapril on the refractoriness of rat papillary muscle was investigated. Strength interval curves were initially obtained under control conditions and after exposing the muscle to tirode solution containing 50 vg/ml of enalapril. The results indicate that enalapril displaced the strength-curves to the right. The minimal current intensity required to elicit a propagated response was clearly increased by enalapril at all interval used. No change in action potential duration was found with enalapril, but the action potential amplitude and the resting potential were both increased. This rise in cardiac refractoriness caused by enalapril might indicate that this drug, when given to patients with ischemic heart disease or left ventricular hypertrophy, will reduce the incidence of ventricular arrhythmias leading to a reduction of sudden death.

Intracellular resistance and conduction velocity in ventricular muscle⁷

Elevated levels of angiotensin II in the periphery and intracellularly is deleterious, not only in the progression of atherosclerosis but in the electrical stability of the heart increasing the incidence of ventricular arrhythmias and sudden death. Angiotensin II increases junction gap resistance resulting in an increase in muscle resistance for electrical conduction. This will produce an increase in ventricular arrhythmias through reentry. The effect of enalapril on the intracellular resistance and conduction velocity was investigated in isolated rat trabeculae. The results indicated a decline in interval resistance of 35.5% (SE±3.3) and an increase in conduction velocity of 58.7% (SE±6.6). The action potential was not altered, but the resting potential was increased by 10.5% MV (SE±4.4). These findings indicate that the renin-angiotensin system is involved in an improvement of the electrical synchronization of heart cells, reduce the incidence of arrhythmias.

Increase in junctional conductance of myocytes⁸

The efficient contraction of the heart exist if the myocytes are well synchronized. This occurs if the junction gap conduction is normal. In ischemia and hypertrophy, junctional conductance increases. This effect will produce an increase in arrhythmias and a higher incidence of congestive heart failure due to uncoupling of the heart cells.

Angiotensin II will uncouple the myocytes and angiotensin II receptor blockers will prevent this. Angiotensin II (1 vgm/ml) reduced the junctional conductance by 55%, within 20 seconds. Dup 753 (losartan) 70 vg/ml was added. It was observed that effect of angiotensin II on junctional conductance was totally suppressed, but interesting the influence of enalapril on junctional conductance, was not altered. Enalapril (1 vgm/ml) increased junctional conductance by 106±3.1% within 4 minutes. The effect of enalapril on junctional conductance was not altered by propanolol (10-6) or by stausporine (Camp dependent protein kinase inhibitor). These observations indicates than an intrinsic renin-angiotensin system in the heart is involved in the control of junction gap conductance in cardiac muscle. The use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers will improve and stabilize the electrical status of the myocytes reducing the incidence of arrhythmias and congestive heart failure.

Clinical electrophysiologic changes

Conduction velocity⁴

We have published that the active drug (enalaprilat) produces important electrophysiologic changes during his bundle recording. Enalaprilat 2.5 mg intravenously was infused in 10 minutes in 10 patients with ischemic heart disease, compared with placebo. There were no significant changes in heart rate (64±9 versus 65±11 beats/min), mean blood pressure (97±11 versus 94±10 mmHg), atrioventricular conduction time (100±20 versus 100±20 msec), and His Purkinge (HV Conduction) (40±12 versus 40±13 ms). The ventricular activity duration was reduced from 110±10 msec to 88±13 ms after enalaprilat administration (p<0.001). No change after placebo infusion. This shows that angiotensin converting enzyme inhibitors will increase ventricular activity conduction reducing the incidence reentry arrhythmias.

Q-T dispersion⁹

Q-T dispersion reflects local differences in the repolarization time of the myocardium. Q-T dispersion abnormalities have been related to sudden death due to ventricular arrhythmias. We studied the Q-T dispersion in 26 patients with hypertensive cardiovascular disease. We found that an infusion of enalaprilat (2.5 mg IV) reduced the Q-T dispersion from 26±5 to 20±5 msec (p<0.001). This study shows that enalaprilat reduces significantly the Q-T dispersion reducing the regional variations in ventricular repolarization and the cardiac electrical instability. This will reduce the incidence of ventricular arrhythmias and sudden death.