Regional contractility. Selective depression of ischemic myocardium by verapamil.

Abstract

SUMMARY The effects of verapamil (0.02-0.2 mg/kg) on contractility in normal and partially ischemic myocardium were compared with the changes following propranolol (0.01-1.0 mg/kg). Regional contractile function was studied in open-chest dogs with ultrasonic crystals and ischemia was controlled by graded occlusion of a carotid-to-coronary artery shunt. Reduction in shunt perfusion pressure (40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55) resulted in hypokinesia. Verapamil depressed contractility in ischemic myocardium in 5/5 dogs, but did not alter the maximum velocity of shortening (max V) or end-VERAPAMIL HAS BEEN USED as an antianginal agent in man' and has been shown to prolong survival2 and reduce ST-segment elevation in dogs following acute coronary artery occlusion.3 Its salutary effects on ST segments during acute coronary occlusion occur without associated changes in collateral blood flow or the rate of anaerobic metabolism, suggesting that the drug may reduce ischemic injury by a direct myocardial effect.4Since verapamill and ischemial both interfere with the movement of calcium ions at the cell membrane level, it seemed possible that verapamil might be capable of selectively depressing contractile function in ischemic myocardium at concentrations too low to affect normal tissue. To test this hypothesis, several parameters of myocardial contractile function were measured in nonischemic and ischemic segments of the left ventricle using small ultrasonic crystals.7 The dose-response relation of verapamil on nonischemic and ischemic myocardium was compared to that of propranolol, a potent beta-blocking agent known to decrease contractility.8 MethodsEighteen mongrel dogs of either sex (weight 20-30 kg) were anesthetized with sodium pentobarbital (20-25 mg/kg) and ventilated with room air through a cuffed endotracheal tube. Normal saline was infused at 50 ml/hr for the remainder of the experiment. The experimental preparation is shown diagrammatically in figure 1. A left lateral thoracotomy was performed through the fifth intercostal space and the heart was suspended in a pericardial cradle. The left anterior descending coronary artery (LAD) was dissected free at about 2 cm from its origin, usually above the first major diagonal branch, and prepared for later cannulation. Catheters were placed in the femoral artery and vein, Small stab incisions were made with a number 11 scalpel blade; two pairs of ultrasonic crystals (diameter 2 mm) were placed at a depth of 3-4 mm in the anterior left ventricle and secured with purse-string sutures. Each pair of crystals was separated by 1.5-2.0 cm of myocardium and aligned for optimum transmission of sound. One pair was placed outside the ischemic zone (normal segment) and the other within the zone of myocardium perfused by the LAD, but 1-2 cm distal to the level of LAD occlusion; i.e., that segment that would become ischemic after occlusion of the vessel (ischemic segment). The ultrasound crystals were made from 3 MHz piezoelectric crystal (LTZ 5, Transd...

The effect of verapamil on mechanical performance of acutely ischemic and reperfused myocardium in the conscious dog.

“…Furthermore, opposite effects on conduction delay were noted by other investigators when verapamil was given subsequent to coronary occlusion (Kupersmith et al, 1976), suggesting that local drug concentrations may exert important effects. These findings also could explain in part the difference between our findings and those of Smith et al (1976), who also administered verapamil after the production of ischemia.…”

“…Presumably, inhibition of transmembrane calcium flux is responsible for the myocardial depressant effects which are seen when verapamil is given in higher dosages (Fleckenstein, 1971;Nayler and Szeto, 1972), and also might be responsible for the antiarrhythmic effects of the drug (Andersson, 1978). Indeed, Smith et al (1976) have suggested that verapamil may reduce myocardial injury through a selective depression of contractility and oxygen requirement in ischemic myocardium when given in doses too low to affect contractility of normal myocardium. These experiments, which were carried out in anesthetized open-chest dogs with partial coronary occlusion, are at variance with the present studies, which showed not only improved postextrasystolic potentiation responses in all areas of ischemia, but also less depression of intrinsic performance in border zones of ischemia in verapamil-treated animals.…”

“…The one study to date that investigated the effect of verapamil on regional performance employed a model of partial ischemia in open-chest dogs. That study suggested that the drug might selectively depress myocardial performance in the partially ischemic region (Smith et al, 1976). Reperfusion of ischemic myocardium may be associated with increased cellular injury (Bresnahan et al, 1974;Lang et al, 1974, Jennings et al, 1975, although the extent of necrosis is dependent on the duration of transient ischemia Maroko et al, 1972).…”

Initial myocardial adjustments to brief periods of ischemia and reperfusion in the conscious dog.

“…20 In an isolated ventricular septum preparation 21 and in the intact isovolumic heart, 22 ischemia depressed the tension or pressure generated more than their time derivatives, i.e., dT/dt of dP/dt. Finally dL/dt in the anesthetized dog, 23 as well as contractile element velocity (V ce ) in patients, 24 were less sensitive to ischemia than shortening.…”

The effects of verapamil, quiescence, and cardioplegia on calcium exchange and mechanical function in ischemic rabbit myocardium.

“…An alternative explanation is that, under ischemic conditions, verapamil might not inhibit calcium influx through the slow channels as it does under control conditions. However, verapamil is reported to have a greater, not smaller, negative inotropic effect on ischemic compared to normal myocardium (Smith et al, 1976), suggesting that verapamil does still block calcium channels under ischemic conditions. The failure of quiescence to alter the calcium influx provides support for the argument that the influx is not through the slow calcium channel.…”