Effect of Verapamil on Postischemic "stunned" Myocardium: Importance of the Timing of Treatment

Timely administration of verapamil has been shown to reduce indexes of ischemic injury in experimental models of prolonged coronary artery occlusion, yet its effect on contractile function of reversibly injured (that is, "stunned") myocardium remains unknown. The objective of the present study was to determine whether verapamil--administered either 30 min before coronary artery occlusion, at the time of reperfusion or 30 min after reperfusion--could attenuate the regional contractile dysfunction and alterations in high energy phosphate metabolism produced by 15 min of transient coronary artery occlusion in anesthetized, open chest dogs. All treatment groups exhibited passive systolic bulging during occlusion. In the control dogs receiving saline solution, segment shortening in the previously ischemic tissue averaged only 31 +/- 8% of normal baseline values after 3 h of reperfusion. In addition, endocardial adenosine triphosphate (ATP) stores were depleted by -8.7 +/- 0.8 nmol/mg cardiac protein to 26.5 +/- 1.1 nmol/mg protein, and endocardial creatine phosphate content increased by 9.6 +/- 4.3 nmol/mg cardiac protein over normal values. Pretreatment with verapamil essentially ablated the phenomenon of postischemic stunning: segment shortening was restored to 115 +/- 8% of normal after 3 h of reflow (p less than 0.01 versus control), endocardial ATP stores were partially preserved (30.6 +/- 1.2 nmol/mg protein; p less than 0.05 versus control) and creatine phosphate overshoot was blunted (endocardial creatine phosphate content decreased by -5.6 +/- 2.9 nmol/mg protein; p less than 0.05 versus control). Verapamil administered at or after reperfusion also attenuated postischemic contractile dysfunction: segment shortening for both groups recovered to 65 +/- 9% of baseline at 3 h after reperfusion (p less than 0.05 versus control). Verapamil given at or after reperfusion had no beneficial effect, however, on high energy phosphate stores. Thus, even when treatment was "delayed," that is, initiated at or after reperfusion, administration of verapamil significantly increased contractile function of the postischemic stunned myocardium.