Differential enhancement of postischemic segmental systolic thickening by diltiazem

Abstract

Prolonged depression of segmental systolic thickening after brief coronary artery occlusion may result principally from events during reperfusion rather than during the ischemic interval. Thus, cellular calcium overload at reperfusion may be a mediator of contractile dysfunction after brief ischemia, and reduction of calcium entry by diltiazem, a calcium channel antagonist, may enhance recovery of systolic thickening after brief periods of ischemia. Thirteen awake unsedated dogs instrumented with hemodynamic catheters, left anterior descending coronary artery occluders and five to six pairs of intramyocardial sonomicrometers underwent two 15 min coronary artery occlusions with 24 h reperfusion. The order of infusion of diltiazem (15 micrograms/kg per min) or saline solution was alternated. Systolic thickening, hemodynamic variables and regional myocardial blood flow were measured serially over 24 h. Despite equally severe ischemic dysfunction during coronary occlusion, diltiazem-treated segments with systolic thinning during ischemia recovered control segmental thickening significantly earlier than saline solution-treated segments (at 30 versus 180 min of reperfusion). Blood pressure was mildly decreased during diltiazem treatment; therefore, a second group of 10 dogs underwent a similar occlusion and reflow period during infusion of nitroprusside to lower mean arterial pressure equivalently. Decreases in blood pressure in this group resulted in some improvement in segmental systolic function; however, this did not reach statistical significance at any time. Regional myocardial blood flows were similar in the saline solution- and diltiazem-treated groups during ischemia and reflow. Thus, it is concluded that 1) diltiazem infusion significantly enhanced recovery of segmental systolic thickening after 15 min of ischemia and 24 h of reperfusion; 2) the enhancement in segmental systolic function could not entirely be attributed to decreased mean arterial pressure; 3) improvement in postischemic segmental ventricular function was seen only in those segments with systolic thinning during ischemia; thus, segments with the most severe ischemic dysfunction benefited most; and 4) there were no important differences in regional myocardial blood flow during ischemia and reperfusion between saline- and diltiazem-treated animals.

Calcium antagonists and stunned myocardium: Importance for clinicians?

“…Taylor and colleagues [3] reported that diltiazem (15 ~g/kg/min), administered preocclusion, enhanced the recovery of wall thickening following 15 minutes of transient ischemia. Furthermore, Taylor…”

“…Ther 1991;5:947-952 During the two decades since the "stunned myocardium" was first documented, considerable investigative effort has focused on elucidating the cause or mechanism of this postischemic dysfunction and thereby identifying agents that might attenuate this phenomenon. Specifically, our laboratory and others found that the calcium-channel blocking agents verapamil [1], nifedipine [2], diltiazem [3], and amlodipine [4,5] significantly enhance the recovery of contractile function in dogs "stunned" by a brief episode of transient coronary artery occlusion. We were particularly interested to find that verapamil and nifedipine improved systolic contraction, even when treatment was "delayed," that is, when the agents were administered 30 minutes after reflow had been established [1,2].…”

“…Specifically, our laboratory and others found that the calcium-channel blocking agents verapamil [1], nifedipine [2], diltiazem [3], and amlodipine [4,5] significantly enhance the recovery of contractile function in dogs "stunned" by a brief episode of transient coronary artery occlusion. We were particularly interested to find that verapamil and nifedipine improved systolic contraction, even when treatment was "delayed," that is, when the agents were administered 30 minutes after reflow had been established [1,2].…”

Dihydropyridine Calcium Antagonists: Beneficial or Adverse Effects in the Setting of Myocardial Ischaemia/Reperfusion?

“…102], dipyridamole and nitroglycerin [102]. However, a Gregg phenomenon appears not to be the underlying mechanism for the improved functional recovery' of stunned myocardium after treatment with calcium antagonists since improved functional recovery was also observed in the absence of improved blood flow during reperfusion [83,86,91] and. on the other hand, a substantial increase in blood flow was not associated with improved functional recovery when the calcium antagonist nisoldipine was given after estab lished reperfusion [89] (fig.…”

“…Since gallopamil has no direct oxygen radical scavenging activity, its protective effect may be linked to a reduction of calcium overload [80], As in the in vitro studies, all in vivo studies using mod els of reversible damage with shortlasting myocardial ischaemia followed by reperfusion revealed improved recovery of regional contractile function when treatment with calcium antagonists was started before ischaemia [30,[81][82][83][84][85][86][87][88][89][90][91][92][93][94], Apart from two studies in anaesthetized pigs [81,94], all studies utilized anaesthetized [82-86, 88-90, 92. 93] or conscious [87,91] canine preparations. In a number of studies the improvement in regional contrac tile function was not fully convincing since arterial pres sure was also reduced by the calcium antagonists after intravenous administration [81.…”