Nisoldipine attenuates myocardial stunning induced by multiple coronary occlusions in conscious pigs and this effect is independent of changes in hemodynamics or coronary blood flow

Recent studies suggest that calcium channel blockers attenuate reversible post-ischemic myocardial dysfunction (myocardial 'stunning') in vivo. This beneficial effect, however, has been shown either in open-chest preparations, which are subject to the confounding influence of many unphysiological conditions, or in models in which treatment caused significant hemodynamic alterations. Furthermore, all of the studies have been conducted in the dog, and almost all of them have examined the effect of calcium antagonists after a single ischemic episode. The goal of the present investigation was to assess the effect of nisoldipine in a conscious pig model of repetitive ischemia, and to determine whether the drug exerts direct cardioprotection independent of hemodynamic changes. A total of 33 conscious pigs were used. Pigs underwent a sequence of 10 2-min coronary occlusions, each separated by 2 min of reperfusion, and were randomly assigned to a treated group (n = 11), in which nisoldipine was infused at a rate of 0.5 μg/kg/min from 15 min before the first coronary occlusion till 30 min after the last reperfusion, and a control group (n = 12), which received vehicle. Results showed that there were no significant differences between the two groups with respect to ischemic bed size or hemodynamic variables throughout the experiment. Collateral blood flow to the ischemic regions was virtually nil in both groups. During the sequence of coronary occlusions, systolic thickening fraction in the ischemic region decreased similarly in the two groups. After the 10th reperfusion, however, the recovery of wall thickening was markedly enhanced in treated compared to control pigs, with the differences being statistically significant at 5, 15, and 30 min and 1, 3, 4 and 5 h. The total deficit of wall thickening after the 10th reperfusion (an integrative assessment of post-ischemic dysfunction) was 51% less in the treated compared with the control group (P < 0.001). This study demonstrates that nisoldipine markedly attenuates myocardial stunning after multiple ischemic episodes in conscious pigs, the improvement is evident immediately after the end of the ischemic episodes and is sustained throughout the recovery phase. This beneficial effect is independent of any favourable hemodynamic changes, and therefore indicates a direct cardioprotective action of nisoldipine.