Dagenais F, Hollmann C, Buluran J, Cartier R
Department of Surgery, Montreal Heart Institute, Quebec.
Can J Cardiol. 1995 Oct;11(9):816-22.
To evaluate the effects of the calcium channel blocker diltiazem and its chloride derivative clentiazem on coronary vasoregulation of isolated rat hearts exposed to ischemia-reperfusion. Diltiazem has been reported to prevent postreperfusion myocardial damage but its beneficial effects on coronary blood-flow regulation remain uncertain.
Two groups of hearts were pretreated with a 10 min infusion of either diltiazem (10(-9) to 10(-6) mol/L) or clentiazem (10(-9) to 10(-7) mol/L) (n = 6 for each concentration) and exposed to 30 mins of no-flow ischemia. Another group (n = 6) received no pretreatment and was used as control. Endothelium-dependent and -independent relaxation were tested by assessing coronary flow increase to 5-hydroxytriptamine (10(-6) mol/L) and sodium nitroprusside (10(-5) mol/L) infusions, respectively, and were assessed before and after ischemia-reperfusion. Left ventricular pressure, dP/dt and coronary basal flow were also recorded. Postreperfusion results are expressed as a percentage of pre-ischemic value. Dunnet variance analysis was used to compare means of pretreated groups with the control group.
Endothelium-dependent relaxation was significantly improved with both drugs. Optimal preservation was obtained with diltiazem 10(-6) mol/L (66 +/- 4%) and clentiazem 10(-7) mol/L (83 +/- 4%), whereas endothelial response was almost abolished in control hearts (6 +/- 11%, P < 0.01). Clentiazem was found to be more potent than diltiazem at low concentration (10(-9) mol/L, clentiazem 89 +/- 13% versus diltiazem 3 +/- 16%, P < 0.05). Optimal endothelium-independent relaxation preservation was achieved at 10(-8) mol/L in both groups (diltiazem 86 +/- 4%, clentiazem 82 +/- 8%, control 47 +/- 10%, P < 0.05). Left ventricular pressure and dP/dt were not affected by any pretreatment. However, postreperfusion coronary basal flow was significantly increased in control hearts.
This study indicated that pre-ischemic infusion of diltiazem and clentiazem enhances endothelium-dependent and -independent coronary artery relaxation following reperfusion in the isolated rat heart model, without affective ventricular hemodynamics, and contributes to preservation of coronary artery autoregulation.
评估钙通道阻滞剂地尔硫䓬及其氯化物衍生物克仑硫䓬对暴露于缺血-再灌注的离体大鼠心脏冠状动脉调节的影响。据报道，地尔硫䓬可预防再灌注后心肌损伤，但其对冠状动脉血流调节的有益作用仍不确定。
两组心脏分别用10分钟输注地尔硫䓬（10⁻⁹至10⁻⁶mol/L）或克仑硫䓬（10⁻⁹至10⁻⁷mol/L）进行预处理（每个浓度n = 6），然后进行30分钟无血流缺血。另一组（n = 6）未接受预处理，用作对照。通过分别评估向5-羟色胺（10⁻⁶mol/L）和硝普钠（10⁻⁵mol/L）输注时冠状动脉血流增加来测试内皮依赖性和非内皮依赖性舒张，并在缺血-再灌注前后进行评估。还记录左心室压力、dP/dt和冠状动脉基础血流。再灌注结果以缺血前值的百分比表示。采用Dunnet方差分析比较预处理组与对照组的均值。
两种药物均显著改善了内皮依赖性舒张。地尔硫䓬10⁻⁶mol/L（66±4%）和克仑硫䓬10⁻⁷mol/L（83±4%）可实现最佳保存，而对照心脏中的内皮反应几乎消失（6±11%，P<0.01）。发现克仑硫䓬在低浓度（10⁻⁹mol/L）时比地尔硫䓬更有效（克仑硫䓬89±13%对等地尔硫䓬3±16%，P<0.05）。两组在10⁻⁸mol/L时均实现了最佳的非内皮依赖性舒张保存（地尔硫䓬86±4%，克仑硫䓬82±8%，对照47±10%，P<0.05）。左心室压力和dP/dt不受任何预处理的影响。然而，对照心脏再灌注后的冠状动脉基础血流显著增加。
本研究表明，在离体大鼠心脏模型中，缺血前输注地尔硫䓬和克仑硫䓬可增强再灌注后内皮依赖性和非内皮依赖性冠状动脉舒张，而不影响心室血流动力学，并有助于维持冠状动脉自动调节。
