Cardioprotective effects of diltiazem when given before, during or delayed after infusion of norepinephrine in anesthetized dogs☆

Abstract Catecholamine excess has been shown to produce 2 distinct forms of irreversible myocardial necrosis termed contraction band lesions. Calcium channel blocking agents provided a variable protective effect from these contraction band lesions. The purpose of this study was to determine the temporal responses of the most effective of these blocking agents, diltiazem, when given before, simultaneous with or after an initial exposure to a necrogenic infusion of norepinephrine (NE). Forty-one adult mongrel dogs were anesthetized with sodium pentobarbital (32 mg/kg) and infused with saline solution or NE (4 μg/kg/min) for 60 minutes or diltiazem at a rate of 20 μg/kg/min for the first 5 minutes and 10 μg/kg/min for the remaining 70 minutes. Diltiazem was infused as pretreatment 15 minutes before continued infusion with NE for 60 minutes, simultaneously infused with NE for 60 minutes or delayed 30 minutes after the start of NE infusion. Diltiazem alone exhibited no significant effect on hemodynamics, but pretreatment with diltiazem was able to moderate the rapid NE-induced increases in heart rate. NE infusion produced significant numbers of the 2 forms of contraction band lesions: (1) paradiscal contraction band lesions involving a small portion of the cell adjacent to the disc, and (2) holocytic contraction band lesions involving the entire cell. Diltiazem reduced the number of contraction band lesions, particularly the holocytic contraction band lesions, provided diltiazem was available before the insult and massive influx of calcium with a pharmacologic dose of NE. Although the exact mechanism of diltiazem's cardio-protective properties is not known, the timing of drug administration does appear to affect the degree of protection.