DILTIAZEM AT REPERFUSION REDUCES NEUTROPHIL ACCUMULATION AND INFARCT SIZE IN DOGS WITH ISCHEMIC MYOCARDIUM

Study objective - The aim was to demonstrate the ability of diltiazem to protect the ischaemic myocardium in the course of coronary reperfusion, and to establish if an interaction with neutrophils is implied. Design - Ischaemia was induced by occluding the left anterior descending coronary artery for 90 min followed by 6 h of reperfusion with a residual critical stenosis left in place. Three groups were studied: group 1 (control) received a saline perfusion; group 2 was given a bolus injection of 400-mu-g.kg-1 of diltiazem 10 min before reperfusion, followed by 4 mu-g.kg-1.min-1 perfusion until termination of experiment; group 3 was made neutropenic by injecting a neutrophil antiserum produced in rabbits and was then treated with diltiazem, as in the second group. Subjects - 60 mongrel dogs of either sex were allocated at random into one of the three groups the day before the experiment. Measurements and main results - Diltiazem plasma concentrations ranged from 68.6(SEM 10.0) to 102.5(15.2)-mu-g.litre-1 during the study. Transmural collateral blood flow, measured with Gd-153 microspheres 15 min after occlusion, and area at risk, evaluated by Evans blue perfusion, did not differ among the three groups. Infarct size, estimated by triphenyltetrazolium staining of heart slices and expressed as a percentage of area at risk, was less (p < 0.05) in the diltiazem [20.5(5.2)%] and diltiazem plus neutropenia [17.6(5.4)%] groups compared to controls [39.8(6.9)%] but neutropenia added no significant benefit to diltiazem alone. The animals treated with diltiazem alone had lower serum creatine kinase levels than controls, at 5719(891) v 14 333(2885) IU.litre-1, p < 0.05. The neutrophilia seen in controls was virtually absent in diltiazem dogs. Myocardial neutrophil accumulation estimated by scintigraphy of In-111 labelled autologous neutrophils was much less in diltiazem than in control dogs, at 3948(1228) v 11 021(2081) In-111-neutrophil.g-1 of infarct, p < 0.02. Conclusions - Diltiazem given during reperfusion reduces infarct size by a mechanism that includes an inhibition of neutrophil accumulation in the post-ischaemic myocardium.