Coronary venous drug infusion in the ischaemic-reperfused isolated rat heart.

OBJECTIVES Coronary venous retroinfusion (CVR) has been used experimentally in large animals for selective drug delivery into ischaemic myocardium. It would be an advantage if CVR could also be used in isolated perfused rat heart models. The aim of the present paper is to develop a regional ischaemic model in the isolated perfused rat heart combined with CVR. METHOD Pharmacokinetic study: The spatial distribution of retrogradely infused felodipine (used as a tracer) during regional myocardial ischaemia was investigated. Following occlusion of the left coronary artery, felodipine was administered over a period of 5 min by CVR. Ischaemia-reperfusion study: Following 30 min of stabilisation, 14 rat hearts were subjected to 60 min of regional ischaemia followed by 60 min of reperfusion. Felodipine (0.7 nmol/kg, n = 7) or vehicle (n = 7) was administered by means of CVR. The infusion was given during the last 5 min of ischaemia at a rate of 0.6 ml/min. RESULTS Pharmacokinetic study: By means of CVR, the compound was distributed specifically into the ischaemic myocardium. The highest tissue concentration was obtained when the coronary vein was occluded during CVR. The maximal concentration in the ischaemic myocardium was 20-70 times that in the non-ischaemic areas. A transmyocardial gradient was noted with higher drug concentration in the subepicardial zone. Ischaemia-reperfusion study: At the end of reperfusion, the recovery of coronary flow, left ventricular developed pressure and double product (DP; LVDP x HR) was 101 +/- 7% (mean +/- s.e.m.), 99 +/- 8% and 98 +/- 4% of the pre-ischaemic values, respectively. This was significantly different from the vehicle group (78 +/- 5, P < 0.05, 74+/- 6, P < 0.01 and 78 +/- 3, P < 0.05). CONCLUSION CVR could easily be accomplished in the isolated perfused rat heart. The drug was specifically delivered into the ischaemic myocardium. Felodipine exerted a myocardioprotective effect in isolated rat hearts subjected to 60 min of regional ischaemia followed by 60 min of reperfusion.