CORONARY VENOUS DRUG INFUSION IN THE ISCHEMIC-REPERFUSED ISOLATED RAT-HEART

Objectives: Coronary venous retroinfusion (CVR) has been used experime ntally in large animals for selective drug delivery into ischaemic myo cardium. it would be an advantage if CVR could also be used in isolate d perfused rat heart models. The aim of the present paper is to develo p a regional ischaemic model in the isolated perfused rat heart combin ed with CVR. Method: Pharmacokinetic study: The spatial distribution o f retrogradely infused felodipine (used as a tracer) during regional m yocardial 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: Pharmac okinetic study: By means of CVR, the compound was distributed specific ally into the ischaemic myocardium. The highest tissue concentration w as obtained when the coronary vein was occluded during CVR. The maxima l concentration in the ischaemic myocardium was 20-70 times that in th e non-ischaemic areas. A transmyocardial gradient was noted with highe r 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-ischa emic values, respectively. This was significantly different from the v ehicle 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 p erfused rat heart. The drug was specifically delivered into the ischae mic myocardium. Felodipine exerted a myocardioprotective effect in iso lated rat hearts subjected to 60 min of regional ischaemia followed by 60 min of reperfusion.