Protection by nifedipine and diltiazem against microsphere-induced ischaemia in working rat hearts

39 COLD CHEMICAL CARDIOPLEGIA: THE PROTECTION OF THE ISCHEMIC MYOCARDIUM DURING OPEN HEART SURGERY The Rayne Institute, St. Thomas' Hospital, London ECl, UK. D.J. Hearse. Effective protection against the consequences of transient myocardial ischemia requires a consideration of events not only during the ischemic interval but also during the pre- and post-ischemic periods. Thus, the promotion of maximal energy reserves and the reduction of catecholamine drive prior to ischemia are likely to increase tissue resistance. Similarly, limitation of various reperfusion effects such as cell swelling,energy over-demand or calcium overload may improve either the rate or extent of conditioning are post-ischemic recovery. Although pre- and post-ischemic little studied, protection during ischemia has been extensively investigated and, in the case of surgically-induced ischemia, has been shown to be of cold chemical cardioplegia to highly effective. Thus, the introduction routine cardiac surgery has allowed the tolerable duration of ischemia to be extended from less than 1 to more than 3 hours and in experimental studies up to 24 hours of reversible ischemia has been reported. Three components of effective protection can be defined: (i)conservation of energy by inducing instantaneous arrest with agents such as potassium;(ii) slowing the metabolic rate of energy consuming and degradative reactions with hypothermia;(iii)combatting deleterious ischemia-induced changes with Analysis of the principles underlying these specific protective agents. three components and the mechanisms of action of specific interventions, reveals the control of calcium movement to be one of the most critical factors in effective myocardial protection.

PROTECTION BY NIFEDIPINE AND DILTIAZEM AGAINST MICROSPHERE-INDUCED ISCHAEMIA IN WORKING RAT HEARTS. A.J. Higgins, D.G. Gardiner and M.H. Gregory. Pfizer Central Research, Sandwich, Kent, U.K. Hearts from starved rats were perfused anterogradely with Krebsbicarbonate containing 5.5mM glucose, insulin (2i.u./1) and 1mM palmitate bound to 0.2mM bovine albumin. After 10 nrins, ischaenria was induced by introducing 0.5mg of carbon microspheres (50~) into the coronary circulation, thus reducing control coronary flow by about 60%. Ischaemic damage was assessed over the next 60 min by (a) decrease in total cardiac output (CO), (b) release of LDH into the perfusate, and (c) histological examination. Perfusion with nifedipine or DL-diltiazem, at a concentration (lo-'M) which did not alter pre-ischaemic CO, in each case attenuated the fall in CO (from 35+2 to 18+2 and 19+2ml/min resp.), decreased LDH release (from 8.1+1.4 to T.7+0.8 2nd 2.6+073U/g resp.) and reduced histological indices of-myocardialnecrosis. Gifedipine increased coronary flow both before (10%) and after (56%) microspheres. However diltiazem had no effect on normal flow and increased ischaemic coronary flow only slightly (14%). Thus, both drugs were equally effective in preserving cardiac function and cellular integrity although diltiazem (unlike nifedipine) had no apparent effect on the coronary vessels. This suggests that the protective actions of these drugs are due only to inhibition of calcium influx into ischaemic myocardial cells.