Effects on infarct size of reperfusion and pretreatment with beta-blockade and calcium antagonists.

The "mass of tissue at risk" and the myocardial infarct developed was studied in dogs subjected to either 24-h occlusion of the left anterior descending coronary artery or 2-h occlusion followed by 22-h reperfusion. The "mass of tissue at risk" was defined under anaesthesia at the time of occlusion using the microsphere technique. Twenty-four hours later the hearts were removed, sliced transversely and stained with 2,3,5-triphenyltetrazolium chloride to define the infarcted tissue. All myocardial tissue was mapped and cut into small pieces for weighing and radioactive counting. Radioactivity was present in all tissue, including the infarct. In the centre of the infarct, counts remained low and then increased very rapidly with distance just beyond the edge. Tissue at risk from infarction was taken as that with less than 15% of the peak left ventricular (non-ischaemic) counts. A linear relationship was found between the mass of the left ventricular infarct and the left ventricular "mass of tissue at risk". The effect of 22 hours reperfusion was examined by this method and expressed by a regression equation. There was a significant decrease in slope for the regression line of the reperfusion data, (p less than 0.05, analysis of covariance), indicating less infarcted tissue for each gram of underperfused tissue. None of the drug pretreatments explored had any effect on infarct size in the 24-h occlusion model. With reperfusion, propranolol and flunarizine diminished infarct size compared with reperfusion only (p less than 0.05 for reduced slope, the new slope being not significantly different from zero). The effect of diltiazem was not so marked. Thus infarct size can be reduced with pretreatment, as long as the myocardium is reperfused.

Mioflazine, a potentially protective drug against ischaemic damage: a study in dogs.

The protective effect of intravenous mioflazine pretreatment was examined in intact dogs on cardiopulmonary bypass. The mechanical function of the left ventricle was measured by isovolumic pressure-volume relationships. Mioflazine alone had no inotropic effect. After one hour of normothermic (37 degrees C) global ischaemia of the whole heart, no control hearts, pretreated with solvent, recovered sufficiently to support the animal's circulation; this was not the case with animals pretreated with mioflazine, they all survived. After the 30-min reperfusion period, the solvent (control) pretreated hearts had a significantly lower (P = 0.05) systolic and higher (P = 0.001) diastolic pressure-volume curve than those given mioflazine.

Origin and immunological hyporeactivity of canine alveolar lymphocytes.

Autochthonous canine thoracic duct lymphocytes were isolated, labelled with 111indium and injected intravenously. Direct sampling showed that the label passed from blood to lymph within 25 hr. By gamma camera imaging, the initial accumulation of 111In the liver and spleen was followed by a striking increase in lymph node associated activity between 24-36 hr. Although initial lung-associated counts were low, a bicarbonate-induced non-specific inflammation of the right lung induced a rapid and selective accumulation of labelled lymphocytes (ratio right to left lung 8:1). Cell suspensions lavaged from the alveolar surface showed only a 9% response to phytohaemagglutinin (PHA) compared to peripheral blood lymphocytes (PBL). The addition of unfractionated lavage cells to PBL caused a macrophage-dependent suppression of mitogen responsiveness. However, macrophage depletion of alveolar lavage cells did not restore the lymphocyte response to PHA. Similarly, the frequency of alloreactive precursors of cytolytic lymphocytes (CTL) was almost 10-fold less in alveolar lymphocytes compared to PBL. Thus, bronchoalveolar lavage provides a technique by which viable cells may be recovered in significant numbers from the alveoli and should be invaluable for the investigation of lung allograft rejection.

Reperfusion-induced ventricular fibrillation. Modification by pharmacological agents.

We have assessed the ability of several of the main groups of antiarrhythmic agents to modify the incidence of reperfusion-induced ventricular fibrillation in the isolated working rat heart preparation with transient coronary artery occlusion. Hearts were perfused with Krebs-Henseleit medium containing 5 microM epinephrine to provide some level of exogenous catecholamine support. Compounds selected were: the fast sodium channel inhibitors lignocaine (1 and 10 microM) and prenylamine (4 microM) (the latter also possessing slow calcium channel antagonistic actions); the beta-adrenergic blocking agents oxprenolol (1.2 microM), timolol (0.13 microM), metoprolol (1.0 microM), and acebutolol (5.6 microM); and the slow calcium channel antagonist nifedipine (0.05 and 0.5 microM). After 15 min of coronary artery occlusion, over 90% of control hearts fibrillated 30-60 sec after the onset of reperfusion. Drugs reduced this to the following: prenylamine, 0% (p less than 0.001); 1 microM lignocaine, 83%; 10 microM lignocaine, 33% (p less than 0.01); oxprenolol, 92% (NS); timolol, 92% (NS); metoprolol, 42% (p less than 0.01); acebutolol, 67% (p less than 0.05); 0.05 microM nifedipine, 83% (NS); and 0.5 microM nifedipine, 67% (NS). Thus, inhibition of the fast inward sodium channel with agents such as prenylamine and lignocaine, (when begun before coronary-artery occlusion) offers maximal protection against reperfusion-induced ventricular fibrillation, while beta-blockade with timolol and oxprenolol and slow calcium channel inhibition with nifedipine do not offer any significant protection. The beta-blocking agents metoprolol and acebutolol produce a partial reduction that may be due to a membrane-stabilizing action, rather than to beta-blockade.