Na+/H+ exchange inhibitors reverse lactate‐induced depression in postischaemic ventricular recovery

Abstract

By use of pharmacological approaches, the present study examined the hypothesis that the deleterious effect of lactate on postischaemic ventricular recovery may be mediated, at least in part, by enhanced activation of the Na+/H+ exchanger at the time of reperfusion. Spontaneously beating isolated hearts of the rat were subjected to 15 min zero‐flow global ischaemia followed by 30 min reperfusion. The effects of lactate (10, 20 or 40 mm) were studied by adding it 20 min before ischaemia whereas reperfusion was carried out with lactate‐free buffer. Pretreatment with 20 or 40 mm lactate significantly reduced postischaemic recovery of developed force to 17 ± 3% and 16 ± 4% of preischaemic values (P < 0.05) compared to a 78 ± 4% recovery in control hearts. Similarly, recovery in ventricular rate was significantly reduced to 34 ± 7.6% and 38 ± 12% with 20 and 40 mm lactate, respectively compared to 97.5 ± 6.4% recovery in control hearts. At a concentration of 10 mm, lactate was without effect on either force or ventricular rate recovery. Coadministration of either of two Na+/H+ exchange inhibitors, amiloride (174 μm) or 5‐N,N‐hexamethylene amiloride (HMA, 1 μm) with lactate and inclusion of the two drugs during the first 5 min of reperfusion resulted in reversal of lactate‐induced inhibition of force recovery with observed recoveries of 69 ± 6.7% and 64 ± 5% with amiloride and HMA, respectively. Similarly, recovery in ventricular rate was significantly enhanced to 92 ± 10% and 89 ± 6% with amiloride and HMA, respectively compared to 38 ± 12% recovery in control hearts. In electrically paced hearts (5 Hz) subjected to 15 min ischaemia and 30 min reperfusion, 40 mm lactate significantly reduced force recovery to 36 ± 5.5% compared to 57 ± 6% in control hearts. In the presence of amiloride or HMA, force recovery in lactate‐treated hearts was significantly increased to 68 ± 16% and 72 ± 4.7% of preischaemic values, respectively. In spontaneously beating hearts, resting tension changes during both ischaemia and reperfusion were not statistically different between treatment groups. However, in paced hearts pretreated with 40 mm lactate the elevation in resting tension during the first 5 min of reperfusion, was significantly reduced by both amiloride and HMA. Changes in functional recoveries produced by either lactate or Na+/H+ exchange inhibitors were unrelated to alterations in high energy phosphate depletion during ischaemia or to repletion of these compounds after 30 min reperfusion either in spontaneously beating or electrically paced hearts. The results suggest that stimulated Na+/H+ exchange activation at reflow contributes, at least partially, to lactate‐induced depression of postischaemic recovery. 1993 British Pharmacological Society