The involvement of lactate and calcium as mediators of the electrical and mechanical responses of the myocardium to conditions of simulated ischaemia

Abstract

Polytechnic, Leicester LE1 9BH 1 Rat isolated and superfused atria weie exposed to a lactate-containing solution simulating the composition of extracellular fluid during myocardial ischaemia (SI). 2 Atria subjected to SI showed a decreased adenosine 5'-triphosphate (ATP) content, a rise in diastolic tension, a diminished conduction velocity of action potentials and shortened refractory periods. All these changes were less pronounced during lactate-free SI. 3 Atria preloaded with calcium displayed exaggerated responses measured electrically and mechanically during exposure to SI, whereas atria previously depleted of calcium displayed diminished electrical and mechanical responses to SI. Neither calcium loading nor calcium depletion modified the SI-induced depletion of the atrial stores of ATP. 4 Sulphinpyrazone protected atria against all aspects of the response to SI, but failed to protect the muscle under conditions of lactate-free SI. It is concluded that during SI, sulphinpyrazone protects against a lactate-mediated inhibition of the glycolytic synthesis of ATP. 5 Flufenamate exaggerated all responses of the atria to SI. These deleterious actions were still observed during lactate-free SI. It is concluded that flufenamate inhibits the synthesis of ATP in the mitochondria. IntroductionSimulated ischaemia (SI) is said to exist when a tissue is exposed in vitro to a solution the composition of which resembles that found extracellularly in regions of ischaemia. During SI in rat atrial muscle the conduction velocity (CV) of action potentials is reduced, as are the durations of both action potentials and refractory periods. These responses are accompanied by progressive contracture development and a characteristic pattern of structural changes, notably in the mitochondria (Northover & Northover, 1988). Return of the myocardium to a solution of normal composition gradually reverses all of these changes. Pretreatment of the atria with sulphinpyrazone protects the myocardium during SI, but flufenamate, another non-steroidal antiinflammatory agent, has a deleterious action (Northover & Northover, 1988).A rise in the diastolic concentration of Ca in the myoplasm is believed to represent an important stage in the series of events responsible for the structural and functional changes observed during SI (Northover & Northover, 1988). In some of the present experiments the diastolic Ca concentration in the myoplasm has been deliberately elevated before exposure to SI. By noting which components of the response to SI were enhanced under these circumstances evidence was obtained concerning the ways in which Ca is involved as a mediator.Lactate is another substance known to accumulate in the ischaemic myocardium (Neely & Grotyohann, 1984), and is an ingredient of the fluid used to produce SI. Moreover, lactate is known to potentiate some of the functional changes in the atria produced by the other ingredients of this fluid (Northover, 1987). Under certain circumstances lactate is known to inhibit glycolysis (Rovetto et al...

Continuous fluorimetric assessment of the changes in cytoplasmic calcium concentration during exposure of rat isolated myocardium to conditions of simulated ischaemia

“…Sulphinpyrazone, like glucose, only slightly delayed the SI-induced reduction in systolic increments in the F400/500 ratio in the present experiments ( (Northover, 1987). Since sulphinpyrazone has been shown to protect against this shortening (Northover, 1987) (Northover, 1989). The fact that the presence of lactate during SI enhanced the rise in end-diastolic [Ca], in the present experiments is consistent with a raised [Ca], being responsible for these electrical disturbances.…”

“…Exposure of the rat atrium to conditions of SI previously was shown to elicit a wide range of mechanical, electrical, biochemical and structural abnormalities (Northover, 1987;1989;Northover & Northover, 1988). The tension changes shown in Figure 3 confirm these earlier findings and permit comparisons to be made with contemporary changes in [Ca],.…”

“…The fact that the presence of lactate during SI enhanced the rise in end-diastolic [Ca], in the present experiments is consistent with a raised [Ca], being responsible for these electrical disturbances. This suggestion gains additional support from the fact that the presence of glucose during SI protected the myocardium not only against the rise in end-diastolic [Ca], in the present experiments (Table 1), but also against the shortening of atrial refractory periods and the slowing of conduction velocity in previous work (Northover, 1989). Possible mechanisms whereby the changes in [Ca], that are seen during SI may provoke these electrical disturbances have been discussed previously (Northover, 1987;1989;Northover & Northover, 1988).…”

“…Why the presence of lactate during SI was necessary for the loss of systolic increments in [Ca]0 is not known. Depletion of the myocardial store of ATP is known to be less severe when rat atria are subjected to SI in the absence rather than the presence of lactate, and this difference has been attributed to the ability of lactate to inhibit glycolysis (Northover, 1989 (Northover, 1989 (Kammermeier et al, 1982;Allen & Orchard, 1983). Kentish & Allen (1986) Sulphinpyrazone is another agent that is known to protect atria against ATP-depletion during the first 15min of SI (Northover, 1989).…”

“…This has permitted some previously described functional and biochemical abnormalities that occur during this type of injury (Northover, 1987;1989;Northover & Northover, 1988) to be correlated with contemporary changes in [Ca], measured with indo-1. It has also permitted a reexamination of the effects of drugs that were shown previously to be protective in this model of cardiac injury.…”