The role of endogenous angiotensin II in ischaemia, reperfusion and preconditioning of the isolated rat heart

Abstract

We examined the possibility that endogenous angiotensin II (AII) is involved in the regulation of the cardiac Na(+)/H(+) exchanger (NHE1) during ischaemia, reperfusion and preconditioning. Mechanical function and intracellular sodium ([Na(+)](i)) were studied in isolated, perfused rat hearts. To test whether AII production might underlie the increased activity of NHE1 on reperfusion, we applied the AII receptor antagonist losartan during ischaemia and reperfusion. Losartan significantly improved mechanical performance on reperfusion and reduced the peak [Na(+)](i) on reperfusion. It has been proposed that preconditioning inhibits the activity of NHE1 in early reperfusion. To test whether this might be because of impaired action of AII on NHE1 we applied AII throughout ischaemia and reperfusion in preconditioned hearts. AII abolished the improved mechanical recovery caused by preconditioning and the peak [Na(+)](i) on reperfusion was similar to that after ischaemia alone. Addition of the NHE1 antagonist cariporide or losartan simultaneously with AII, reversed the deleterious effects of AII on the preconditioned heart. These studies suggest that AII contributes to the activation of NHE1 in early reperfusion and that part of the beneficial effect of preconditioning may be attributed to the abolition of AII-induced activation of NHE1.

The rise of [Na+]i during ischemia and reperfusion in the rat heart—underlying mechanisms

“…It is accepted that the magnitude of the rise in [Na + ] i , measured during reperfusion, correlates inversely with the magnitude of recovery [28,34,46]. As a consequence, imaging of myocardial [Na + ] i has potential for recognizing ischemic regions of the heart and assessing viability after reperfusion [20].…”

The role of Na+/H+ exchanger in Ca2+ overload and ischemic myocardial damage in hearts from type 2 diabetic db/db mice

“…In addition, the use of HCO 3 - free, HEPES buffered perfusion solution might have enhanced the contribution of NHE1 in the present study [30]. Among known factors stimulating cardiac NHE1 activity are [Ca 2+ ] i [31,32] and angiotensin II [33-35]. In ventricular myocytes of diabetic db/db mice, NHE1 activity might be stimulated by basal alterations in [Ca 2+ ] i , due to increased Ca 2+ leakage [18].…”

“…Concerning clinical applications, blockade of NHE may provide salutary effects for diabetic patients with ischemic heart disease through an interaction with PKB/Akt [39,40] and other mechanisms [29,31-35]. However, it is unfortunate that the majority of trials conducted to test the effects of NHE inhibitors in ischemic heart disease cases have failed [41].…”

AICAR inhibits the Na+/H+ exchanger in rat hearts—possible contribution to cardioprotection

“…A number of studies have demonstrated an inverse correlation between Na + influx on reperfusion and degree of mechanical recovery on reperfusion [32,41,44]. Our previous study [44] used a model of ischemia identical to that of the present study and showed a strong correlation between peak [Na + ] i on reperfusion and percent of recovery of LVDP under five different experimental conditions (see Fig.…”

“…Our previous study [44] used a model of ischemia identical to that of the present study and showed a strong correlation between peak [Na + ] i on reperfusion and percent of recovery of LVDP under five different experimental conditions (see Fig. 4 in Xiao and Allen [44]). The strength of this correlation suggests that the level of [Na + ] i can explain most of the variation in the degree of recovery.…”