e0063 Cardioprotection by ischaemic preconditioning is lost in isolated diabetic hearts: role of transient receptor potential vanilloid 1

Objective Extensive studies demonstrated that diabetes abolished the effectiveness of cardioprotection by ischaemic preconditioning (IPC) during ischaemia/reperfusion. Transient receptor potential vanilloid type 1 (TRPV1) contributes to the cardioprotective effect of IPC against ischaemia/reperfusion injury through the release of calcitonin gene-related peptide (CGRP) and substance P (SP). Our previous study found that the expression of TRPV1 receptor and the level of CGRP and SP were decreased in diabetic hearts. However, whether the underlying mechanism of the loss of cardioprotection by IPC during diabetes is associated with the impairment of TRPV1 receptor remains largely unknown. Methods Isolated hearts from streptozotocin-induced diabetic rats and normal control rats were subjected to 30 min of global ischaemia followed by 40 min of reperfusion. IPC was initiated by 3 cycles of 5 min of global ischaemia and 5 min of reperfusion before prolonged ischaemia in the presence or absence of CGRP or SP receptor inhibitor. Diabetic and normal control hearts were also pre-treated with CGRP or SP before prolonged ischaemia. Cardiac function parameters including left ventricular end-diastolic pressure, left ventricular developed pressure, maximum rise/fall rate of LV pressure, coronary flow and rate-pressure product and myocardial injury markers including creatine kinase (CK) and cardiac troponin I (cTnI) in coronary effluent were monitored during the experiment. In addition, CGRP and SP release in coronary effluent during IPC were measured in the presence or absence of TRPV1 receptor inhibitors. Results IPC effectively protected the hearts against ischaemia/reperfusion injury by improving the recovery of cardiac function and lowering CK and cTnI release in coronary effluent in normal control rats, but not in diabetic rats. Pre-treatment with CGRP or SP significantly increased the recovery of cardiac function and decreased CK and cTnI release during ischaemia/reperfusion in both normal control and diabetic rats, and these cardioprotection of pre-treatment with CGRP or SP in normal control rats were comparable to those of IPC. In addition, inhibition of CGRP or SP receptor essentially abolished the cardiac protective effects of IPC in normal control rats, but not in diabetic rats. IPC resulted in significant increase of CGRP and SP release in coronary effluent of normal control hearts, and which were effectively inhibited by TRPV1 receptor inhibitor, capsazepine or ruthenium red. However, IPC had no effects on CGRP and SP release in coronary effluent of diabetic hearts in the presence or absence of capsazepine or ruthenium red. Conclusions Cardioprotection by IPC against ischaemia/reperfusion injury is lost during diabetes, and their underlying mechanism is partly associated with the decreased CGRP and SP release due to the impairment of TRPV1 receptor in diabetic hearts.