Cardioprotective effect of hyperthyroidism on the stunned rat heart during ischaemia–reperfusion: energetics and role of mitochondria

Abstract

New Findings r What is the central question of this study?Hyperthyroidism is a cardiac risk factor, but thyroid therapy is used on myocardial stunning. What is the consequence of hyperthyroidism for mitochondrial metabolism and Ca 2+handling of the postischaemic stunned heart? r What is the main finding and its importance?Hyperthyroidism reduced stunning and improved muscle economy of the postischaemic rat heart. The activities of the mitochondrial sodium-calcium exchanger and mitochondrial K + channel in hyperthyroid rat hearts were different from those in the euthyroid rat hearts. These findings contribute to the understanding of mitochondrial bioenergetics in pathology and support thyroid therapy in the stunning induced by ischaemia.Transient ischaemia and hyperthyroidism are cardiovascular risk factors. Nevertheless, 3,5,3 -triiodothyronine/thyroxine therapy has been used to revert myocardial stunning. We studied the influence of hyperthyroidism on the role played by mitochondria in myocardial stunning consequent to ischaemia-reperfusion. Rats were injected s.c. daily with 20 μg kg −1 triiodothyronine for 15 days (HpT group). Isolated ventricles from either HpT or euthyroid (EuT) rats were perfused in a calorimeter, and left intraventricular pressure (in millimetres of mercury) and heat release (Ht; in milliwatts per gram) were measured. Stunning was evoked by 20 min of no-flow ischaemia and 45 min reperfusion. The HpT hearts developed higher postischaemic contractile recovery (PICR) and improved total muscle economy (P/Ht) with lower diastolic contracture ( LVEDP) than EuT hearts. Release of Ca 2+ from the sarcoplasmic reticulum during reperfusion with 10 mm caffeine in low-[Na + ] Krebs solution evoked a higher contracture in EuT than in HpT hearts. Blockade of the mitochondrial sodium-calcium exchanger with clonazepam increased LVEDP and reduced P/Ht and PICR in HpT but not in EuT hearts. The clonazepam-induced dysfunction in HpT hearts was reduced by ciclosporin, suggesting a dependance on activation of the mitochondrial permeability transition pore. Blockade of the mitochondrial Ca 2+ uniporter with Ru360 reduced P/Ht and PICR to ß10% in both HpT and EuT hearts. Blockade of mitochondrial K + channels with 5-hydroxydecanoate increased LVEDP and reduced PICR and P/Ht in HpT hearts, while it only increased LVEDP in EuT hearts. The results suggest that hyperthyroidism prevents the stunning with high dependence on the mitochondrial sodium-calcium exchanger and mitochondrial K + channels. IntroductionThyroid dysfunction, either clinical or subclinical, has been related to the increase in morbidity and mortality associated with cardiovascular episodes (Klein & Danzi, 2007). In particular, hyperthyroidism predisposes to long-term cardiac conditions such as hypertrophy and cardiac remodelling. Severe and untreated hyperthyroidism induces tachycardia, high cardiac workload and a risk of atrial fibrillation related to the upregulation of β-adrenergic receptors (Nyirenda et al. 2005). Some patients suffer symptoms...

Low-flow ischaemia and reperfusion in rat hearts: energetic of stunning and cardioprotection of genistein

“…Results suggest that the mNCX inhibition increases the mitochondrial Ca 2+ ‐dependent metabolism and the associated Ht (P/Ht falls) while reduces the cytosolic Ca 2+ and consequently the ∆LVEDP, in agreement to that suggested for these selective drugs . We have found that Clzp increased PICR in guinea‐pig hearts and in rat hearts exposed to no‐flow ischaemia. Results suggest that mitochondria contribute to the stunning because under LFI the mitochondria may be losing Ca 2+ through the mNCX.…”

“…Results suggested that blockade of mitochondrial Ca 2+ uptake through the UCam with Ru360 reduced P during both LFI and R in FH, with a fall in muscle economy during the hypoperfusion (Figure ). On this model, P was less affected than in a model of rat hearts exposed to no‐flow ischaemia and R with the same degree of stunning, in which Ru360 reduced PICR from about 75–20% . It was also reported that Ru360 reduced the rise in [Ca 2+ ]m suffered by rabbit cardyomyocytes under simulated I/R .…”

“…Hearts were retrogradely perfused by Langerdorff technique with Krebs solution, at a constant flow of 8 ml/min per gram with a peristaltic pump (Gilson Minipuls, Villiers‐le‐Bel, Paris, France) . As described in previous works, perfusion flow was calculated by the equation CF = 7.43*HW 0.56 (where CF is coronary flow and HW is the heart weight) to prevent heart edema . Atria and any focus of spontaneous beating in the right ventricle were removed.…”

“…[20,23,24] As described in previous works, perfusion flow was calculated by the equation CF = 7.43*HW 0.56 (where CF is coronary flow and HW is the heart weight) to prevent heart edema. [25,26] Atria and any focus of spontaneous beating in the right ventricle were removed. A latex balloon filled with water was introduced in the left ventricle and connected by a cannula to a Bentley DEL900 pressure transducer.…”

“…After 45 min of ischaemia the hearts exposed to all the treatments were reperfused during 45 min with Krebs-C, except those pretreated with Cys-A which were reperfused with C + Cys-A, as previously reported. [24,26,31] Figure 2 shows a typical mechano-energetical recording of a control heart exposed to LFI/R (up) and a heart from a Gen-ip treatment (down).…”