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We have previously shown that long-term thyroxine administration can protect the heart against ischemia. In the present study, we investigated whether thyroxine-induced cardioprotection can mimic the pattern of protection that is afforded by a well-established cardioprotective means such as ischemic preconditioning. In a Langendorff-perfused rat heart preparation, after an initial stabilization, normal and thyroxine-treated hearts were subjected to 20 minutes of zero-flow global ischemia followed by 43 minutes of reperfusion. In thyroxine-treated hearts, phospho-p38 mitogen-activated protein kinase (MAPK) was found to be less at the end of the ischemic period, whereas ischemic contracture was accelerated and postischemic recovery was increased in comparison to normal hearts. In addition, normal hearts were subjected to a four-cycle preconditioning protocol before ischemia. Phospho-p38 MAPK was found to be less at the end of the ischemic period in preconditioned hearts, whereas ischemic contracture was accelerated and postischemic functional recovery was increased in those hearts in comparison to nonpreconditioned hearts. An increase in basal expression and phosphorylation of PKCdelta was also found to occur after long-term thyroxine administration. We conclude that long-term thyroxine administration can protect the heart from ischemic injury through a pattern of protection that closely resembles that of ischemic preconditioning.

The present study was undertaken to investigate heat stress protein (HSP)-70 mRNA induction and p38 MAP kinase (MAPK) activity in response to ischaemic stress in the hyperthyroid rat heart. L-Thyroxine (T-4) (25 mug/100g body weight) was administered to Wistar rats for 2 days (THYRacute) or 14 days (THYR), while animals treated similarly with normal saline served as controls (NORMacute and NORM). In addition, abdominal aortic banding was performed in another group of rats to produce constriction-induced hypertrophy (HYP), while sham-operated (SOP) animals served as controls. Isolated rat hearts were perfused in a Langendorff mode. Hearts from NORMacute (n = 6), THYRacute animals (n = 8), NORM (n = 6), THYR (n = 6), SOP (n = 5) and HYP (n = 7) animals were subjected to 20 min of zero-flow global ischaemia followed by 45 min of reperfusion. HSP70 mRNA expression and phosphorylated p38 MAPK protein expression were detected in response to ischaemia and protein kinase C-epsilon (PKC epsilon) protein expression was detected at baseline. Thyroid hormones were measured in plasma. Long-term T-4 administration and aortic constriction resulted in the development of cardiac hypertrophy. Thyroid hormones were increased in both THYR and THYRacute as compared with normal groups (P < 005). HSP70 mRNA induction was increased 2.3-fold in THYR as compared with NORM hearts (P < 0.05), whereas there was not any difference between THYRacute and NORMacute hearts (P > 0.05). Phosphorylated p38 MAPK protein expression was 22-fold more in NORM than in THYR hearts (P < 0.05), but it was not different between NORMacute and THYRacute hearts (P > 0.05). HSP70 mRNA induction was 1.8-fold greater in HYP than in SOP hearts (P < 0.05), whereas phosphorylated p38 MAPK protein expression was similar between the two groups (P > 0.05). PKC epsilon protein expression at baseline was 1.7-fold more in NORM than in THYR hearts (P < 0.05), and not different between NORMacute and THYRacute hearts (P > 0.05) as well as HYP and SOP hearts (P > 0.05). This study shows that HSP70 mRNA expression is increased, whereas p38 MAPK activation is attenuated in response to ischaemia in long-term T-4-treated rat hearts as compared with normal and acute hyperthyroid hearts.