Long-term thyroxine administration increases heat stress protein-70 mRNA expression and attenuates p38 MAP kinase activity in response to ischaemia.

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 microg/100 g 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 (PKCepsilon) 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<0.05). 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 2.2-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). PKCepsilon 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.

Propranolol diminishes cardiac hypertrophy but does not abolish acceleration of the ischemic contracture in hyperthyroid hearts.

This study was undertaken to define the contributions of left ventricular hypertrophy (LVH) and increased adrenergic activity to the acceleration of ischemic contracture (IC) that occurs in chronic hyperthyroid rat heart. Acute and chronic hyperthyroidism (THYR) were induced by thyroxine administration for 2 and 14 days, respectively, and normal animals (NORM) served as controls. Isolated hearts were perfused in a Langendorff mode. NORM alpha acute, n = 6; THYR alpha acute, n = 8; and THYR alpha, n = 13; and NORM alpha, n = 13 were subjected to 20-min zero-flow global ischemia (I) and 45-min reperfusion (R). Additional THYR and NORM hearts treated with propranolol (prop) were subjected to 30-min I; THYR beta prop, n = 6 and NORM beta prop, n = 8, and THYR beta, n = 6, NORM beta, n = 8 served as controls. Acceleration of IC was measured by the time to peak contracture (Tmax). Left ventricular hypertrophy (LVH) was assessed by the ratio of left ventricular weight in milligrams (LVW) to animal body weight (BW) in grams. Cardiac hypertrophy developed in chronic but not acute hyperthyroidism. Propranolol reduced the extent of LVH. Contracture occurred earlier in chronic than in acute hyperthyroid and normal hearts. Propranolol did not alter contracture. In conclusion, IC is accelerated by thyroxine administration, and this is probably not due to LVH or increased beta-adrenergic activity. Propranolol diminishes LVH in hyperthyroidism.

Hyperthyroidism is associated with preserved preconditioning capacity but intensified and accelerated ischaemic contracture in rat heart.

BACKGROUND: The present study was undertaken to define the effects of thyroxine administration on ischaemic preconditioning (PC) and the ischaemic contracture. METHODS: Hyperthyroidism was induced by administration of L-thyroxine in rats (THYR) while normal animals served as controls (NORMa). Isolated rat hearts were perfused in a Langendorff preparation. NORMa control (n = 16) and THYR control (n = 9) hearts underwent 20 min of ischaemia and 45 min reperfusion while NORMa PC (n = 16) and THYR PC (n = 14) were subjected to PC before ischaemia. Additional normal hearts were subjected to 30 min of ischaemia with and without PC, NORMb control, n = 8 and NORMb PC, n = 6. Postischaemic recoveries of left ventricular (LV) developed pressure were expressed as % of the initial value (LVDP%). Severity of contracture was measured by the time (Tmax) and magnitude (Cmax) of peak contracture. RESULTS: LVDP% was significantly higher after PC, both in NORMa and THYR rats. In NORMa control hearts, ischaemic contracture had not yet reached a plateau at 20 min of ischaemia. Contracture appeared earlier in THYR control and PC than in NORMa control and PC groups. Tmax was 22.1 (0.9) vs 16.8 (1.4) min for NORMb control and PC, p < 0.05 and 12.5 (1.0) vs 9.3 (1.1) min for THYR control and PC hearts, p < 0.05. Tmax was earlier in both THYR groups compared to NORMb groups, p < 0.05. Cmax was significantly higher in both THYR groups compared to both NORMb groups. CONCLUSION: Ischaemic contracture is both accelerated and accentuated in thyroxine treated hearts while preconditioning capacity is preserved. Preconditioning and thyroxine administration shorten Tmax in an additive way, whereas Cmax in hyperthyroid hearts did not further increase by preconditioning.

Ischaemic preconditioning protects against myocardial dysfunction caused by ischaemia in isolated hypertrophied rat hearts.

Although ischaemic preconditioning (PC) has been shown to protect normal hearts from a subsequent ischaemic insult, its protective effect on the hypertrophied myocardium has not been widely studied. This study was designed to investigate whether ischaemic preconditioning protects hearts with hypertrophy (HYP). Cardiac HYP was produced in rats by suprarenal abdominal aortic constriction of 5 weeks' duration, and was defined as left ventricular weight: body weight [LVW: BW (mg/g)] ratio over 3.0. Isolated rat hearts were perfused with a modified Krebs-Henseleit buffer at 37 degrees C in a Langendorff preparation. Hearts from sham-operated animals (NORM) and those with HYP underwent a PC protocol consisting of 3 min of global zero flow ischaemia, 5 min of reperfusion followed by 5 min of ischaemia and 5 min of reperfusion. This was followed by 20 min ischaemia and 45 min reperfusion. Control hearts in the HYP and NORM groups were not subjected to the PC protocol. There were, thus, four experimental groups: NORM control (n = 9), NORM, PC (n = 9), HYP control (n = 9), HYP, PC (n = 11). The recovery of function after ischaemia was evaluated by recovery of left ventricular developed pressure (LVDP) expressed as % of the initial value (LVDP%). The LVW: BW ratio for the HYP groups was 3.4 (SEM 0.08). LVDP% was higher (p < 0.01) in preconditioned groups as compared with controls. In NORM control recovery was 49.3 (6.1), NORM, PC 76.5 (3.4), HYP control 39.8 (4.6) HYP, PC 70.1 (4.1). These data indicate that the ability of preconditioning to protect against ischaemic ventricular dysfunction is preserved in this model of cardiac hypertrophy.