Pregnancy and the perinatal period: The impact of attachment theory.

Ιn this study we aim to examine and integrate current literature and research on attachment theory and its expression on the specific field of obstetrics, the perinatal period. In medical settings in general, and in the field of obstetrics in specific, which is the clinical domain of the perinatal period, obstetricians, psychiatrists and psychologists frequently come across antenatal and postnatal concerns, psychological issues as well as psychiatric symptomatology stemming from closer observation of the women's difficulties or reported by women themselves. To our theoretical understanding, in order to better comprehend these psychosocial concerns and deliver timely and more effective personalized interventions to women in need, it is of paramount importance to thoroughly examine the perspective proposed by attachment theory, as it was first developed by child psychiatrist-psychoanalyst John Bowlby and the newest theoretical developments on the field that followed. Subtypes of attachment style are examined regarding their imprint on the benefits, as well as the difficulties and risks they place on women during each perinatal stage. "Insecurity" in attachment and significant relationships appears to render women more vulnerable in relation to psychopathology, according to the literature reviewed. As far as the psychopathological symptoms and disorders related to the perinatal period and their connection to attachment are concerned, the main disorders and symptomatology discussed in the literature appear to be perinatal depression, postpartum depression, perinatal anxiety and posttraumatic stress symptoms related to pregnancy and labor. At the same time, "security" attachment-wise, tangibly observed in couples with strong intramarital support, appears to offer a protective barrier against adversities by enabling securely attached women to remain calmer and make better use of their emotional and social resources throughout the challenging perinatal phase. Consequently, mothers-to-be become more eligible to overcome perinatal difficulties by the use of patterns of behavior that promote their well-being. Through the in-depth review of the current literature on attachment theory available and the tools of knowledge it equips us with, we attempted to assemble the real challenges and needs deriving from the demands that pregnancy, labor and the postpartum place on new mothers, as well as the way close relationships become affected by or, correspondingly, can be positively used in order to protect and shield women and their families from acknowledged stressful perinatal phases.

Intracerebroventricular endothelin receptor-A blockade in rats decreases phase-II ventricular tachyarrhythmias during acute myocardial infarction.

Endothelin alters central sympathetic responses, but the resultant effects on arrhythmogenesis are unknown. We examined ventricular tachyarrhythmias after endothelin receptor-A blockade in the brain of Wistar rats with acute myocardial infarction. For this aim, BQ-123 (n=6) or phosphate-buffered saline (n=6) were injected intracerebroventricularly. After 10 min, the left coronary artery was ligated, followed by implantation of telemetry transmitters. Electrocardiography and voluntary activity (as a surrogate of acute left ventricular failure) were continuously monitored for 24 h. Infarct-size was similar in the two groups. There were fewer episodes of ventricular tachyarrhythmias of shorter average duration in treated rats, leading to markedly shorter total duration (12.3+/-8.9 s), when compared to controls (546.2+/-130.3 s). Voluntary activity increased in treated rats during the last hours of recording, but bradyarrhythmic episodes were comparable between the two groups. Endothelin receptor-A blockade in the brain of rats decreases the incidence of ventricular tachyarrhythmias post-ligation, without affecting bradyarrhythmic episodes. These findings call for further research on the pathophysiologic role of endothelin during acute myocardial infarction.

Clenbuterol favorably remodels neonatal cardiac cells via activation of p38 MAPK signalling pathway.

AIM: Pharmacologic treatments which aim to induce physiological hypertrophy are now thought as novel treatments for heart failure. Thus, clenbuterol, a beta-2 adrenergic agonist has recently been shown to partially reverse cardiac remodeling by inducing physiological hypertrophy. The present study further investigated potential underlying mechanisms of this effect in a neonatal cardiomyocytes cell based model. METHODS: Neonatal cardiomyocytes obtained from newborn rats were exposed to clenbuterol (CLEN, 1µM) for five days, while untreated cells served as controls. CLEN administration resulted in well organized orientation of cytoskeletal fibers manifesting as a longitudinal cell shape, while had no effect on myosin heavy chain (MHC) isoform expression. CLEN increased cell growth as indicated by protein content: total protein per cell (pg/cell) was 116 (6.0) for CLEN and 77 (5.0) for the untreated cells, P<0.05. This response was accompanied by a 2.2 fold increase in phospho-p38 MAPK levels as compared to untreated cells, P<0.05 while no changes were observed in ERK, JNK and Akt. Administration of SB203580 (a p38 MAPK inhibitor) abrogated the CLEN induced changes in cardiomyocyte morphology, while it had no effect on protein content. CONCLUSION: Clenbuterol induces favorable changes in neonatal cardiomyocyte shape and geometry without affecting MHC isoform expression. Activation of p38 MAPK signaling seems, at least in part, to be implicated in this response.

Masked hypertension unfavourably affects haemostasis parameters.

OBJECTIVE. Recent evidence demonstrates that masked hypertension (MH) is a significant predictor of cardiovascular disease. The aim of our study was to examine the impact of MH on haemostasis parameters and to compare the findings to those of healthy normotensives matched for age, sex, body mass index and the rest of risk factors. DESIGN AND METHOD. 130 (60 male, 70 female) healthy subjects mean age 45 ± 12 years who had clinic blood pressure < 140/90 mmHg were studied. The whole study population underwent 24-h ambulatory blood pressure monitoring (ABPM). According to the ABPM recordings, 24 individuals (eight males, 16 females) had MH (daytime systolic blood pressure ≥ 135 mmHg or daytime diastolic blood pressure ≥ 85 mmHg - group A) and the remaining 106 subjects (52 males, 54 females) had normal ABPM recordings - group B. Fibrinogen, thrombomodulin ™, the antigens of plasminogen activator inhibitor 1 (PAI-1Ag) and tissue plasminogen activator (tPA-Ag) were determined in the two groups. Results. The PAI-1 Ag, tPA-Ag, fibrinogen and TM levels were significantly higher in the masked hypertensive group than to normotensive control group. CONCLUSIONS. Our findings suggest that subjects with MH have significantly higher fibrinogen, TM, PAI-1Ag and tPA-Ag plasma levels compared with normotensives. This observation may have prognostic significance for future cardiovascular events in subjects with MH and needs further investigation.

Thyroid hormone receptor alpha1 downregulation in postischemic heart failure progression: the potential role of tissue hypothyroidism.

Thyroid hormone (TH) signaling is altered in response to various stresses including myocardial ischemia. The present study investigated potential implication of TH signaling in the pathophysiology of postischemic remodeling. Acute myocardial infarction was induced in rats by coronary artery ligation (AMI). After 34 weeks, 6 animals were on congestive heart failure (CHF) as indicated by measurements in lung and right ventricular weight. 7 animals were in compensated state (Non-CHF) and 8 sham-operated animals (SHAM) served as controls. Progression to congestive heart failure was characterized by marked decrease in EF% and all other functional echocardiographic parameters. Furthermore, beta-MHC expression was significantly increased in CHF. A distinct pattern of thyroid hormone receptor (TR) expression was observed in the course of postischemic remodeling; TR alpha 1 was upregulated and TR beta 1 was downregulated in Non-CHF, and TR alpha 1 expression was markedly decreased during the transition from Non-CHF to CHF resulting in tissue hypothyroidism. Circulating T3 and T4 remained unchanged. This response was associated with marked decrease in mTOR activation. A potential link between mTOR and TR alpha 1 expression was shown in a neonatal cardiomyocytes model of PE (phenylephrine)-induced pathological growth. Phenylephrine increased the expression of TR alpha 1 in nucleus and this response was abrogated in the case of mTOR inhibition by rapamycin. In conclusion, progression to congestive heart failure after myocardial infarction is associated with suppressed expression of TR alpha 1 and results in tissue hypothyroidism. This process may, at least in part, be mTOR dependent.

Thyroid hormone at supra-physiological dose optimizes cardiac geometry and improves cardiac function in rats with old myocardial infarction.

Thyroid hormone (TH) is critical in cardiac cell differentiation (regulating contractile proteins and cell geometry) and this effect could be potentially exploited therapeutically in reversing the process of de-differentiation which underlies postischemic cardiac remodeling. Acute myocardial infarction was induced in male Wistar rats by ligating left coronary artery (AMI, n=8), while sham operated animals served as control (SHAM, n=8). 13 weeks after AMI, TH was administered in a group of animals for 4 weeks (AMI-THYR, n=9). TH significantly increased beta-MHC and decreased alpha-MHC expression in the myocardium. This response was accompanied by changes in cardiac geometry: sphericity index, (SI, long to short axis ratio) was found to be 1.95 (SEM, 0.02) in SHAM, 1.51(0.03) in AMI and 1.64(0.03) in AMI-THYR, p<0.05. As a consequence, cardiac function was significantly improved: left ventricular ejection fraction (EF%) was 74.5% (SEM, 2.8) in SHAM vs 29.5% (2.1) in AMI, and 40.0% in AMI-THYR, p<0.05. Furthermore, +dp/dt and -dp/dt were 4250 (127) and 2278 (55) in SHAM vs 2737(233) and 1508 (95) in AMI vs 3866 (310) and 2137(111) in AMI -THYR, respectively, p<0.05. TH treatment partially reverses cardiac dysfunction in rats with old myocardial infarction by favorably changing cardiac chamber geometry and expression of myosin isoforms. Thyroid hormone, unlike current treatments, appears to be a paradigm of therapeutic intervention which aims at restoring cardiac geometry and may prove new effective treatment for heart failure.

Thyroid hormone modulates the responsiveness of rat aorta to alpha1-adrenergic stimulation: an effect due to increased activation of beta2-adrenergic signaling.

AIM: The ability of the thyroid hormone to increase cardiac output and to lower systemic vascular resistance may provide a novel treatment for cardiovascular diseases. Therefore, understanding the mechanisms of thyroid hormone action on the heart and peripheral vasculature could be of clinical importance. We previously found that thyroid hormone modulates the alpha1-adrenergic effect on vascular reactivity of rat aortas. In the present study we further investigated possible mechanisms of this response. METHODS: Hyperthyroidism was induced on Wistar-Kyoto male rats with L-Thyroxine, (THYR) treatment for two weeks, N.=18 while untreated rats used as controls (NORM), N.=16. The thoracic aorta was dissected and cut into rings that were suspended in an isolated organ bath with Krebs-Henseleit buffer. Maximal tension, Tmax, in g was measured in response to Potassium Chloride (KCl) and Phenylephrine (PE) in rings in the presence of Ritodrine, a beta-2 agonist (NORM-RITO, N:=8, THYR-RITO, N.=9), or in the absence of Ritodrine (THYR, N.=9, NORM, N.=8). RESULTS: With KCL, Tmax was not different between the THYR, NORM, NORM-RITO, and THYR-RITO groups. With PE, there was a difference in Tmax between NORM-RITO and NORM, 0.66 (0.056) g vs 1.00 (0.066) g, P<0.05 and THYR and NORM, 0.75 (0.055) g vs 1.00 (0.066) g, P<0.05. No significant difference was observed between THYR-RITO AND THYR. Furthermore, Relax % was not significantly different between the NORM and the THYR, NORM-RITO, and THYR-RITO groups, 64.5%(3.7) vs 67.3%(6.7), 73.5% (4.3) and 81.8 %(4.7), P>0.05. CONCLUSIONS: PE induced vasoconstriction in isolated rat aortic rings was reduced after both ritodrine and thyroxine treatment. However, co-administration of thyroid hormone and ritodrine did not result in a synergistic reduction of PE induced vasoconstriction. Thus, thyroxine may modulate the alpha1-adrenergic vascular responsiveness by enhancing beta2-adrenergic stimulation.

Ischemic preconditioning fails to confer additional protection against ischemia-reperfusion injury in the hypothyroid rat heart.

There is accumulating evidence showing that ischemic preconditioning (PC) may lose its cardioprotective effect in the diseased states. The present study investigated whether PC can be effective in hypothyroidism, a clinical condition which is common and often accompanies cardiac diseases such as heart failure and myocardial infarction. Hypothyroidism was induced in rats by 3-week administration of 6n-propyl-2-thiouracil in water (0.05 %). Normal and hypothyroid hearts (HYPO) were perfused in Langendorff mode and subjected to 20 min of zero-flow global ischemia and 45 min of reperfusion. A preconditioning protocol (PC) was also applied prior to ischemia. HYPO hearts had significantly improved post-ischemic recovery of left ventricular developed pressure, end-diastolic pressure and reduced lactate dehydrogenase release. Furthermore, phospho-JNK and p38 MAPK levels after ischemia and reperfusion were 4.0 and 3.0 fold lower in HYPO as compared to normal hearts (P<0.05). A different response to PC was observed in normal than in HYPO hearts. PC improved the post-ischemic recovery of function and reduced the extent of injury in normal hearts but had no additional effect on the hypothyroid hearts. This response, in the preconditioned normal hearts, resulted in 2.5 and 1.8 fold smaller expression of the phospho-JNK and phospho-p38 MAPK levels at the end of reperfusion, as compared to non-PC hearts (P<0.05), while in HYPO hearts, no additional reduction in the phosphorylation of these kinases was observed after PC. Hypothyroid hearts appear to be tolerant to ischemia-reperfusion injury. This response may be, at least in part, due to the down-regulation of ischemia-reperfusion induced activation of JNKs and p38 MAPK kinases. PC is not associated with further reduction in the activation of these kinases in the hypothyroid hearts and fails to confer added protection in those hearts.

Thyroid hormone receptor alpha 1: a switch to cardiac cell "metamorphosis"?

Thyroid hormone receptor alpha1 (TRalpha1) is predominantly expressed in the myocardium but its biological function under physiological or pathological conditions remains largely unknown. The present study investigated possible interactions between alpha1 adrenergic and thyroid hormone signaling at the level of TRalpha1, potential underlying mechanisms and physiological consequences, as well as the role of TRalpha1 in cell differentiation. This may be of physiological relevance since both thyroid hormone and adrenergic signalling are implicated in the pathophysiology of cardiac remodelling. Neonatal cardiomyocytes obtained from newborn rats (2-3 days) were exposed to phenylephrine (PE, an alpha1 adrenergic agonist) for 5 days, in the absence or excess of T3 in the culture medium. PE, in the absence of T3, resulted in 5.0 fold increase in TRalpha1 expression in nucleus and 2.0 fold decrease in TRalpha1 expression in cytosol, P<0.05. As a result, a fetal pattern of myosin isoform expression with marked expression of beta-MHC was observed in PE treated vs the untreated cells, P<0.05. PD98059 (an ERK signalling inhibitor) abrogated this response. In the presence of T3 in the culture medium, TRalpha1 expression was increased 1.6 fold in nucleus and 2.0 fold in cytosol in PE-T3 vs PE treated cells, P<0.05, and the fetal pattern of myosin isoform expression was prevented. Parallel studies with H9c2 myoblasts showed that reduction of T3 binding to TRalpha1 receptor delayed cardiac myoblasts differentiation without affecting proliferation. In conclusion, in neonatal cardiomyocytes, nuclear TRalpha1 is overexpressed after prolonged activation of the alpha1- adrenergic signalling by PE. This response seems to be an ERK kinase dependent process. Over-expression of TRalpha1 may lead to fetal cardiac phenotype in the absence of thyroid hormone availability. Furthermore, TRalpha1 seems to be critical in cardiac myoblast differentiation.

Pharmacological inhibition of TRalpha1 receptor potentiates the thyroxine effect on body weight reduction in rats: potential therapeutic implications in controlling body weight.

It has been previously reported that thyroid hormone receptor alpha1 (TRalpha1) is involved in the regulation of food intake and heart rhythm. Herein, we show that pharmacological inhibition of TRalpha1 by dronedarone, an amiodarone like compound (shown to antagonize thyroid hormone binding to TRalpha1), prevented the thyroid hormone induced increase in food intake and heart rate acceleration in rats. This resulted in a marked reduction in body weight. It is likely that thyroid analogs may prove potential therapeutic agents for controlling body weight.

Decreased vascular reactivity to alpha1 adrenergic stimulation in the presence of hypothyroid state: a part of an adaptive response?

AIM: A hypothyroid state frequently accompanies cardiac illnesses but its physiological significance for the cardiovascular hemodynamics remains largely unknown. Therefore, the present study investigated possible physiological consequences on vascular function in an experimental model of low thyroid hormone state. METHODS: Hypothyroidism was induced in rats by the administration of 6-n-propyl-2-thiouracil in drinking water (final concentration of 0.05%) for 3 weeks, HYPO rats, and untreated rats served as controls (Control). Isolated aortic rings with or without endothelium (E+, E-) were contracted with KCl (10 to 60 mM) and phenylephrine (PE) (10(-10) to 10(-5) M). Maximal tension (Tmax) in g and EC(50) in response to PE and KCl were measured. RESULTS: Tmax was significantly lower while EC(50) was significantly higher in response to PE in HYPO(E+) than in Control(E+). Upon endothelium removal, Tmax was not significantly different between the groups but EC(50) was still significantly higher in HYPO(E-) than in Control(E-). EC(50) in response to KCl was significantly higher in HYPO with or without endothelium and no difference was found in Tmax. CONCLUSIONS: Hypothyroid aortic rings respond less to a1 adrenergic stimulation probably due to the endothelium modulatory effect as well as to intrinsic smooth muscle defect. This seems to be of important clinical relevance.

Hyperthyroid hearts display a phenotype of cardioprotection against ischemic stress: a possible involvement of heat shock protein 70.

Hyperthyroid hearts are shown to display a phenotype of cardioprotection against ischemic stress, but the underlying signaling mechanisms remain largely unknown. The present study investigated the possible relation of HSP70 to the thyroid hormone induced cardioprotection. HSP70 is a redox-regulated molecular chaperone, and enhances cell survival under stress. Thyroxin (25 microg/100 g body weight) was administered to Wistar male rats for four days (THYR-4d) and two weeks (THYR-14d), respectively, while untreated animals served as controls (CON-4d, CON-14d). Isolated hearts from control and thyroxin treated rats were subjected to 20 min zero-flow ischemia followed by 45 min of reperfusion (I/R). The amount of HSP70 in the myocardium for THYR-14d was 1.85 times the levels of CON-14d (p < 0.05). The levels of HSP70 expression were no different between THYR-4d and CON-4d, p > 0.05. This was only accompanied by an increase in MDA levels (used as an index of oxidative stress) in THYR-14d compared to untreated hearts. These changes corresponded to a differential response of the heart to I/R; post-ischemic recovery of function was significantly increased in THYR-14d compared to CON-14d, and was no different between the THYR-4d and CON-4d hearts. In conclusion, long-term thyroxin administration results in increased tolerance of the myocardium to I/R and enhances the expression of HSP70 which may, at least in part, account for this response.

Thyroid hormone receptors alpha1 and beta1 are downregulated in the post-infarcted rat heart: consequences on the response to ischaemia-reperfusion.

There is accumulating evidence that thyroid hormone metabolism is altered after myocardial infarction (AMI) but its physiological relevance remains largely unknown. The present study investigated the possible role of thyroid hormone signaling in the response of the post-infarcted heart to ischaemia-reperfusion. Wistar rats were subjected to left coronary artery ligation (AMI), or sham operation (SHAM). After 8 weeks, hearts from AMI and SHAM rats were perfused in Langendorff mode and subjected to 20 min of zero-flow global ischaemia (I) and 45 min of reperfusion (R); AMI(I/R), n = 7 and SHAM(I/R), n = 7. Basal left ventricular pressure (LVDP), +dp/dt, and -dp/dt were significantly reduced. Left ventricular weight of the viable myocardium was increased by 14% in the AMI as compared to SHAM hearts, P < 0.05. T(3) and T(4) plasma levels in nM were 1.83 (0.08) and 53.3 (2.9) for SHAM and 1.76 (0.06) and 59.4 (5.2) for AMI rats, respectively, P > 0.05. TRalpha1 and TRbeta1 expression levels were 1.3- and 1.8-fold less in AMI than in SHAM hearts, P < 0.05. Furthermore, SERCA and NHE1 expression levels were 2.1- and 1.8-fold less in AMI than in SHAM, P < 0.05. PKCepsilon was 1.35-fold more in AMI compared to SHAM, P < 0.05. Myocardial glycogen content (in micromol/g) was 7.8 (1.2) in AMI as compared to 4.4 (0.5) for SHAM hearts, P < 0.05. After I/R, left ventricular end-diastolic pressure at 45 min of R (LVEDP45 in mmHg) was 20.3 (3.2) for AMI(I/R) vs 50.6 (4.8) mmHg for SHAM(I/R), P < 0.05. LDH release per gram of tissue was 251 (103) for AMI(I/R) and 762 (74) for SHAM(I/R), P < 0.05. In conclusion, TRalpha1 and TRbeta1 are downregulated after myocardial infarction and this was associated with altered expression of thyroid hormone responsive genes and increased tolerance of the post-infarcted heart to ischaemia-reperfusion injury.

Blockade of angiotensin II type 1 receptor diminishes cardiac hypertrophy, but does not abolish thyroxin-induced preconditioning.

Growth and stress seem to share common intracellular pathways and activation of growth signaling can increase resistance to stress. Thyroid hormone induces cardiac hypertrophy and preconditions the myocardium against ischemia reperfusion injury. The present study investigated whether this response is mediated by renin-angiotensin system (RAS). RAS is shown to be activated in hyperthyroidism and is involved in the development of cardiac hypertrophy. Male Wistar rats were treated with L-thyroxin (25 microg/100 g, sc, od) for fourteen days, while normal rats served as controls. In addition, irbesartan (150 mg/kg po), a potent blocker of angiotensin II type 1 receptor (AT1), was given with L-thyroxin for fourteen days. Isolated hearts were perfused in Langendorff mode; after stabilization, they were subjected to 20 min zero-flow global ischemia and 45 min of reperfusion. Thyroxin induced cardiac hypertrophy, which was diminished with irbesartan administration. Post-ischemic recovery of function was increased in thyroxin-treated hearts as compared to controls while ischemic contracture was accelerated and intensified. Irbesartan did not abolish this response. In conclusion, blockade of angiotensin II type 1 receptor with irbesartan preserves thyroxin-induced cardioprotection while diminishing cardiac hypertrophy. It is likely that thyroxin-induced cardioprotection is due to a direct effect of thyroid hormone.

Propylthiouracil-induced hypothyroidism is associated with increased tolerance of the isolated rat heart to ischaemia-reperfusion.

The present study investigated the response of the hypothyroid heart to ischaemia-reperfusion. Hypothyroidism was induced in Wistar rats by oral administration of propylthiouracil (0.05%) for 3 weeks (HYPO rats), while normal animals (NORM) served as controls. Isolated hearts from NORM and HYPO animals were perfused in Langendorff mode and subjected to zero-flow global ischaemia followed by reperfusion (I/R). Post-ischaemic recovery of left ventricular developed pressure was expressed as % of the initial value (LVDP%). Basal expression of protein kinase C epsilon (PKCepsilon) and PKCdelta and phosphorylation of p46 and p54 c-jun NH(2)-terminal kinases (JNKs) in response to I/R were assessed by Western blotting. LVDP% was found to be significantly higher in HYPO hearts than in NORM. At baseline, PKCepsilon expression was 1.4-fold more in HYPO than in NORM hearts, P<0.05, while PKCdelta was not changed. Furthermore, basal phospho-p54 and -p46 JNK levels were 2.2- and 2.6-fold more in HYPO than in NORM hearts, P<0.05. In response to I/R, in NORM hearts, phospho-p54 and -p46 JNK levels were 5.5- and 6.0-fold more as compared with the baseline values, P<0.05, while they were not significantly altered in HYPO hearts. HYPO hearts seem to display a phenotype of cardioprotection against ischaemia-reperfusion and this is associated with basal PKCepsilon overexpression and attenuated JNK activation after I/R.

Phenylephrine induced aortic vasoconstriction is attenuated in hyperthyroid rats.

BACKGROUND: Abnormal vascular responsiveness to vasoconstrictors may play an important role in peripheral vascular resistance in hyperthyroidism. The aim of the present study was to evaluate whether the vascular response to potassium chloride and phenylephrine is abnormal in a rat model of thyroxine-induced cardiac hypertrophy. METHODS: Left ventricular hypertrophy was induced in Wistar rats by subcutaneous administration of L-thyroxine for two weeks ("THYR"), n=17. Animals treated with normal saline served as controls, ("NORM"), n=20. The thoracic aorta was dissected and cut into rings that were suspended in an isolated organ bath with Krebs-Henseleit buffer. Maximal tension, Tmax, in g was measured in response to KCl and PE at the highest concentration in rings with endothelium (+E) and without endothelium (-E) in both groups. Relaxation response (Relax percent) to acetylcholine administration was expressed as percent of the maximal tension induced by phenylephrine. RESULTS: Left ventricular weight was 0.9 (SEM, 0.04) g for THYR group vs 0.7 (0.02) g for the NORM group, p<0.05. With KCl, Tmax was not different between the THYR and NORM groups with and without endothelium. With PE, there was a difference in Tmax between THYR+E and NORM+E, 1.2 (0.05) g vs 1.5 (0.09) g, p<0.05. Tmax was also different between THYR-E and NORM-E, 1.5 (0.08) g vs 1.7 (0.07) g, p<0.05. Relax percent was not significantly different between THYR+E and NORM+E (45.9 percent vs 42.8 percent, p>0.05). CONCLUSIONS: We conclude that: a) Vascular tension of the thoracic aorta in response to PE is lower in thyroxine-treated rats as compared to controls, probably due to enhanced PE-induced vasorelaxation at high concentration. b) Relaxation response of the thoracic aorta to acetylcholine is not different between THYR and NORM groups.

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.