Importantly, levels of myocardial calcium handling proteins SERCA2a and PLB, and HSP70 remained unchanged after DITPA treatment

Importantly, levels of myocardial calcium handling proteins SERCA2a and PLB, and HSP70 remained unchanged after DITPA treatment. at 0.937, 1.875, 3.75, or 7.5 mgkg1day1for 7 days, and the results were compared with untreated mice for ex vivo and/or in vivo myocardial ischemia-reperfusion (I/R). DITPA experienced no effects on baseline body temperature, body weight, or heart rate; however, it mildly increased blood pressure. In isolated hearts, baseline contractile function was significantly impaired in DITPA-pretreated mice; however, postischemic recovery was comparable SKLB-23bb between untreated and DITPA-treated groups. In vivo baseline cardiac parameters were significantly affected by DITPA, with increased ventricular sizes and decreased contractile function. Importantly, DITPA-treated mice exhibited high prevalence of fatal cardiac rhythm abnormalities during in vivo ischemia and/or reperfusion. There were no improvements in myocardial infarction and postischemic fractional shortening with DITPA. Myocardial sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), phospholamban (PLB), and warmth shock protein (HSP) levels remained unchanged with DITPA treatment. Thus DITPA administration impairs baseline cardiac parameters in mice and can be fatal during in vivo acute myocardial I/R. Keywords:cardiac function, postischemic recovery, fatal cardiac rhythm thyroid hormone(TH) has profound effects around the heart and cardiovascular system. The biologically active TH, 3,5,3-triiodothyronine (T3), increases cardiac output through inotropic, chronotropic, and vasodilatory mechanisms (18). A TH analog, 3,5-diiodothyropropionic acid (DITPA), has been reported to have less effect on cardiac metabolism and heart rate (HR) (22), and thus it is considered to be a safer therapeutic agent than T3. DITPA was identified as a compound that differs chemically SKLB-23bb from thyroxine (T4) in the absence of iodides at the 3,5 positions and in the substitution of a propionic acid side chain for the alanine side chain (34). It has been shown that DITPA exerts greater positive inotropic than chronotropic effects (32), induces angiogenesis (45), enhances vasorelaxation (37), and enhances calcium handling (33) in different experimental conditions. These properties of DITPA are thought to contribute to the beneficial SKLB-23bb effects of the compound in clinical application. Circulating and cardiac T3levels are reduced in advanced heart disease, after acute myocardial infarction (AMI), and in patients with cardiopulmonary bypass (14,15,18,24). Clinical and experimental studies have exhibited that increased circulating levels of T3improved cardiac contractile function in normal myocardium as well as after acute ischemic injury to the myocardium (8,18,26). Recently, DITPA has been in phase II clinical trials for its efficacy as a cardiotonic agent in stable heart failure patients; however, there was no symptomatic benefit in patients despite some improvements in hemodynamic and metabolic parameters (11). DITPA treatment was initially reported to increase baseline cardiac contractility (13,32); however, administration Rabbit Polyclonal to GSC2 of DITPA is usually reported to have diverse effects on postischemic/postinfarct myocardial function (for review, observe Refs.19,22). Effects of DITPA on fractional shortening and ejection portion have been mixed, one showing an increase (33,45) as well as others no switch (19). Thus it is uncertain whether and/or when a clear benefit from DITPA is usually achievable. It is also unknown whether the inconsistencies are related to experimental protocols or species. TH can regulate contractile function and heart rhythm via its genomic or nongenomic actions (18,27). In fact, most of the important regulatory contractile proteins and ion channels are TH responsive (2,7). Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) is usually positively, while phospholamban (PLB) is usually negatively, regulated by TH (2). It has been reported that the effects of TH on cardiac contractility as well as rates of contraction and relaxation are SKLB-23bb mainly mediated by increases in the levels of SERCA2a and decreases in PLB in cardiomyocytes (2). DITPA has been shown to prevent downregulation of SERCA2a proteins following myocardial infarction in rabbits (33). Interestingly, short-term in vitro DITPA pretreatment has been shown to induce upregulation of genes encoding contractile proteins and SERCA2a in isolated rat cardiomyocytes (1). Recent studies have provided evidence that TH can also regulate intracellular survival signaling pathways and enhance the induction of cardioprotective molecules such as warmth shock proteins (HSPs) (27). TH-induced HSP70 expression has been reported to increase the tolerance of the myocardium to ischemia-reperfusion (I/R) and preserve contractile function in rats (28). Mice with increased SERCA expression demonstrate protection against myocardial I/R injury (40), and conversely mice with reduced SERCA expression are susceptible to accelerated myocardial I/R injury (39). Deletion of the inducible 70-kDa HSP genes in mice is usually reported to impair cardiac contractile function and calcium handling (17). While murine models are widely used and provide unique opportunity for the use of genetic modification, you will find no prior reports evaluating the effects of DITPA in mice with SKLB-23bb regard to baseline cardiac function and cardioprotection. Pretreatment of a putative cardioprotective agent in animal studies is performed to know the drug effects at baseline and after specific interventions. The cardioprotective effects of T3or T4pretreatments have been reported (26,27,2931). The rationale of using DITPA was to avoid the adverse sympathomimetic effects of exogenously administered TH while.