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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 2015 Jun 9;172(13):3426–3433. doi: 10.1111/bph.13131

3-Iodothyroacetic acid lacks thermoregulatory and cardiovascular effects in vivo

Carolin S Hoefig 1, Simon F Jacobi 1, Amy Warner 1, Lisbeth Harder 2, Nancy Schanze 1, Björn Vennström 1, Jens Mittag 1,2,✉
PMCID: PMC4500376  PMID: 25765843

Abstract

Background and Purpose

3-Iodothyronamine (3-T1AM) is an endogenous thyroid hormone derivative reported to induce strong hypothermia and bradycardia within minutes upon injection in rodents. Although 3-T1AM is rapidly converted to several other metabolites in vivo, these strong pharmacological responses were solely attributed to 3-T1AM, leaving potential contributions of downstream products untested. We therefore examined the cardiometabolic effects of 3-iodothyroacetic acid (TA1), the main degradation product of 3-T1AM.

Experimental Approach

We used a sensitive implantable radiotelemetry system in C57/Bl6J mice to study the effects of TA1 on body temperature and heart rate, as well as other metabolic parameters.

Key Results

Interestingly, despite using pharmacological TA1 doses, we observed no effects on heart rate or body temperature after a single TA1 injection (50 mg·kg−1, i.p.) compared to sham-injected controls. Repeated administration of TA1 (5 mg·kg−1, i.p. for 7 days) likewise did not alter body weight, food and water intake, heart rate, blood pressure, brown adipose tissue (BAT) thermogenesis or body temperature. Moreover, mRNA expression of tissue specific genes in heart, kidney, liver, BAT and lung was also not altered by TA1 compared to sham-injected controls.

Conclusions and Implications

Our data therefore conclusively demonstrate that TA1 does not contribute to the cardiovascular or thermoregulatory effects observed after 3-T1AM administration in mice, suggesting that the oxidative deamination constitutes an important deactivation mechanism for 3-T1AM with possible implications for cardiovascular and thermoregulatory functions.

Tables of Links

Targets
GPCRsa Transportersd
β1-adrenoceptor Ca2+-ATPase
β2-adrenoceptor Na+/K+-ATPase
β3-adrenoceptor UCP1 (uncoupling protein 1)
M1 receptor Enzymese
Ion channelsb AC (adenylyl cyclase)
HCN2 ACC1
HCN4 ACE (angiotensin-converting enzyme)
Voltage-gated potassium channels DIO1 (deiodinase, type 1)
Nuclear hormone receptorsc Malonyl-CoA decarboxylase (MLYCD)
Thyroid hormone receptor α Renin
Thyroid hormone receptor β
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Ligands
3-iodothyronamine
3,5,3′-triiodothyroacetic acid
Angiotensin
Triiodothyronine
TSH
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These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 (a,b,c,d,eAlexander et al., 2013a,b,c,d,e).

Introduction

Thyronamines (TAMs) are decarboxylated and deiodinated metabolites of thyroid hormone (TH), and were initially discovered in the early 1950s (Hillmann et al., 1958). However, clinical and basic research has only recently shown an interest in thyronamines (Scanlan et al., 2004); several studies on rodents have reported that 3-iodothyronamine (3-T1AM) elicits rapid endocrine, metabolic and behavioural effects (Scanlan et al., 2004; Chiellini et al., 2007; Braulke et al., 2008; Musilli et al., 2014).

The most pronounced effects of 3-T1AM were observed on body temperature and cardiac parameters: a single i.p. injection of 3-T1AM at 50 mg·kg−1 led to a rapid and drastic decrease in body temperature, severe bradycardia and a reduction in cardiac output (Scanlan et al., 2004; Chiellini et al., 2007). As these properties may have beneficial effects when treating ischaemic injuries such as stroke (Doyle et al., 2007), 3-T1AM became a highly interesting molecule from a clinical perspective. However, it has been demonstrated in vitro, ex vivo and in vivo that 3-T1AM can be rapidly metabolized via oxidative deamination followed by aldehyde oxidation to the corresponding 3-iodothyroacetic acid (TA1) (Wood et al., 2009; Saba et al., 2010; Agretti et al., 2011; Hackenmueller and Scanlan, 2012). Importantly, a recent study has proposed that TA1 might elicit the same behavioural effects including amnesia, stimulation of learning and hyperalgesia as 3-T1AM, suggesting that TA1 constitutes a 3-T1AM derivative with biological activity (Musilli et al., 2014). However, it remains unknown whether TA1 also contributes to the profound thermoregulatory and cardiac effects observed after 3-T1AM administration.

Here we demonstrated that pharmacological doses of TA1 do not significantly affect the cardiovascular function or temperature regulation in mice. Our findings clearly demonstrate that TA1 is not involved in mediating the effects of 3-T1AM, indicating that the amino group ethylamine side chain is essential for the rapid effects of 3-T1AM.

Methods

Animal husbandry

C57BL/6J male mice at the age of 3–4 months were housed in single cages at 21–22°C on a 12 h light/12 h dark cycle, and had ad libitum access to food and water. Animal care procedures were in accordance with the guidelines set by the European Community Council Directives (86/609/EEC) and were approved by Stockholm's Norra Djurförsöksetiska Nämnd. The total number of animals used in this study was 38. All studies involving animals are reported in accordance with the ARRIVE guidelines for reporting experiments involving animals (Kilkenny et al., 2010; McGrath et al., 2010).

Reagents and drugs

TA1 was synthesized as previously described (Wood et al., 2009) by Alinda Chemical Limited (Moscow, Russia) and dissolved in 60% DMSO and 40% physiological saline (pH 7.4) for in vivo studies. The purity of TA1 determined by NMR analysis was <95%. 3-T1AM was kindly provided by Thomas S. Scanlan (OHSU, Portland, OR, USA). T3 was purchased from Sigma-Aldrich (Munich, Germany).

Single-injection experiment

Implantable radio transmitters and receiver plates (Mini Mitter Respironics, Bend, OR, USA) were used to determine heart rate and body temperature of conscious and freely moving mice (Mittag et al., 2013). The mice were anaesthetized using isoflurane 4% to induce anaesthesia, then 2.5% during surgery; depth of anaesthesia was controlled using toe-pinch reflex.The transmitters were implanted into the peritoneal cavity with the electrodes sutured to the right shoulder and the lower left chest wall. Subsequently, the animals were allowed to recover for 7 days before recording started. Mice received a single i.p. injection of TA1 (50 mg·kg−1, 5 μL·g−1 body weight), 3-T1AM (50 mg·kg−1, 5 μL·g−1 body weight) or the same volume of vehicle (60% DMSO and 40% saline, pH 7.4 for TA1 or 30% ethanol for T1AM) and were returned to their home cages for recordings.

Repeated injection experiment

Body weight and food and water intake were measured daily for 7 days before and during treatment with TA1 (5 mg·kg−1 i.p. daily, 5 μL·g−1 body weight) or the same volume of vehicle. Brown fat, tail and inner ear temperature were measured non-invasively using an infrared camera (T335, FLIR Systems Termisk Systemteknik, Linköping, Sweden, ± 0.05°C sensitivity). Rectal temperature was measured using a thermometer probe. Systolic, diastolic, mean arterial pressure and pulse rate were recorded non-invasively using a tail-cuff system on a platform at 34°C (SC1000, Hatteras Instruments, Cary, NC, USA) (Warner et al., 2013). The mice were killed 24 h after the last injection, and organs were collected for subsequent analysis.

Quantitative real-time PCR (qPCR)

RNA was isolated from snap-frozen tissues using the RNeasy Mini Kit (Qiagen, Solna, Sweden). Subsequent cDNA synthesis was carried out using oligo(dT) primers and the transcriptor first-strand cDNA synthesis kit (Roche, Stockholm, Sweden). qPCR was performed with the 7300 real-time PCR system (Applied Biosystems, Stockholm, Sweden) and SYBR Green PCR master mix (Roche) using a two-step PCR protocol with 40 cycles and a temperature of 60°C for annealing and extension. Primer sequences have been published previously (Sjogren et al., 2007; Mittag et al., 2010). A standard curve was used to correct for PCR efficiency, and the results were normalized using Hprt as reference gene. T3-treated animals were used as control (Vujovic et al., 2009). A melting curve was recorded to confirm the specificity of the reaction. Nomenclature of receptors adheres to the Concise Guide to Pharmacology 2013/2014 (Alexander et al., 20132013a).

T4 and T3 elisa for mouse serum analysis

Serum total T4 (EIA 1781, DRG Instruments GmbH, Marburg, Germany) and total T3 (DNOV053, NovaTec Immundiagnostica GmbH, Dietzenbach, Germany) were determined by commercial elisa kits according to the manufacturer's instructions.

Statistical analysis

GraphPad Prism 5 software (GraphPad Software, La Jolla, CA, USA) was used to analyse the data. All data are represented as mean ± SEM. Statistical significance was defined as P < 0.05 (*), P < 0.01 (**) or P < 0.001 (***).

Results

TA1 does not alter heart rate and body temperature after a single injection

To identify any rapid TA1-mediated effects on thermoregulation or cardiac function, radio transmitters were implanted to measure heart rate and body temperature of conscious and freely moving mice before and during a 6 h post-injection period. However, the results revealed no obvious alterations in body temperature (Figure 1A) or heart rate (Figure 1B) after an i.p. TA1 (50 mg·kg−1) injection when compared with sham-injected controls. As expected from previous studies (Scanlan et al., 2004), an i.p. injection of 3-T1AM caused a significant reduction in body temperature (Figure 1A), and a minor albeit not significant bradycardia (Figure 1B).

Figure 1.

Figure 1

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Effects of single TA1 injection on heart rate and body temperature. (A) Body temperature and (B) heart rate were measured using radiotelemetry before and during 6 h post injection (X) in TA1-injected (50 mg·kg−1) compared with sham-injected animals. Data are presented as mean ± SEM of 8–12 male mice for each group. The area under the curve was calculated for the first hour post injection, including a positive control using 3-T1AM (50 mg·kg−1, grey bars). *P < 0.05 (Student's t-test)

Repeated administration of TA1 does not affect metabolic function, heart rate or body temperature

To test if TA1 exerts effects on cardiovascular function and thermoregulation after repeated administration, we measured metabolic, cardiac and thermogenic parameters for 7 days before and during a daily treatment with 5 mg·kg−1 TA1 in a comparison with sham-injected controls. No significant effect of TA1 was observed on body weight (Figure 2A left panel) or food or water intake (Figure 2A right panel). Furthermore, heart rate and blood pressure (systolic, diastolic and mean arterial blood pressure) were not affected by TA1 injection as assessed 24 h after TA1 injection by a tail-cuff system. Infrared thermography showed no significant effect of TA1 on thermoregulation: daily inner ear temperature (Figure 2C upper panel), temperature of the skin overlaying the interscapular brown adipose tissue (BAT) (Figure 2C middle panel), tail tip temperature (Figure 2C lower panel) and rectal temperature measured on the last day (sham 32.8 ± 0.9°C; TA1 33.5 ± 1.0°C; P < 0.05, unpaired Student's t-test) were similar between the treatment groups.

Figure 2.

Figure 2

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Effects of repeated TA1 treatment on metabolic effects, cardiac function and thermoregulation. (A) There was no significant difference between sham-injected and TA1-injected animals (5 mg·kg−1) in body weight, food or water intake. (B) No significant effect was observed on heart rate and blood pressure (systolic, diastolic and mean arterial blood pressure). (C) Infrared thermography was used to quantify surface heat over the interscapular brown fat depot, inner ear and tail tip. Data are presented as the average of the last three injection days of five animals for each group, dashed line indicates the mean value of all animals before treatment (n.s.: P < 0.05).

Analysis of TH-regulated target genes and total T4 and T3 serum concentrations

To determine whether repeated administration of TA1 could interfere with peripheral TH metabolism, we analysed the mRNA expression levels of TH-responsive genes SPOT14, deiodinase type I (DIO1) and selenoprotein S in liver, as well as renal DIO1 and brown fat deiodinase type II. qPCR revealed no change upon TA1 treatment, indicating unaffected TH signalling, whereas as expected hepatic DIO1 was elevated by T3 treatment used as positive control (Figure 3A). The lack of effect of TA1 on TH signalling was further supported by comparable levels of serum total T4 and total T3 concentrations in sham and TA1-injected animals (Figure 3B).

Figure 3.

Figure 3

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Effect of repeated TA1 treatment on gene expression and thyroid hormone levels. (A) mRNA expression of TH-regulated genes assessed by real-time PCR, (B) total T4 and T3 serum levels, and (C) mRNA expression of cardiac, blood pressure and metabolic genes in sham-injected and TA1-injected (5 mg·kg−1) animals. Data are represented as mean ± SEM of five animals for each group. ACC1/2, acetyl-CoA carboxylase; ADRB1/2/3, β1/2/3-adrenoceptors; ANGT, angiotensinogen; CHRM2, muscarinic M2 receptor; DIO 1/2, deiodinase type 1/2; HCN2/4; potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2/4; Klf2, krüppel-like factor 2; MCD, malonyl-CoA decarboxylase; PEPCK, phosphoenolpyruvate carboxykinase; PYRK, pyruvate kinase; SecS, selenoprotein S; UCP1, uncoupling protein 1. ***P < 0.001 (Student's t-test).

Expression profiling in tissues after repeated TA1 administration

To identify tissues potentially affected by the repeated TA1 administration, gene expression analysis was performed on the heart, kidney, lung, liver and BAT (Figure 3C). The results showed no effect of TA1 on the expression of cardiac genes involved in heart rate regulation: the expression levels of β1-adrenoceptors, β2-adrenoceptors, muscarinic M2 receptors, the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) or HCN4 mRNA were unaltered by TA1.

Expression of pulmonary ACE, renal renin, renal krüppel-like factor 2 and liver angiotensin remained likewise unaffected, concurring with the lack of TA1 effect on blood pressure. Similarly, as expected from the infrared thermography, TA1 did not alter uncoupling protein 1 (UCP1) and β3-adrenoceptor mRNA levels in BAT. Liver and BAT genes involved in energy metabolism, such as phosphoenolpyruvate carboxykinase, pyruvate kinase, acetyl-CoA carboxylase 1 and 2 (ACC1, ACC2), and malonyl-CoA decarboxylase, were also similarly expressed in both groups.

Discussion and conclusion

Our data show that TA1 lacks the cardiovascular and thermoregulatory properties of 3-T1AM as it did not induce bradycardia and hypothermia in mice upon single (50 mg·kg−1, i.p.) and repeated (5 mg·kg−1, i.p. 7 days) administration. The dose was chosen based on the published cardiac and thermoregulatory effects of 50 mg·kg−1 3-T1AM (Scanlan et al., 2004), as we hypothesized that the conversion to TA1 could play an important role in these processes. For the long-term application, a 10-fold lower dose was used for 7 days, which is still in the pharmacological range and several fold higher than what would be used for the experimental induction of thyrotoxicosis by TH.

However, despite the relatively high doses, neither the highly sensitive radiotelemetry nor the non-invasive infrared camera were able to detect any difference in cardiovascular or thermoregulatory systems between the treatment groups. This concurs with previous findings showing that TA1 also has no direct effect on oxygen uptake of cardiac muscle in chicks (Newcomer and Barrett, 1960). Furthermore, in contrast to other TH metabolites (Mendoza et al., 2013), TA1 (5 mg·kg−1, i.p. 7 days) does not interfere with TH metabolism, as TH-regulated genes and T4 as well as T3 serum levels were unaltered in our experiments.

THs are well known for their pronounced cardiovascular and thermoregulatory effects (Kahaly and Dillmann, 2005; Mullur et al., 2014). The biological active triiodothyronine (T3) increases facultative and obligatory thermogenesis as well as cardiac output by affecting vascular resistance, blood volume, cardiac contractility and heart rate (Kahaly and Dillmann, 2005). At the molecular level, both non-genomic and genomic cardiovascular effects have been observed to play a role in T3 action in the heart (Klein and Ojamaa, 2001a; Dillmann, 2010). Non-genomically, T3 acts at the cardiomyocyte cell membrane on ion channels for sodium, potassium and calcium ions in the heart, which can increase inotropy and chronotropy (Klein and Ojamaa, 2001b). Genomically, T3 effects are largely mediated by thyroid hormone receptor α1, which is the main isoform in heart (Makino et al., 2012). Several genes encoding ion channels involved in cardiac contractile activity have been shown to be positively or negatively regulated by T3 in the adult mouse heart including those for Ca2+-ATPase and phospholamban, myosin, β-adrenoceptor, AC, guanine nucleotide-binding proteins, Na+/Ca2+ exchanger, Na+/K+-ATPase and voltage-gated potassium channels (Klein and Ojamaa, 2001b). Of particular interest is the potassium/sodium HCN2, which constitutes a component of the pacemaker in the sinoatrial node of the heart and is positively regulated by T3, thus mediating the positive chronotropic effect of the hormone. However, we did not observe any change in the expression of HCN2 or other cardiac TH target genes upon TA1 injection, demonstrating that the compound does not interfere with cardiac TH signalling.

In contrast to TA1, the three times iodinated 3,5,3′-triiodothyroacetic acid (TRIAC) exerts cardiac and thermogenic effects (Symons et al., 1975; Liang et al., 1997; Medina-Gomez et al., 2008). Interestingly, TRIAC has about a 1.5-fold higher affinity for the thyroid hormone receptor α and about a 3.5-fold higher affinity for the thyroid hormone receptor β than T3 (Schueler et al., 1990). In rats, TRIAC has different effects on cardiac DIO1 activity and on cardiac function, resulting in significantly less increase of heart weight with TRIAC than with T3 or T4. This discrepancy might be due to the rapid metabolic clearance rate and short half-life of TRIAC, resulting in only a transient activation of the nuclear receptors (Liang et al., 1997). Our findings, however, suggest that TA1 does not bind to nuclear thyroid receptors, as none of the target genes were altered.

Using brown adipocytes, it was also shown that TRIAC has higher thermogenic potency than T3 towards the adrenergic stimulation of UCP1 mRNA without concomitant inhibition of TSH or hypothyroxinemia (Medina-Gomez et al., 2008). Again, we did not observed any effect of TA1 on body temperature or UCP1 mRNA expression, demonstrating that TA1 displays no thermoregulatory action upon repeated administration.

Like TRIAC, 3-T1AM is a potent modulator of cardiovascular and thermoregulatory action. It has been reported that 3-T1AM induces hypothermia and reduces cardiac output, heart rate, systolic pressure and coronary flow in isolated heart preparation within minutes as a result of the reduced amplitude and duration of the calcium transients (Scanlan et al., 2004; Chiellini et al., 2007; Ghelardoni et al., 2009; Zucchi et al., 2010). Hence, the inactivation of 3-T1AM is physiologically of great relevance to terminate the rapid effects of this potent compound. Detailed ex vivo studies have demonstrated that TA1 is indeed produced from 3-T1AM in rat cardiac tissue (Saba et al., 2010), suggesting that oxidative deamination followed by aldehyde oxidation constitutes an important inactivation mechanism for 3-T1AM directly in the heart (Scanlan et al., 2004; Chiellini et al., 2007; Frascarelli et al., 2011).

At the molecular crossroad downstream of 3-T1AM and TRIAC metabolism, TA1 constitutes a major metabolite (Wood et al., 2009; Saba et al., 2010; Hackenmueller and Scanlan, 2012), which has recently been identified endogenously in human serum and mouse brain (Wood et al., 2009; Musilli et al., 2014). However, the exact biosynthesis of TA1 as well as its export and uptake in different tissues is still enigmatic, and may differ substantially from 3-T1AM, which is taken up by several organs such as gallbladder, stomach, liver, kidney, muscle and adipose tissue (Chiellini et al., 2012). Therefore, at this point, we cannot fully exclude that the levels of TA1 after i.p. injection might differ from the ones obtained after i.p. injection of the precursor 3-T1AM.

In vivo, TA1 is further metabolized by deiodinases to the iodine-free thyroacetic acid TA0, the likely end product of TH metabolism (Pittman et al., 1972). Although TA0 is excreted via the urine, the released iodine can be recycled for TH synthesis within the thyroid gland (Pittman et al., 1972). Our results that TA1 lacks any significant cardiovascular or thermoregulatory activity are thus quite significant: they demonstrate that TA1 can in fact constitute an inactivation product, which terminates the powerful cardiovascular and thermoregulatory effects of other TH derivates such as 3-T1AM or TRIAC. Moreover, our results provide molecular evidence that the ethylamine side chain is essential for the rapid cardiac and thermogenic effects of 3-T1AM.

Acknowledgments

We thank the staff of the CMB animal facility for technical assistance. This work is supported by grants from the Deutsche Forschungsgemeinschaft (C. S. H.: HO 5096/1-1, J. M.: Mi1242/2-1 and Mi1242/3-1), Karolinska Institutets Foundation (C. S. H., A. W. and J. M.), the Swedish Research Council (A. W., B. V. and J. M.) and Hjärt-och Lungfonden (B. V., J. M.).

Glossary

3-T1AM

3-iodothyronamine

ACC1

acetyl-CoA carboxylase 1

BAT

brown adipose tissue

DIO1

deiodinase type I

TA1

3-iodothyroacetic acid

TH

thyroid hormone

TRIAC

3,5,3′-triiodothyroacetic acid

Author contributions

C. S. H. and J. M. designed research. C. S. H., S. F. J., A. W., L. H. and N. S. performed the research. B. V. and J. M. contributed new reagents/analytic tools. C. S. H., S. F. J., A. W. and J. M. analysed the data. C. S. H., B. V. and J. M. wrote the paper.

Conflict of interest

None.

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