Methimazole suppresses, and 3-iodothyronamine (T1AM) activates GPCRs, TRs and Na+/K+-ATPase subunit isoform expression in air-breathing fish hearts

3-iodothyronamine (T₁AM), an endogenous aminergic derivative of thyroid hormone (TH), exhibits cardioprotective effects in mammals. However, it is unclear whether T₁AM has similar effects in fish hearts to counteract hypothyroidism. We hypothesise that T₁AM may regulate the expression patterns of GPCR-associated neuroendocrine receptors, thyroid hormone receptors (TRs), and Na⁺, K⁺-ATPase (NKA) subunit isoform genes, and may exert protection against hypothyroidism. The effects of T₁AM on ion transporter activities in fish hearts under euthyroid conditions were first examined in vitro and in vivo to ascertain its direct impact on euthyroid fish hearts. Subsequently, the effects of methimazole (MMI), an antithyroid drug, and T₁AM replacement in hypothyroid hearts of the air-breathing fish (Anabas testudineus) were studied. Dose-dependent effects of T₁AM on ion-dependent ATPase activities were observed both in vitro and in vivo in euthyroid hearts. While MMI treatment increased NKA activity, T₁AM replacement decreased its activity in hypothyroid hearts. The downregulation of NKA subunit isoform expressions (nkaα1a, nkaα1b, nkaα1c, atp1b1, atp1b2) by MMI was reversed when T₁AM was added in hypothyroid hearts. Similarly, MMI suppressed and T₁AM activated the transcript of trace amine-associated receptors taar1 and taar8c, as well as TR isoforms (thra, thrab, thrb) in the hypothyroid heart. MMI activated adra2a and suppressed adrb2 expression, while T₁AM reversed these effects; however, both MMI and T₁AM downregulated drd2 expression. These data indicate a novel targeted action of T₁AM on cardiac GPCRs, TR function, and NKA-mediated ion osmotic homeostasis in hypothyroid fish, suggesting potential cardioprotective effects of T₁AM against hypothyroidism.