Modulation of cardiac ionic homeostasis by 3-iodothyronamine.

3-iodothyronamine (T(1)AM) is a novel endogenous relative of thyroid hormone, able to interact with trace amine-associated receptors, a class of plasma membrane G protein-coupled receptors, and to produce a negative inotropic and chronotropic effect. In the isolated rat heart 20-25 microM T(1)AM decreased cardiac contractility, but oxygen consumption and glucose uptake were either unchanged or disproportionately high when compared to mechanical work. In adult rat cardiomyocytes acute exposure to 20 microM T(1)AM decreased the amplitude and duration of the calcium transient. In patch clamped cardiomyocytes sarcolemmal calcium current density was unchanged while current facilitation by membrane depolarization was abolished consistent with reduced sarcoplasmic reticulum (SR) calcium release. In addition, T(1)AM decreased transient outward current (I(to)) and I(K1) background current. SR studies involving 20 microM T(1)AM revealed a significant decrease in ryanodine binding due to reduced B(max), no significant change in the rate constant of calcium-induced calcium release, a significant increase in calcium leak measured under conditions promoting channel closure, and no effect on oxalate-supported calcium uptake. Based on these observations we conclude T(1)AM affects calcium and potassium homeostasis and suggest its negative inotropic action is due to a diminished pool of SR calcium as a result of increased diastolic leak through the ryanodine receptor, while increased action potential duration is accounted for by inhibition of I(to) and I(K1) currents.

Cardiac effects of 3-iodothyronamine: a new aminergic system modulating cardiac function.

3-Iodothyronamine T1AM is a novel endogenous thyroid hormone derivative that activates the G protein-coupled receptor known as trace anime-associated receptor 1 (TAAR1). In the isolated working rat heart and in rat cardiomyocytes, T1AM produced a reversible, dose-dependent negative inotropic effect (e.g., 27+/-5, 51+/-3, and 65+/-2% decrease in cardiac output at 19, 25, and 38 microM concentration, respectively). An independent negative chronotropic effect was also observed. The hemodynamic effects of T1AM were remarkably increased in the presence of the tyrosine kinase inhibitor genistein, whereas they were attenuated in the presence of the tyrosine phosphatase inhibitor vanadate. No effect was produced by inhibitors of protein kinase A, protein kinase C, calcium-calmodulin kinase II, phosphatidylinositol-3-kinase, or MAP kinases. Tissue cAMP levels were unchanged. In rat ventricular tissue, Western blot experiments with antiphosphotyrosine antibodies showed reduced phosphorylation of microsomal and cytosolic proteins after perfusion with synthetic T1AM; reverse transcriptase-polymerase chain reaction experiments revealed the presence of transcripts for at least 5 TAAR subtypes; specific and saturable binding of [125I]T1AM was observed, with a dissociation constant in the low micromolar range (5 microM); and endogenous T1AM was detectable by tandem mass spectrometry. In conclusion, our findings provide evidence for the existence of a novel aminergic system modulating cardiac function.

Prenatal exposure to carbon monoxide temporarily impairs maturation of rat cardiomyocytes: Electrophysiological evidence.

BACKGROUND: Maternal smoking is an independent risk factor for sudden infant death syndrome. Carbon monoxide (CO) is a major component of cigarette smoke. No information is available concerning the effect of CO and/or smoking on postnatal maturation of the heart. OBJECTIVES: To investigate the effect of prenatal exposure to CO on cellular electrophysiological maturation in male Wistar rats. METHODS: The patch-clamp technique was used to measure the action potential and ionic currents (transient outward current and long-lasting type Ca(2+) current) from rat ventricular myocytes. RESULTS: During growth, action potential duration (APD) measurements at -20 mV and -50 mV (APD(-20) and APD(-50)) progressively decreased in both groups. APD was significantly delayed in rats prenatally exposed to 150 parts per million CO: at four weeks APD(-20) and APD(-50) were 90 ms and 148 ms, respectively, in CO-exposed rats (n=13), and 36 ms and 78 ms, respectively, in control rats (n=14; P<0.01 and P<0.05, respectively); this normalized at eight weeks. After four weeks, the density of long-lasting type Ca(2+) current increased by 34% and the density of transient outward current decreased by 37% in CO-exposed versus control rats; this normalized at eight weeks. CONCLUSIONS: Prenatal CO exposure affects the physiological shortening of APD in neonatal rats. It is speculated that prolonged myocyte repolarization induced by prenatal exposure to smoke may establish a period of vulnerability for life-threatening arrhythmias during infancy.