Thyroxine (T(4)) is the predominant form of thyroid hormone (TH). Hyperthyroidism, a condition associated with excess TH, is characterized by increases in metabolic rate, core body temperature and cardiac performance. In target tissues, T(4) is enzymatically deiodinated to 3,5,3'-triiodothyronine (T(3)), a high-affinity ligand for the nuclear TH receptors TR alpha and TR beta, whose activation controls normal vertebrate development and physiology. T(3)-modulated transcription of target genes via activation of TR alpha and TR beta is a slow process, the effects of which manifest over hours and days. Although rapidly occurring effects of TH have been documented, the molecules that mediate these non-genomic effects remain obscure. Here we report the discovery of 3-iodothyronamine (T(1)AM), a naturally occurring derivative of TH that in vitro is a potent agonist of the G protein-coupled trace amine receptor TAR1. Administering T(1)AM in vivo induces profound hypothermia and bradycardia within minutes. T(1)AM treatment also rapidly reduces cardiac output in an ex vivo working heart preparation. These results suggest the existence of a new signaling pathway, stimulation of which leads to rapid physiological and behavioral consequences that are opposite those associated with excess TH.
The zebrafish embryo is transparent and can tolerate absence of blood flow because its oxygen is delivered by diffusion rather than by the cardiovascular system. It is therefore possible to attribute cardiac failure directly to particular genes by ruling out the possibility that it is due to a secondary effect of hypoxia. We focus here on pickwickm171 (pikm171), a recessive lethal mutation discovered in a large-scale genetic screen. There are three other alleles in the pik complementation group with this phenotype (pikm242, pikm740, pikm186; ref. 3) and one allele (pikmVO62H) with additional skeletal paralysis. The pik heart develops normally but is poorly contractile from the first beat. Aside from the edema that inevitably accompanies cardiac dysfunction, development is normal during the first three days. We show by positional cloning that the 'causative' mutation is in an alternatively-spliced exon of the gene (ttn) encoding Titin. Titin is the biggest known protein and spans the half-sarcomere from Z-disc to M-line in heart and skeletal muscle. It has been proposed to provide a scaffold for the assembly of thick and thin filaments and to provide elastic recoil engendered by stretch during diastole. We found that nascent myofibrils form in pik mutants, but normal sarcomeres are absent. Mutant cells transplanted to wildtype hearts remain thin and bulge outwards as individual cell aneurysms without affecting nearby wildtype cardiomyocytes, indicating that the contractile deficiency is cell-autonomous. Absence of Titin function thus results in blockage of sarcomere assembly and causes a functional disorder resembling human dilated cardiomyopathies, one form of which is described in another paper in this issue.
10%O 2 ) resulted in a lower mean arterial pressure at 90% of incubation, while heart rate was lower in the 10%O 2 group only. Acute (5·min) exposure to 10%O 2 in the normoxic group resulted in a biphasic response, with a normotensive bradycardia occurring during the period of exposure and a hypertensive tachycardic response occurring during recovery. The embryos incubated under hypoxia also showed a blunted response to acute hypoxic stress. In conclusion, the main responses elicited by chronic hypoxic incubation, namely, cardiac enlargement, blunted hypoxic response and systemic vasodilation, may provide chronically hypoxic embryos with a new physiological repertoire for responding to hypoxia.
Adrenergic and cholinergic tone on the cardiovascular system of embryonic chickens was determined during days 12, 15, 19, 20, and 21 of development. Administration of the muscarinic antagonist atropine (1 mg/kg) resulted in no significant change in heart rate or arterial pressure at any developmental age. In addition, the general cardiovascular depressive effects of hypoxia were unaltered by pretreatment with atropine. In addition, the ganglionic blocking agent hexamethonium (25 mg/kg) did not induce changes in heart rate. The beta-adrenergic antagonist propranolol (3 mg/kg) induced a bradycardia of similar magnitude on all days studied, with a transient hypertensive action on days 19-20, indicating the existence of an important cardiac and vascular beta-adrenergic tone. Injections of the alpha-adrenergic antagonists prazosin or phentolamine (1 mg/kg) reduced arterial pressure significantly on all days of incubation studied. Collectively, the data indicate that embryonic chickens rely primarily on adrenergic control of cardiovascular function, with no contribution from the parasympathetic nervous system.
Reptile embryos tolerate large decreases in the concentration of ambient oxygen. However, we do not fully understand the mechanisms that underlie embryonic cardiovascular short- or long-term responses to hypoxia in most species. We therefore measured cardiac growth and function in snapping turtle embryos incubated under normoxic (N21; 21% O₂) or chronic hypoxic conditions (H10; 10% O₂). We determined heart rate (fH) and mean arterial pressure (Pm) in acute normoxic (21% O₂) and acute hypoxic (10% O₂) conditions, as well as embryonic responses to cholinergic, adrenergic, and ganglionic pharmacological blockade. Compared with N21 embryos, chronic H10 embryos had smaller bodies and relatively larger hearts and were hypotensive, tachycardic, and following autonomic neural blockade showed reduced intrinsic fH at 90% of incubation. Unlike other reptile embryos, cholinergic and ganglionic receptor blockade both increased fH. β-Adrenergic receptor blockade with propranolol decreased fH, and α-adrenergic blockade with phentolamine decreased Pm. We also measured cardiac mRNA expression. Cholinergic tone was reduced in H10 embryos, but cholinergic receptor (Chrm2) mRNA levels were unchanged. However, expression of adrenergic receptor mRNA (Adrb1, Adra1a, Adra2c) and growth factor mRNA (Igf1, Igf2, Igf2r, Pdgfb) was lowered in H10 embryos. Hypoxia altered the balance between cholinergic receptors, α-adrenoreceptor and β-adrenoreceptor function, which was reflected in altered intrinsic fH and adrenergic receptor mRNA levels. This is the first study to link gene expression with morphological and cardioregulatory plasticity in a developing reptile embryo.
Mammals and birds have a specialized cardiac atrioventricular conduction system enabling rapid activation of both ventricles. This system may have evolved together with high heart rates to support their endothermic state (warm-bloodedness) and is seemingly lacking in ectothermic vertebrates from which first mammals then birds independently evolved. Here, we studied the conduction system in crocodiles (Alligator mississippiensis), the only ectothermic vertebrates with a full ventricular septum. We identified homologues of mammalian conduction system markers (Tbx3-Tbx5, Scn5a, Gja5, Nppa-Nppb) and show the presence of a functional atrioventricular bundle. The ventricular Purkinje network, however, was absent and slow ventricular conduction relied on trabecular myocardium, as it does in other ectothermic vertebrates. We propose the evolution of the atrioventricular bundle followed full ventricular septum formation prior to the development of high heart rates and endothermy. In contrast, the evolution of the ventricular Purkinje network is strongly associated with high heart rates and endothermy.
Renewed interest in the use of the embryonic chicken as a model of perinatal cardiovascular regulation has inspired new questions about the control mechanisms that respond to acute perturbations, such as hypoxia. The objectives of this study were to determine the cardiovascular responses, the regulatory mechanisms involved in those cardiovascular responses, and whether those mechanisms involved the central nervous system (CNS) of embryonic chickens. Heart rate (f(H)) and blood pressure were measured in chicken embryos of different incubation ages during exposure to different levels of hypoxia (15, 10, and 5% O(2)). At all levels of hypoxia and at all developmental ages, a depression of f(H) and arterial pressure was observed, with the exception of day 20 embryos in 15 and 10% O(2). The intensity of the embryonic f(H) and blood pressure responses were directly related to the level of hypoxia used. Muscarinic and alpha-adrenergic receptor stimulation limited the hypoxic hypotension on days 15-19 and 15-21, respectively, as indicated after blockade with atropine and phentolamine. During the final 3 days of incubation, the intensity of the hypoxic hypotension was magnified due to alpha-vasodilation caused by beta-adrenergic and muscarinic receptor stimulation. In 19- to 21-day-old embryos, the f(H) response to hypoxia was limited by alpha-adrenergic receptor stimulation as indicated by the accentuated bradycardia after blockade with phentolamine. Furthermore, on day 21, atropine limited the hypoxic bradycardia, indicating that muscarinic receptors also play a role in the f(H) response at this age. In addition, the muscarinic actions on the heart and the adrenergic effects on the vasculature appeared to occur through a hypoxic-induced direct release from chromaffin tissue and autonomic nerve terminals. Thus, in embryonic chickens, the only cardiovascular response to hypoxia that involves the CNS was the cholinergic regulation of arterial pressure after day 15 of incubation. Therefore, although embryonic chickens and fetal sheep, the standard models of perinatal cardiovascular physiology, respond to hypoxia with a similar redistribution of cardiac output, the underlying mechanisms differ between these species.
Embryonic alligator responses to adrenergic blockade with propranolol and phentolamine were very similar to previously reported responses of embryonic chicken, and demonstrated that embryonic alligator have α and β-adrenergic tone over the final third of development. However, adrenergic tone originates entirely from circulating catecholamines and is not altered by chronic hypoxic incubation, as neither cholinergic blockade with atropine nor ganglionic blockade with hexamethonium altered baseline cardiovascular variables in N21 or H10 embryos. In addition, both atropine and hexamethonium injection did not alter the generally depressive effects of acute hypoxia -bradycardia and hypotension. However, H10 embryos showed significantly higher levels of noradrenaline and adrenaline at 70% of development, as well as higher noradrenaline at 80% of development, suggesting that circulating catecholamines reach maximal levels earlier in incubation for H10 embryos, compared to N21 embryos. Chronically elevated levels of catecholamines may alter the normal balance between α and β-adrenoreceptors in H10 alligator embryos, causing chronic bradycardia and hypotension of H10 embryos measured in normoxia.
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