Oxytocin (OT), traditionally associated with reproductive functions, was revisited recently, and several new functions in cardiovascular regulation were discovered. These functions include stimulation of the cardioprotective mediators nitric oxide (NO) and atrial natriuretic peptide. OT’s cardiovascular outcomes comprise: (i) natriuresis, (ii) blood pressure reduction, (iii) negative inotropic and chronotropic effects, (iv) parasympathetic neuromodulation, (v) NO pathway involvement in vasodilatation and endothelial cell growth, (vi) anti-inflammatory and (vii) antioxidant activities as well as (viii) metabolic effects. In addition, we have reported abundant OT in the early developing heart with its capacity to generate cardiomyocytes (CMs) from mouse embryonic stem cells and stem cells residing in the heart. OT increases glucose uptake by cultured CMs, in normal, hypoxic and even in insulin resistance conditions. In experimentally-induced myocardial infarction in rats, continuous in vivo OT delivery improves the cardiac healing process and cardiac work, diminishes inflammation, and stimulates angiogenesis. Therefore, in pathological situations, OT plays an anti-inflammatory and cardioprotective role, enhancing vascular and metabolic functions, with potential therapeutic application(s).
As early as 1910, Henry Dale wrote in Biochemistry Journal: "It does not seem justifiable to draw…the conclusion that the principle (in pituitary body extracts) acting on the plain muscle of the uterus is different from that which acts on the arteries".
Ott and Scott demonstrated that besides their effect on uterine activity, posterior pituitary extracts also promote milk ejection – the two principal activities of oxytocin (OT), the structure and synthesis of which were not elucidated until 50 years later by Du Vigneaud and co-workers. OT, the most abundant hormone in the human body, is mainly produced in the paraventricular nucleus and supraoptic nucleus of the hypothalamus, and released from hypothalamic nerve terminals of the posterior pituitary into the circulation. It differs, by only two amino acids, from vasopressin (AVP), which is also produced in these nuclei and stored in the posterior pituitary. OT in the circulation was originally believed to stimulate uterine contractions to start parturition and milk-ejection during lactation. However, similar numbers of oxytocinergic neurons have been found in the male and female hypothalamus, and the same stimuli induce OT release in both genders, suggesting other physiological functions. In fact, OT receptors (OTR), widely expressed in several organs, elicit a variety of physiological responses, such as complex sexual and maternal behavior. Indeed, OT is also involved in cognition, tolerance and cardiovascular regulation. Our interest in the cardiac OT system emerged from longitudinal investigations into the role of the brain in the control of cardio-renal homeostasis. These experiments led to the observations that OT and its OTR are synthesized in the human and rat heart and that OT exerts cardioprotection either directly or via stimulation of mediators such as the natriuretic peptides (NPs) and nitric oxide (NO). In addition, OT has been identified as a potent, naturally-occurring cardiomyogen, which, by upregulation of its own receptors in mouse embryonic stem (ES) cells and stem cells isolated from the adult mouse and rat heart promotes differentiation into functional cardiomyocytes (CMs). A recent study has disclosed that OT stimulates glucose uptake in rat CMs. Consequently, OT emerges as a pleiotropic hormone involved in cardiovascular and metabolic functions.
Although the pathophysiological role of OT is beginning to be understood, accumulating evidence indicates multiple beneficial effects in the heart and vasculature. To date, OT’s cardiovascular properties include: i. the induction of stem cell differentiation into CMs; ii. natriuresis, and decreased blood pressure (BP), possibly secondary to atrial natriuretic peptide (ANP) release. iii. negative inotropic and chronotropic effects and parasympathetic neuromodulation; iv. vasodilatation via the OTR-induced NO pathway; v. endothelial cell growth and possible vessel generation; and vi. modulation of insulin release and anti-diabetic actions.
OT’s effects are mediated by OTR, G protein-coupled receptors that contain seven transmembrane domains. In uterine cells, OTR transduce signalling primarily via Galphaq subunits to activate phospholipase C-beta and mitogen-activated protein kinase (MAPK). In cardiac cells, several signalling pathways have also been postulated in conjunction with specific functions in the heart. Figure 1 illustrates the hypothetical pathways in the heart that are associated with cardioprotection, such as the prevention of apoptosis, CMs hypertrophy, and fibrosis, with stimulation of glucose uptake, cell proliferation and differentiation.
Figure 1. Schematic diagram of potential signalling pathways of OTR in CMs. AMPK—AMP—activated protein kinase; ANP—atrial natriuretic peptide; AVPR2—vasopressin receptor R2; CaM—calmodulin; CaMKK—Ca+2 calmodulin-dependent protein kinase; cGMP—cyclic guanosine monophosphate; CMs—cardiomyocytes; EC—endothelial cells; eEF2—eukaryotic translation elongation factor 2; eNOS—endothelial nitric oxide synthase; ERK—extracellular signal-regulated kinase; IP3—inositol triphosphate; MAPK−mitogen-activated protein kinases; MEK—MAPK/ERK; NFAT—nuclear factor of activated T-cells; NO—nitric oxide; NPR-A—natriuretic peptide receptor A; OTR—oxytocin receptor; PIP2—phosphatidylinositol 4,5-bisphosphate; PI3K—phosphatidyl-3 kinase; PKC—protein kinase C; PLC—phospholipase C; RTKs—receptor tyrosine kinases; sGC—soluble guanylyl cyclase.
In addition, this signalling depends on coupling to specific G-proteins, cell type, and localization on the cell membrane surface. As a result, OTR stimulate different second messengers which, consequently, exert various physiological effects. Due to its organ- and tissue-specific expression patterns, it is believed that OTR is regulated largely at the gene transcription level. In the cardiovascular system, OTR are associated with the ANP-cGMP and NO-cGMP pathways, which reduce the force and rate of contraction and increase vasodilatation. In addition, OT and the other neurophyseal hormone AVP can evoke similar effects in some organs, including the differentiation of stem cells into CMs. The absence of either OT or its receptors in knockout mice, however, has not been reported to produce cardiac insufficiencies. Although OT knockout mice have a normal heart structure, experiments have shown augmented intrinsic heart rates in these animals, indicating that an intracardiac OT system controls cardiac electrical activity. Correspondingly, our studies have demonstrated that OT slows heart rate and contractility via stimulation of the cardiac cholinergic system and NO. These OT outcomes can be recognized as being beneficial to the heart. At the cellular level, protective OT has: (i) antioxidant properties and (ii) anti-inflammatory actions, (iii) potentiates glucose uptake in neonatal and adult CMs exposed to hypoxia and conditions of insulin resistance mimicked by the presence of ketone bodies, (iv) stimulates endothelial markers in mesenchymal cells and stem cells isolated from the heart as a side population (Figure 2).
The different cardioprotective actions of OT were recently demonstrated in animal models of myocardial infarction (MI). In rat, rabbit and pig models of ischemic heart disease, OT treatment significantly reduced infarct size and improved parameters of heart function.
OT’s negative chronotropic action was recently associated with attenuation of cardiac damage evinced by ischemia-reperfusion. Therefore, OT, by activating intrinsic cardiac cholinergic neurons and NO release, can effectively inhibit cardiac sympathetic nerve activity and improve left ventricular ejection fraction in rats subjected to MI. Positive cardiac effects can also be attributed to the fact that OT stimulates ANP release from isolated, perfused hearts by improving hydromineral homeostasis as well as cardiac hypertrophy and reducing pro-inflammatory mediators. ANP, a member of the NPs family that includes BNP, C type natriuretic peptide, and urodilatin, is released into the circulation after volume expansion, atrial stretch, hypoxia and in response to various hormones and neurotransmitters. ANP causes BP to decline with a concomitant increment of diuresis, natriuresis, and decrease of plasma volume. NPs also inhibit the sympathetic nervous system and hormones involved in cardiac hypertrophy, such as angiotensin II, endothelin and AVP. NPs signalling via functional receptors (NPR-A and NPR-B) prevents pathological hypertrophy and cardiac fibrosis by attenuating both DNA and collagen synthesis i
