The role of oxytocin in cardiovascular regulation

“(17) who showed that the heart is the site of the synthesis of a potent diuretic and natriuretic hormone.”

“Sir Henry Dale (2) reported in 1906 that intravenous injection of ox posterior pituitary gland extracts into a cat caused the animal’s uterus to contract.”

“Furthermore, OT infusion has been shown to stimulate transforming growth factor (TGF)-b expression in injured heart tissue (36), pointing to improvement of LV function (68) as well as beneficial effects such as reduced apoptosis and increased cell proliferation (69).”

“Indeed, PKG inhibits the opening of mPTP through the prolongation of intracellular acidosis, resulting in Ca normalization and prevention of hypercontracture (51).”

“The deficit in processing of the extended forms in patients with autism might be implicated in the development of this syndrome (71).”

“OT-deficient mice exhibit increased stress responses associated with a significant hyperactivation of the hypothalamic-pituitaryadrenal (HPA) axis (63).”

“Since this first study showing that OT induces cardiac differentiation, several reports confirmed OT-stimulated cardiomyogenesis in several lines of embryonic stem cells including somatic stem cells (Sca-1), isolated from adult mouse and rat hearts (39,40), and cardiac stem cell progenitors identified by side populati…”

“Depending on the coupling to distinct G-proteins, cell type, and their location on cellular membranes, OTRs stimulate different second messengers, inducing various physiological effects (30).”

“Immunocytochemical localization of OTR shows the most prominent staining in postnatal cardiomyocytes (CMs) and declines with age to low levels in the adult heart.”

“Indeed, OT displays anti-inflammatory effects, abolishes the sepsis-induced increase in tumor necrosis factor (TNF)-a, and protects against multiple organ damage (60-62).”

“Immunocytochemical localization of OTR shows the most prominent staining in postnatal cardiomyocytes (CMs) and declines with age to low levels in the adult heart.”

“Remarkably, new evidence associates OT with regulation of obesity and diabetes (13), conditions attributed to insulin resistance and insulin deficiency.”

“The functionality of heart OTRs was demonstrated by the ability of OT to release ANP from isolated perfused rat heart (25) as well as from cardiomyocytes in culture (Figure 1).”

“Furthermore, electrophysiological studies demonstrated that intranasal OT administration to healthy university-age (20-25 years old) participants produced significant increases in both sympathetic and parasympathetic autonomic cardiac control, and the effects of OT on cardiac autonomic control were significantly assoc…”

“Incubation of cells with physiological levels of OT has been shown to protect against oxidative stress and to reduce H2O2-stimulated NADPH-dependent superoxide activity in vascular cells, monocytes, and macrophages (31).”

“The results presented here update our previous analyses of the functional OT system in rat heart and vasculature (73-75).”

“Injection (ip or iv) of OT into rats not only increased sodium excretion but concomitantly elevated plasma ANP (21,22).”

“Furthermore, OT infusion has been shown to stimulate transforming growth factor (TGF)-b expression in injured heart tissue (36), pointing to improvement of LV function (68) as well as beneficial effects such as reduced apoptosis and increased cell proliferation (69).”

“The activation of AMPK in the heart following ischemia and reperfusion is recognized as cardioprotective, because AMPK limits apoptosis and suppresses cardiac pathological hypertrophy (52).”

“The results presented here update our previous analyses of the functional OT system in rat heart and vasculature (73-75).”

“Another property of OT was reported a few years later by Ott and Scott (7) who found that, in addition to its effect on the uterus, posterior pituitary extracts promoted milk flow in lactating goats by contraction of mammary myoepithelial cells during lactation.”

“Furthermore, OT infusion has been shown to stimulate transforming growth factor (TGF)-b expression in injured heart tissue (36), pointing to improvement of LV function (68) as well as beneficial effects such as reduced apoptosis and increased cell proliferation (69).”

“Indeed, OT displays anti-inflammatory effects, abolishes the sepsis-induced increase in tumor necrosis factor (TNF)-a, and protects against multiple organ damage (60-62).”

“Indeed, OT displays anti-inflammatory effects, abolishes the sepsis-induced increase in tumor necrosis factor (TNF)-a, and protects against multiple organ damage (60-62).”

“Observation of the highest activation of the heart OT system in fetal and newborn heart, at the stage of intense hyperplasia (29), suggested the role of OT in the heart as a growth and development or maturation factor.”

“NO OT was also shown to have transient negative inotropic and chronotropic effects on perfused isolated dog right atria in a mechanism independent of ANP release and mediated by NO production and acetylcholine release at cardiac parasympathetic postganglionic neurons (49).”

“Initial experiments demonstrated that ANP inhibits sodium chloride and water intake, since injection of ANP into the third ventricle (3V) caused a reduction in dehydration-induced drinking and also the drinking of salt solution by salt-depleted rats (18).”

“Injection (ip or iv) of OT into rats not only increased sodium excretion but concomitantly elevated plasma ANP (21,22).”

“OT treatment can compensate ATP shortages by stimulating enhanced glucose uptake in CMs (34).”

“ANP is an established cardioprotective agent; it inhibits the release of renin, inhibits aldosterone synthesis, inhibits sympathetic nerve activity, ameliorates endothelial function, and decreases fibrosis, inflammation, and apoptosis in myocytes that are associated with left ventricle (LV) remodeling (47).”

“Moreover, OT increases proliferation of mesenchymal cells and alters gene expression of endothelial markers, adhesion molecules, and matrix metalloproteinases, contributing to improved cell motility and growth (33).”

“Therefore, the intracardiac OT stimulating ANP release may be at least in part responsible for the control of cardiovascular homeostasis (23,24).”

“Hypophysectomy and posterior lobectomy completely inhibited the ANP responses to BVE, indicating that a factor originating in the posterior hypophysis is responsible for ANP release (20) and revealing that diuresis and natriuresis, as well as the release of ANP, do not occur in neurohypophysectomized animals.”

“Exogenous OT administration has direct negative chronotropic effects (50).”

“MI is recognized as a definitive factor for amplification of an excessive and inappropriate inflammatory response (64).”

“In vivo chronic OT infusion in Apo-E knockout mice attenuated aortic atherosclerosis and inhibited the secretion of the pro-inflammatory cytokine IL-6 in visceral adipose tissue (45).”

“, protein kinase B), signal transducer and activator of transcription 3 (STAT3), ERK, matrix metalloproteinase (MMP)-1, and eNOS (35).”

“Moreover, OT affects NO and cytokine production by sepsis-sensitized macrophages (59).”

“The introduction of carbachol in this region caused natriuresis accompanied by a strong increase in plasma ANP concentration and accumulation of the peptide in the medial basal hypothalamus, neurohypophysis, and anterior pituitary gland (19).”

“In several studies with a reperfusion model in vivo, ANP showed inhibition of the occurrence of reperfusion arrhythmia, preservation of ATP content in the ischemic myocardium, and inhibition of neutrophil-induced endothelial cytotoxity (48).”

“It has also been shown that OT promotes the migration of human dermal endothelial cells (ECs), breast-derived ECs, and human umbilical vein ECs (32).”

“In contrast, OTR was downregulated by 40-50% in the injured left ventricle of mice (42) and rats (36) following MI.”

“OT and OTR The expression of OT and its receptor was strongly induced both in the heart and hypothalamus of ovariectomized and sham-operated rats following exercise training, indicating a possible involvement of OT in the cardioprotective effects of exercise (41).”

“In fact, lowered OT expression in the hypothalamus was reported in spontaneously hypertensive rats (15), and a decrease in OT mRNA was correlated with development of hypertension in those animals (16).”

“Further studies by Paton and Watson in 1912 (8) associated neurohypophysis extracts with blood pressure lowering in birds, the so-called avian depressor effect and von den Velden in 1913 (9) reported inhibition of urine excretion in humans, the antidiuretic effect.”

“Several groups (4-6) observed a wide variety of physiological effects of neurohypophysis extracts and found conclusive evidence, using fractional precipitation, of the presence of two ‘‘active principles’’, one that produced a rise in blood pressure in dogs and another that stimulated the contraction of uterine muscle…”

“The results presented here update our previous analyses of the functional OT system in rat heart and vasculature (73-75).”

“The binding of OT to OTR on pre-T cells induces a rapid phosphorylation of focal adhesion-related kinases (58).”

“(44) demonstrated that icv administration of an OT antagonist significantly enhanced the pressor and tachycardic responses to stress only in shamoperated rats, whereas OT significantly attenuated both responses in infarcted but not in sham-operated rats.”

“Indeed, OT-GKR has potent OTR-mediated cardiomyogenic activity (72), and to understand better these mechanisms of OT-GKR, an embryonic stem cell line overexpressing this elongated form of OT was generated.”

“(43) on isolated, perfused heart showed that the infarct size reduction in the anesthetized rat heart induced by a pretreatment with OT 25 min prior to ischemia was abrogated by a selective mitochondrial KATP (mitoKATP) channel blocker and mitochondrial permeability transition pore (mPTP) opener, suggesting that the c…”

“Enhanced TGF-b can activate CM differentiation from cardiac stem cells (70).”

“In the rat heart, an angiogenic and antiapototic OT effect was indicated by vascular endothelial growth factor (VEGF) and B-cell lymphoma (Bcl)-2 protein upregulation in association with increased CD31 microvessels (36,37).”

“In a study by Das and Sarkar (54), the infarct size-reducing and anti-arrhythmic effects of OT were achieved via selective activation of OTR, CM mitoKATP channels, and NO.”

“OT is synthesized by thymic epithelial cells from different species (56), and each of the major T cell subsets (CD4, CD8, and gamma delta) express OTR (57).”

“In fact, lowered OT expression in the hypothalamus was reported in spontaneously hypertensive rats (15), and a decrease in OT mRNA was correlated with development of hypertension in those animals (16).”

“Several groups (4-6) observed a wide variety of physiological effects of neurohypophysis extracts and found conclusive evidence, using fractional precipitation, of the presence of two ‘‘active principles’’, one that produced a rise in blood pressure in dogs and another that stimulated the contraction of uterine muscle…”

“We have shown that treatment with OT reduced the expression of pro-inflammatory cytokines (TNF-a, IL-1b, and IL-6) produced by MI back to the levels seen in sham-operated rats; OT also reduced immune cell infiltration including T lymphocytes, macrophages, and especially neutrophils (36,65).”

“IL-1b and TNF-a reduce ATP production, probably due to the induction of oxidative stress, and thereby myocardial oxygen consumption (67).”

“Studies in mice also suggest that both oxytocin and the extended form have a critical role in tissue differentiation in the heart and in survival or restoration of heart tissue after damage (such as hypoxia) or disease (such as diabetes) (Gutkowska et al., 2014; Jankowski et al., 2016).”

“There has also been some suggestion that oxytocin has important effects in the periphery, moderating cardiovascular functioning and the peripheral cortisol response, which may influence social behaviour (Cardoso et al., 2014b; Gutkowska et al., 2014).”