Negative Inotropic and Chronotropic Effects of Oxytocin

Abstract

Abstract-We have previously shown that oxytocin receptors are present in the heart and that perfusion of isolated rat hearts with oxytocin results in decreased cardiac flow rate and bradycardia. The mechanisms involved in the negative inotropic and chronotropic effects of oxytocin were investigated in isolated dog right atria in the absence of central mechanisms. Perfusion of atria through the sinus node artery with 10 Ϫ6 mol/L oxytocin over 5 minutes (8 mL/min) significantly decreased both beating rate (Ϫ14.7Ϯ4.9% of basal levels, nϭ5, PϽ0.004) and force of contraction (Ϫ52.4Ϯ9.1% of basal levels, nϭ5, PϽ0.001). Co-perfusion with 10 Ϫ6 mol/L oxytocin receptor antagonist (nϭ3) completely inhibited the effects of oxytocin on frequency (PϽ0.04) and force of contraction (PϽ0.004), indicating receptor specificity. The effects of oxytocin were also totally inhibited by co-perfusion with 5ϫ10Ϫ8 mol/L tetrodotoxin (PϽ0.02) or 10 Ϫ6 mol/L atropine (PϽ0.03) but not by 10 Ϫ6 mol/L hexamethonium, which implies that these effects are neurally mediated, primarily by intrinsic parasympathetic postganglionic neurons. Co-perfusion with 10 Ϫ6 mol/L NO synthase inhibitor (L-NAME) significantly inhibited oxytocin effects on both beating rate (Ϫ1.85Ϯ1.27% versus Ϫ14.7Ϯ4.9% in oxytocin alone, PϽ0.05) and force of contraction (Ϫ24.9Ϯ4.4% versus Ϫ52.4Ϯ9.1% in oxytocin alone, nϭ4, PϽ0.04). The effect of oxytocin on contractility was further inhibited by L-NAME at 10 Ϫ4 mol/L (Ϫ8.1Ϯ1.8%, PϽ0.01). These studies imply that the negative inotropic and chronotropic effects of oxytocin are mediated by cardiac oxytocin receptors and that intrinsic cardiac cholinergic neurons and NO are involved in these actions. (Hypertension. 2001;38:292-296.) Key Words: receptors Ⅲ neurons Ⅲ heart rate Ⅲ contractility Ⅲ nervous system, parasympathetic Ⅲ nitric oxide O xytocin, 1 of 2 major posterior pituitary hormones (oxytocin and vasopressin), is a neuropeptide synthesized primarily in magnocellular neurons in the paraventricular and supraoptic nuclei of the hypothalamus, which project to posterior pituitary, median eminence, and several brain regions. Oxytocin is also produced in peripheral tissues, 1 including the heart. We have recently shown that the heart is an important source of oxytocin production and synthesis. 2 In addition to its well-known effects on reproductive functions, such as uterine contraction, milk-ejection reflex, and induction of maternal behavior, 3,4 oxytocin was recently shown to be involved in endocrine and neuroendocrine regulation through receptor-mediated actions exerted on the heart, vasculature, and kidneys. [5][6][7][8][9] In humans, intravenous oxytocin injections cause biphasic dose-dependent changes in mean arterial pressure that consist of an initial pressor response accompanied by bradycardia and a decrease in cardiac output, followed by a prolonged fall in mean arterial pressure accompanied by increased cardiac output. 10 Oxytocin administration at the rat upper spinal cord 11 or into acutely decentralized canine stel...

Deficits in plasma oxytocin responses and increased negative affect, stress, and blood pressure in mothers with cocaine exposure during pregnancy

“…Recent studies in oxytocin knockout mice have confirmed that these animals have abnormal autonomic and baroreflex control over heart rate (HR) and BP, and that female mice lacking oxytocin have increased anxiety-like behaviors (Mantella, Vollmer, Li, & Amico, 2003;Michelini, Marcelo, Amico, & Morris, 2003). Other recent research in both male and female animal models indicates that in addition to its production within the hypothalamus, oxytocin is produced and released in the heart and the vasculature, and that oxytocin specifically activates receptors that are present in both sites, leading to decreases in HR, contractile force and vascular resistance (Jankowski et al, 2000;Mukaddam-Daher, Yin, Roy, Gutkowska, & Cardinal, 2001;Thibonnier et al, 1999). Thus, oxytocin may act both centrally and peripherally to lower BP.…”

Oxytocin induces differentiation of P19 embryonic stem cells to cardiomyocytes

“…OT's indirect actions could be related to its cardiovascular functions observed in adult rats (7,(21)(22)(23). Indeed, we uncovered the entire OT͞OTR system in the rat heart, and showed that cardiac OTR activation is coupled to the release of atrial natriuretic peptide (ANP), a potent diuretic, natriuretic, and vasorelaxant hormone that is also involved in cell growth regulation (7,8).…”

Neonatal oxytocin treatment modulates oxytocin receptor, atrial natriuretic peptide, nitric oxide synthase and estrogen receptor mRNAs expression in rat heart

“…However, coadministration with OTA completely inhibited the effects of OT on beating rate and force, which suggested that these effects are mediated by OT receptors [28]. Oxytocin receptors in the heart may be localized on intrinsic cholinergic neurons, and upon activation, they release acetylcholine (ACh) to decrease heart rate and force of contraction [28]. Oxytocin may act in an autocrine/ paracrine manner to modulate the release of ACh from intrinsic cardiac cholinergic neurons [28], to clarify the OTR localization.…”

“…Further, it was reported that perfusion with OTA alone did not have any effect on heart rate and force of contraction. However, coadministration with OTA completely inhibited the effects of OT on beating rate and force, which suggested that these effects are mediated by OT receptors [28]. Oxytocin receptors in the heart may be localized on intrinsic cholinergic neurons, and upon activation, they release acetylcholine (ACh) to decrease heart rate and force of contraction [28].…”

“…Oxytocin receptors in the heart may be localized on intrinsic cholinergic neurons, and upon activation, they release acetylcholine (ACh) to decrease heart rate and force of contraction [28]. Oxytocin may act in an autocrine/ paracrine manner to modulate the release of ACh from intrinsic cardiac cholinergic neurons [28], to clarify the OTR localization. It has been shown that stimulation of oxytocin receptors leads to elevation of intracellular Ca 2+ .…”