Volume 23, Issue 2, Pages 111-121 (June 2016) Oxytocin decreases diurnal and nocturnal arterial blood pressure in the conscious unrestrained spontaneously hypertensive rat  Jolanta Gutkowska, Yessoufou Aliou, Julie L. Lavoie, Katie Gaab, Marek Jankowski, Tom L. Broderick  Pathophysiology  Volume 23, Issue 2, Pages 111-121 (June 2016) DOI: 10.1016/j.pathophys.2016.03.003 Copyright © 2016 Elsevier B.V. Terms and Conditions

Fig. 1 Mean arterial pressure in Sprague–Dawley (SDR, top panel) and spontaneously hypertensive rats (SHR, bottom panel) during the 90min after the injections oxytocin at the concentrations of 0.1, 0.2 and 0.4mg/kg. Values are reported as mean±SEM every two minutes for 10 rats in each group. *P<0.05 compared to the control saline infusion. Pathophysiology 2016 23, 111-121DOI: (10.1016/j.pathophys.2016.03.003) Copyright © 2016 Elsevier B.V. Terms and Conditions

Fig. 2 Heart rate in Sprague–Dawley (SDR, top panel) and spontaneously hypertensive rats (SHR, bottom panel) during the 90min after the injections oxytocin at the concentrations of 0.1, 0.2 and 0.4mg/kg. Values are reported as mean±SEM every two minutes for 10 rats in each group. *P<0.05 compared to the control saline infusion. Pathophysiology 2016 23, 111-121DOI: (10.1016/j.pathophys.2016.03.003) Copyright © 2016 Elsevier B.V. Terms and Conditions

Fig. 3 Locomotor activity in Sprague–Dawley (SDR, top panel) and spontaneously hypertensive rats (SHR, bottom panel) during the 90min after the injections oxytocin at the concentrations of 0.1, 0.2 and 0.4mg/kg. Values are reported as mean±SEM every two minutes for 10 rats in each group. *P<0.05 compared to the control saline infusion. Pathophysiology 2016 23, 111-121DOI: (10.1016/j.pathophys.2016.03.003) Copyright © 2016 Elsevier B.V. Terms and Conditions

Fig. 4 Mean arterial pressure (A), heart rate (B) and locomotor activity (C) during the diurnal cycles in male SDR 4(a) and SHR 4(b) in response to 5 consecutive subcutaneous injections of oxytocin at the concentrations of 0.5mg/kg and 1.0mg/kg. Values are compared and expressed as difference from baseline prior to the injections. Values are reported as mean±SEM of data collected every 12h for 10 rats in each group. *P<0.05; #P<0.05; +P<0.05 compare to baseline (BL). Pathophysiology 2016 23, 111-121DOI: (10.1016/j.pathophys.2016.03.003) Copyright © 2016 Elsevier B.V. Terms and Conditions

Fig. 5 Blood pressure (A), heart rate (B) and locomotor activity (C) during the nocturnal cycles in male SDR 5(a) and SHR 5(b) in response to 5 consecutive subcutaneous injections oxytocin at the concentrations of 0.5mg/kg and 1mg/kg. Values are compared and expressed as difference from baseline prior to the injections. Values are reported as mean±SEM of data collected every 12h. *P<0.05; #P<0.05; +P<0.05 compare to baseline (BL). Pathophysiology 2016 23, 111-121DOI: (10.1016/j.pathophys.2016.03.003) Copyright © 2016 Elsevier B.V. Terms and Conditions

Fig. 6 Schematic diagram of the role of OT in the regulation arterial blood pressure. Activation of peripheral aortic and renal baroreceptors in response stimuli (i.e. blood volume expansion, hypertension, hyperosmotic stress) and integration within the NTS results in activation of the OTn, which in turn induces synthesis of OT in the hypothalamic PVN and SON. OT may modify blood pressure and heart rate through effects within the CNS. OT is stored in and released from the PP into the plasma. In plasma, OT can bind to OTRs present in the vasculature, kidney and cardiac tissue. In peripheral arterioles, OT induces NO-dependent vasodilation, decreasing pressure and resistance to blood flow. This vasodilatory effect is enhanced in the presence of estrogen. In cardiac muscles, OT can also bind to OTR resulting in the synthesis and release of ANP and NO, both stimulating cGMP and protein kinase G-dependent negative inotropic and chronotropic effects. ANP induces vasodilation of peripheral arterioles after binding to the NPR-A. At physiological concentrations OT stimulates diuresis and natriuresis via renal OTR. NPR-A are present in the renal vasculature and enhanced ANP in the plasma induces arteriolar dilation, diuresis, natriuresis, kaliuresis, and a decrease in plasma volume. With increased plasma levels of OT or increased synthesis from OTn, a reduction in hypothalamic CRF leads to a decreased production of cortisol. OT, oxytocin; NTS, nucleus tractus solitarius; OTn, oxytocinergic neurons; PVN, paraventricular nuclei; SON, supraoptic nuclei; CNS, central nervous system; OTR, oxytocin receptor; NO, nitric oxide; ANP atrial natriuretic peptide; NPR-A, natriuretic peptide receptor, type A; CRF, corticotropic releasing hormone; AP, anterior pituitary; PP, posterior pituitary. Pathophysiology 2016 23, 111-121DOI: (10.1016/j.pathophys.2016.03.003) Copyright © 2016 Elsevier B.V. Terms and Conditions

Fig. 7 Schematic representation of the baroreflex arc in SHR with OT treatment. Pressure-induced stretch of the carotid bodies is converted into a signal in afferent fibers (cranial nerve IX). Impulses travel to the NTS within the medullary cardiovascular center of the medulla oblongata, the central site of baroreceptor afferents. Neurons within the NTS, in turn, activate inhibitory neurons in the CVLM that extend to the RVLM. Projections from the RVLM to the spinal cord regulate sympathetic nervous tone to peripheral organs, including heart, blood vessels and kidney. With increased pressure-induced stretch of the carotid bodies, activation of neurons in the NTS and CVLM suppress peripheral sympathetic outflow by inhibiting the RVLM neurons. In addition, increased baroreceptor input to the NTS evokes the release of OT from the PP which then circulates to the heart to (1) induce a bradycardia, (2) act on OTR to cause the release of ANP, and (3) induce vasodilation of vessels and a decrease in blood volume. The hypothalamo-neurohypophyseal system is altered in the SHR. In PVN and SON, mRNA expression for the VP system exhibits increased activity, while the OT system exhibits lower activity [28]. Increased mRNA VP expression and decreased OT expression is also observed in the PP of SHR, contributing to an increase in plasma levels of VP and reduced OT levels. The reduction in both MAP and HR seen in SHR with OT maybe be caused by an increased in OT expression in PVN and SON. Increased responsiveness of locus coeruleus α-2 adrenoceptors with OT treatment may also explain the decrease in MAP seen in SHR [36]. SHR, spontaneously hypertensive rat; SDR, Sprague-Dawley rat, OT, oxytocin; NTS, nucleus tractus solitarius; CVLM, caudal ventrolateral medulla; RVLM, rostral ventrolateral medulla; OTR, oxytocin receptor, ANP, atrial natriuretic peptide; PVN, paraventricular nuclei, SON, supraoptic nuclei; PP, posterior pituitary; AP, anterior pituitary; VP, vasopressin. Pathophysiology 2016 23, 111-121DOI: (10.1016/j.pathophys.2016.03.003) Copyright © 2016 Elsevier B.V. Terms and Conditions