Oxytocin Blocks Tachycardic Responses in the Restraint Stress Model Acting on the Oxytocin Receptor Coupled to Gq Protein

Abstract

IntroductionStress is common in modern life and demands physiological, endocrine and behavioral responses to cope. In acute restraint stress model (ARS), increased OXY is found in plasma whereas no changes are seen in novelty stress (NS). OXT acts on G‐protein receptor (OXTR) recruiting coupled to Gq, Gi and Gs. Atosiban (ATO) was initially categorized as an OXTR antagonist, but was reclassified as an OXTR biased agonist favoring Gi/o over Gq.AimThis study aimed to evaluate the selective functional effects of oxytocin on ARS after treatment with Atosiban.MethodsAll experimental procedures were approved by the University of São Paulo Ethical Committee (number 079/2017). Male Wistar rats, 250g, were used. Pulsatile arterial pressure (PAP) was recorded. Some animals were subjected to hypophysectomy (HYP) or sinoaortic denervation (SAD). Animals were divided into: vehicle, Atosiban (0.3, 1 and 3 μg/kg), dTyr AVP (V1a antagonist receptor, 30 μg/kg), homatropine (M2 antagonist receptor, 200 μg/kg) and exposed to ARS. One vehicle and one Atosiban (1μg/kg) group were exposed to NS. From PAP were calculated: mean arterial pressure (MAP) and heart rate (HR) for time curve analysis, and systolic arterial pressure (SAP) and cardiac interval (CI) for heart rate variability (HRV) and spontaneously baroreflex sensitivity (SBS).ResultsARS increased MAP and HR, due to increased autonomic activity. ATO inhibited ARS‐evoked tachycardia (F3,19=4.074; P<0.05), without effecting MAP increase (F3,19=0.1664, P>0.05). Pretreatment with dTYR AVP did not affect the ATO blockade of tachycardia. HRV analysis of PAS and CI showed a tendency for Atosiban to reduce the low frequency band (P=0.08) and increase the high frequency band (P=0.053) under ARS. The tendency to increase parasympathetic activity was evidenced by parasympathetic blockade with HOM, that reversed ATO effect (HR ‐ ATO vs. HOM+ATO; P<0.05) to that of vehicle group (HR ‐ Vehicle vs. HOM+ATO; P>0.05). SBS analysis of baroreflex effectiveness index (BEI) showed a significant difference in time and treatment for the BEI UP (BEI UP – Time: F8, 32 = 2,702; P<0.05; Treatment: F1, 8 = 6,277; P<0.05). BEI UP tended to increase after ATO on the first hour of restraint (P=0.08). Gain mean analysis showed results similar to BEI; GAIN UP was significantly different after ATO (P<0.05). No differences were observed after ATO in the SAD vs vehicle group. To test if ATO effect depends on oxytocin, HYP animals either ATO or vehicle were subjected to ARS. No differences were observed between ATO and vehicle. Animals were treated with ATO or vehicle were also subjected to NS, an oxytocin secretion‐free stress model, and no differences were observed.ConclusionOur results suggest that OXY secreted to periphery attenuates tachycardic responses evoked by ARS, possibly by a parasympathetic activity facilitation. Atosiban acts on OXTR coupled to Gi/o and OXY secreted is dislocated to OXTR coupled to Gq to promote effects on cardiac frequency during ARS.Support or Funding InformationCAPES, CNPq, FAEPA‐HCFMRP and FAPESP [2016/25502‐7]. Oxytocin mechanism in restraint stress after Atosiban treatmentimageOxytocin mechanism in restraint stress after Atosiban treatmentThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.