Effect of oxytocin on cardiovascular modulation in normal and post-traumatic stress disorder model rats

Abstract

Oxytocin (OXT) is associated with cardioprotective effects and shows to alleviate symptoms of post-traumatic stress disorder (PTSD). This study investigates blood pressure and electrocardiographic (ECG) parameters in anesthetized normal rats utilizing intravenous (iv) and intracerebroventricular (icv) administration of oxytocinergic agents. We also assessed the effects of cervical vagotomy on the cardiovascular responses to iv OXT. Furthermore, we compared the cardiovascular responses to iv OXT in PTSD model rats with those in normal controls. The mean arterial pressure (MAP), mean heart rate (HR) and the standard deviation of normal-to-normal intervals (SDNN, an indicator of HR variability) were measured and analyzed. Results showed that iv, rather than icv, administration of OXT led to a concentration-dependent increase in MAP, a decrease in HR, and an increase in the SDNN. Cervical vagotomy did not significantly alter the MAP responses but reduced cardiac activities (both HR and SDNN) during OXT stimulation. PTSD model rats exhibited higher baseline MAP and HR, but showed a diminished cardiovascular response to OXT compared to normal rats. These findings suggest that OXT induces distinct cardiovascular effects in normal versus PTSD model rats, underscoring the need to consider the cardiovascular implications of OXT in clinical applications.

Keywords: Blood pressure; Heart rate; Oxytocin; Post-traumatic stress disorder; Standard deviation of normal-to-normal intervals.

Fig. 1

Schematic representation of the experimental process. (A) Experimental design. (Exp 1) Rats received iv injections of saline, LD-OXT, and HD-OXT simultaneously for BP and ECG recordings, followed by analyses of MAP, HR, and the SDNN. (Exp 2) Rats received icv injections of saline and OXT for BP and ECG recordings, followed by analyses of MAP, HR, and SDNN. (Exp 3) Rats received iv injections of the selective OXT receptor antagonist L-371,257 (L371) or a control (DMSO), followed by iv injection of HD-OXT for BP and ECG recordings, with subsequent analyses of MAP, HR, and SDNN. (Exp 4) Rats received icv injections of L371 and DMSO, followed by iv injection of HD-OXT for BP and ECG recordings, and subsequent analyses of MAP, HR, and SDNN. (Exp 5) Rats underwent either bilateral CVT or sham surgery, followed by iv injection of HD-OXT for BP and ECG recordings, and subsequent analyses of MAP, HR, and SDNN. (Exp 6) Rats underwent the SPS regimen for PTSD modeling, followed by iv injections of saline, LD-OXT, and HD-OXT for BP and ECG recordings, and subsequent analyses of MAP, HR, and SDNN. (B) Histological identification of the microinjection site in the lateral ventricle (left), based on a rat stereotaxic atlas (right). BP, blood pressure; CVT, cervical vagotomy; ECG, electrocardiography; Exp, experiment; HD-OXT, high dose OXT (0.03 mg/kg); HRV, heart rate variability; LD-OXT, low dose OXT (0.01 mg/kg); MAP, mean arterial pressure; SDNN, standard deviation of normal-to-normal intervals.

Fig. 2

Cardiovascular response to iv injection of OXT. (A–C) Representative recordings of cardiovascular changes following iv injection of saline (A), LD-OXT (0.01 mg/kg; B), and HD-OXT (0.03 mg/kg; C). (A1, B1, C1) BP; (A2, B2, C2) HR; (A3, B3, C3) ECG. (D–F) Histograms depicting iv OXT-mediated changes to MAP (D), HR (E), and SDNN (F). In panels A1, A2, B1, B2, C1, and C2, the short line indicates the 1-min time window used for BP and HR measurements. In panels A3, B3, and C3, the short line indicates the 5-min time window used for ECG measurement to calculate SDNN. In panels A1 and C1, the dashed box highlights representative magnified BP and ECG waveforms. **P < 0.01; *P < 0.05; n.s. = not significant (one-way ANOVA and followed by Fisher’s LSD test). BP, blood pressure; ECG, electrocardiography; HD-OXT, high dose OXT (0.03 mg/kg); HR, heart rate; LD-OXT, low dose OXT (0.01 mg/kg); MAP, mean arterial pressure; max., maximum response; SDNN, standard deviation of normal-to-normal intervals.

Fig. 3

Cardiovascular response to icv injection of OXT. (A,B) Representative recordings of cardiovascular changes following icv injection of saline (A) and OXT (0.003 mg/kg, B). (A1,B1) BP; (A2,B2) HR; (A3,B3) ECG. (C–E) Histograms depicting icv OXT-mediated changes to MAP (C), HR (D), and SDNN (E). n.s. = not significant (one-way ANOVA and followed by Fisher’s LSD test). BP, blood pressure; ECG, electrocardiography; HR, heart rate; MAP, mean arterial pressure; max., maximum response; SDNN, standard deviation of normal-to-normal intervals.

Fig. 4

The iv OXT-induced cardiovascular response was dramatically attenuated by pre-iv injection of the OXT receptor antagonist. (A,B) Representative recordings of cardiovascular changes following iv injection of OXT after iv pretreatment with DMSO (A) and L371 (B). (A1,B1) BP; (A2,B2) HR; (A3,B3) ECG. (C–E) Histograms comparing iv OXT-mediated changes to MAP (C), HR (D), and SDNN (E) between iv pretreatment with L371 and DMSO. **P < 0.01; n.s. = not significant (one-way ANOVA and followed by Fisher’s LSD test). BP, blood pressure; ECG, electrocardiography; HD-OXT, high dose OXT (0.03 mg/kg); HR, heart rate; MAP, mean arterial pressure; max., maximum response; SDNN, standard deviation of normal-to-normal intervals.

Fig. 5

The iv OXT-induced cardiovascular response was not affected by pre-icv injection of the OXT receptor antagonist. (A,B) Representative recordings of cardiovascular changes following iv injection of OXT with icv pretreatment of DMSO (A) and L371 (B). (A1,B1) BP; (A2,B2) HR; (A3,B3) ECG. (C–E) Histograms comparing iv OXT-mediated changes to MAP (C), HR (D), and SDNN (E) between icv pretreatment with L371 and DMSO. **P < 0.01; n.s. = not significant (one-way ANOVA and followed by Fisher’s LSD test). BP, blood pressure; ECG, electrocardiography; HD-OXT, high dose OXT (0.03 mg/kg); HR, heart rate; MAP, mean arterial pressure; max., maximum response; SDNN, standard deviation of normal-to-normal intervals.

Fig. 6

Effect of CVT on cardiovascular response to iv injection of OXT. (A,B) Representative recordings of cardiovascular changes following iv injection of OXT in the sham surgery (A) and CVT (B) groups. (A1,B1) BP; (A2,B2) HR; (A3,B3) ECG. (C–E) Histograms depicting OXT-mediated changes to MAP (C), HR (D), and SDNN (E). **P < 0.01; *P < 0.05; n.s. = not significant (one-way ANOVA and followed by Fisher’s LSD test). BP, blood pressure; CVT, cervical vagotomy; ECG, electrocardiography; HD-OXT, high dose OXT (0.03 mg/kg); HR, heart rate; MAP, mean arterial pressure; max., maximum response; SDNN, standard deviation of normal-to-normal intervals.

Fig. 7

Cardiovascular response to iv injection of OXT in PTSD model rats. (A–C) Representative recordings of cardiovascular changes following iv injection of saline, LD-OXT (0.01 mg/kg), and HD-OXT (0.03 mg/kg). (A) BP; (B) HR; (C) ECG. (D–F) Histograms depicting OXT-mediated changes in MAP (D), HR (E), and SDNN (F). **P < 0.01; *P < 0.05; n.s. = not significant (one-way ANOVA and followed by Fisher’s LSD test). BP, blood pressure; ECG, electrocardiography; HD-OXT, high dose OXT (0.03 mg/kg); HR, heart rate; LD-OXT, low dose OXT (0.01 mg/kg); MAP, mean arterial pressure; max., maximum response; SDNN, standard deviation of normal-to-normal intervals.