Angiotensin-(1-7) Receptor Mas in Hemodynamic and Thermoregulatory Dysfunction After High-Level Spinal Cord Injury in Mice: A Pilot Study

Abstract

Spinal cord injury (SCI) above mid-thoracic levels leads to autonomic dysfunction affecting both the cardiovascular system and thermoregulation. The renin-angiotensin system (RAS) which is a potent regulator of blood pressure, including its novel beneficial arm with the receptor Mas could be an interesting target in post-SCI hemodynamics. To test the hypothesis that hemodynamics, activity and diurnal patterns of those are more affected in the Mas deficient mice post-SCI we used a mouse model of SCI with complete transection of spinal cord at thoracic level 4 (T4-Tx) and performed telemetric monitoring of blood pressure (BP) and heart rate (HR). Our data revealed that hypothermia deteriorated physiological BP and HR control. Preserving normothermia by keeping mice at 30°C prevented severe hypotension and bradycardia post-SCI. Moreover, it facilitated rapid return of diurnal regulation of BP, HR and activity in wild type (WT) mice. In contrast, although Mas deficient mice had comparable reacquisition of diurnal HR rhythm, they showed delayed recovery of diurnal rhythmicity in BP and significantly lower nocturnal activity. Exposing mice with T4-Tx (kept in temperature-controlled cages) to 23°C room temperature for one hour at different time-points post-SCI, demonstrated their inability to maintain core body temperature, Mas deficient mice being significantly more impaired than WT littermates. We conclude that Mas deficient mice were more resistant to acute hypotension, delayed nocturnal recovery, lower activity and more severely impaired thermoregulation. The ambient temperature had significant effect on hemodynamics and, thus it should be taken into account when assessing cardiovascular parameters post-SCI in mice.

Keywords: blood pressure; diurnal rhythm; heart rate; renin-angiotensin system; telemetry.

FIGURE 1

Autonomic functions at 30°C. (A) Systolic blood pressure (SBP), (B) heart rate (HR) and (C) locomotor activity in the cage prior to and after spinal cord injury (SCI). Data are presented as mean values of every 3 h and standard error of the mean (SEM). Significances pre-injury vs. post-T4-Tx for SBP, HR and activity in WT and Mas^-/- groups, respectively, Student’s t-test ^∗∗∗p < 0.001. Baseline, acute phase and chronic phase SBP (D–F, respectively), HR (G–I) and activity (J–L) for daytime and night time. Significances ^∗(^∗∗/^∗∗∗)p < 0.05 (0.01/0.001) one-way ANOVA with Bonferroni-adjusted post hoc analysis, (above bar graphs); right side box for the effect of time point (pre, acute and chronic phase of SCI) 2-way repeated measures ANOVA with Bonferroni-adjusted post hoc analysis, ns, not significant.

FIGURE 2

Body core temperature of mice with sham-OP or T4-Tx at indicated time-points post surgery measured prior to (at 30°C) and 1 h after keeping the mice at room temperature (23°C). On 17 and 26 days post injury (dpi) mice were additionally exposed to a 2nd hour at RT. Sham: WT n = 5 and Mas^-/-n = 5, T4-Tx: WT n = 10 and Mas^-/- n = 10. 2-way repeated measures ANOVA, significance of interaction between genotype (WT, Mas^-/-) and time (0, 1, and 2 h at RT) displayed on figure, Bonferroni-adjusted post hoc analysis, ^∗(^∗∗/^∗∗∗) p < 0.05 (0.01/0.001).