Chronic, complete cervical6-7 cord transection: distinct autonomic and cardiac deficits

Abstract

Spinal cord injury (SCI) resulting in tetraplegia is a devastating, life-changing insult causing paralysis and sensory impairment as well as distinct autonomic dysfunction that triggers compromised cardiovascular, bowel, bladder, and sexual activity. Life becomes a battle for independence as even routine bodily functions and the smallest activity of daily living become major challenges. Accordingly, there is a critical need for a chronic preclinical model of tetraplegia. This report addresses this critical need by comparing, for the first time, resting-, reflex-, and stress-induced cardiovascular, autonomic, and hormonal responses each week for 4 wk in 12 sham-operated intact rats and 12 rats with chronic, complete C_6-7 spinal cord transection. Loss of supraspinal control to all sympathetic preganglionic neurons projecting to the heart and vasculature resulted in a profound bradycardia and hypotension, reduced cardiac sympathetic and parasympathetic tonus, reduced reflex- and stress-induced sympathetic responses, and reduced sympathetic support of blood pressure as well as enhanced reliance on angiotensin to maintain arterial blood pressure. Histological examination of the nucleus ambiguus and stellate ganglia supports the profound and distinct autonomic and cardiac deficits and reliance on angiotensin to maintain cardiovascular stability following chronic, complete cervical_6-7 cord transection. NEW & NOTEWORTHY For the first time, resting-, reflex-, and stress-induced cardiovascular, autonomic, and hormonal responses were studied in rats with chronic, complete C_6-7 cord transection. Loss of supraspinal control of all sympathetic preganglionic neurons reduced cardiac sympathetic and parasympathetic tonus, reflex and stress-induced sympathetic responses, and sympathetic support of blood pressure as well as enhanced reliance on angiotensin to maintain arterial blood pressure. Histological examination supports the distinct deficits associated with cervical cord injury.

Keywords: blood pressure regulation; parasympathetic nervous system; sympathetic nervous system; tetraplegia.

Fig. 1.

High-resolution sagittal image documenting the site of the cervical injury by fast-spin echo MRI. The brain stem, cerebellum, vertebral bodies, and lesion are clearly visible.

Fig. 2.

Resting mean arterial blood pressure (A) and heart rate (B) each week for 4 wk in chronic sham-transected (intact) and complete cervical_6–7 spinal cord-transected (C_6–7X) rats. Resting arterial blood pressure and heart rate were significantly lower in C_6–7X rats compared with intact rats. *P < 0.05, intact vs. C_6–7X, group effect; #P < 0.05, intact vs. C_6–7X each week, group × time interaction.

Fig. 3.

Cardiac sympathetic tonus (A) and cardiac parasympathetic tonus (B) each week for 4 wk in chronic sham-transected (intact) and complete cervical 6–7 spinal cord-transected (C_6–7X) rats. Sympathetic and parasympathetic tonus were significantly lower in C_6–7X rats compared with intact rats. *P < 0.05, intact vs. C_6–7X, group effect.

Fig. 4.

Intrinsic heart rate each week for 4 wk in chronic sham-transected (intact) and complete cervical 6–7 spinal cord-transected (C_6–7X) rats. Intrinsic heart rate was determined as the heart rate response after complete cardiac autonomic blockade. C_6–7X rats had a lower intrinsic heart rate compared with intact rats. *P < 0.05, intact vs. C_6–7X, group effect.

Fig. 5.

Sympathetic (A) and angiotensin support (B) of blood pressure each week for 4 wk in chronic sham-transected (intact) and complete cervical 6–7 spinal cord-transected (C_6–7X) rats. C_6–7X rats had a reduced sympathetic support of blood pressure and an enhanced reliance on angiotensin to maintain arterial blood pressure compared with intact rats. *P < 0.05, intact vs. C_6–7X, group effect.

Fig. 6.

Change in arterial pressure (A) and heart rate (B) in response to 20 min of restrainer stress each week for 4 wk in chronic sham-transected (intact) and complete cervical 6–7 spinal cord-transected (C_6–7X) rats. C_6–7X rats had virtually no arterial pressure or heart rate responses to restrainer stress each week for 4 wk. *P < 0.05, intact vs. C_6–7X, group effect; #P < 0.05, intact vs. C_6–7X each week, group × time interaction.

Fig. 7.

A: reflex-induced arterial pressure and heart rate responses to a single dose of sodium nitroprusside each week for 4 wk in chronic sham-transected (intact) and complete cervical 6–7 spinal cord-transected (C_6–7X) rats. Although there were no differences in the arterial pressure responses, the reflex heart rate responses were significantly lower each week for 4 wk in the C_6–7X rats compared with intact rats. B: rebound increase in arterial pressure above control and the decrease in heart rate for the C_6–7X rats (intact rats did not have a rebound increase in arterial pressure above control). Rebound increase in arterial pressure above control induced a significant and robust reduction in heart rate in the C_6–7X rats, documenting preservation of cardiovagal baroreflexes. *P < 0.05, intact vs. C_6–7X, group effect.

Fig. 8.

Photomicrographs of 30-μm sagittal sections through the right brain stem processed for cholera toxin B subunit (CTB) immunoreactivity from 1 chronic sham-transected rat (intact; A) and 1 complete cervical 6–7 spinal cord-transected (C_6–7X) rat (B). C: mean no. of intersections per CTB-labeled neurons between each ring in a series of concentric rings. Premotor cardioinhibitory vagal neuron dendritic arborization was reduced in C_6–7X rats. *P < 0.05, intact vs. C_6–7X, group effect.

Fig. 9.

Soma area (A), maximum dendritic length (B), no. of intersections per animal (C), and total no. of neurons (D) of nucleus ambiguus neurons back-labeled from the heart from chronic sham-operated intact rats and complete cervical 6–7 spinal cord transected rats (C_6–7X). Although there was no difference in premotor cardioinhibitory vagal neuron soma area between intact and C_6–7X rats, maximum dendritic length, no. of interactions per animal, and the total no. of labeled neurons were reduced in C_6–7X rats. *P < 0.05, intact vs. C_6–7X, group effect.

Fig. 10.

Photomicrographs of 30-μm horizontal sections through the stellate ganglia processed for CTB immunoreactivity from 1 chronic sham-transected rat (intact; A) and 1 complete cervical 6–7 spinal cord-transected rat (C_6–7X; B). C: mean no. of intersections per CTB-labeled neurons between each ring in a series of concentric rings. Stellate ganglia neuron dendritic arborization was increased in C_6–7X rats. *P < 0.05, intact vs. C_6–7X, group effect.

Fig. 11.

Stellate ganglia neuron soma area (A), maximum dendritic length (B), no. of intersections/animal (C), and total no. of neurons (D). None of the neuron characteristics were altered by cervical spinal cord injury.