Elsevier

The Spine Journal

Volume 10, Issue 12, December 2010, Pages 1108-1117
The Spine Journal

Basic Science
Recurrent autonomic dysreflexia exacerbates vascular dysfunction after spinal cord injury

https://doi.org/10.1016/j.spinee.2010.09.018Get rights and content

Abstract

Background context

Individuals with high spinal cord injury (SCI) are prone to significant fluctuation in blood pressure with episodes of very high and low blood pressure during autonomic dysreflexia (AD) and orthostatic hypotension, respectively. We do not know how such blood pressure lability affects the vasculature.

Purpose

We used a well-characterized animal model of AD to determine whether increasing the frequency of AD during recovery from SCI would exacerbate injury-induced dysfunction in resistance vessels.

Study design/setting

Experimental animal study. International Collaboration On Repair Discoveries (ICORD), University of British Columbia, Canada.

Methods

Complete transection of the T3 spinal cord was performed in male Wistar rats. For 14 days after injury, AD was induced via colorectal distension (CRD; 30 minutes per day) in the experimental group (SCI-CRD). One month after SCI, baseline cardiovascular parameters and severity of CRD-induced AD were assessed in SCI-CRD animals and SCI-only controls. Mesenteric arteries were harvested for in vitro myography to characterize vasoactive responses to phenylephrine (PE) and acetylcholine (ACh).

Results

Mesenteric arteries from SCI-CRD animals exhibited larger maximal responses to PE than arteries from SCI-only controls. Hyperresponsiveness to PE was not a product of endothelial dysfunction because mesenteric arteries from both groups had similar vasodilator responses to ACh. Both SCI-only controls and SCI-CRD animals exhibited CRD-evoked AD 1 month after SCI; however, CRD-induced hypertension was less pronounced in animals that were previously exposed to CRD.

Conclusions

Injury-induced changes within the vasculature may contribute to the development of AD after SCI. Here, we provide evidence that AD itself has significant and long-lasting effects on vascular function. This finding has implications for the medical management of AD and provides an impetus for maintaining stable blood pressure.

Introduction

Spinal cord injury (SCI) disrupts descending autonomic pathways and consequently impairs cardiovascular homeostasis [1], [2]. Deficits in cardiovascular control are particularly marked in individuals with cervical or high thoracic SCI [3], [4], [5], [6]. A large proportion of individuals with SCI above the sixth thoracic level (T6) experience autonomic dysreflexia (AD) and episodic hypertension elicited by sensory stimulation below the level of injury [7], [8]. Many individuals with SCI also experience episodes of low blood pressure because of orthostatic hypotension (OH). Although OH is particularly common in the acute phase of injury [9], [10], it persists in up to 70% of individuals with chronic SCI [11].

Episodes of AD and OH frequently occur numerous times per day, such that blood pressure fluctuates dramatically: for example, systolic blood pressure can fall to 60 mm Hg during OH [12], [13] and increase to 300 mm Hg during AD [14].

The effects of such pronounced changes in blood pressure on the vasculature and cardiovascular function over the lifetime of individuals with SCI are unknown. However, several lines of evidence suggest that chronic blood pressure lability is likely to be detrimental. For example, animal studies reveal that experimental manipulations of arterial hemodynamics to increase shear stress produce deterioration of the vascular endothelium [15]. In addition, preeclampsia, an intermittent hypertensive state that occurs during pregnancy, is associated with impaired flow-mediated dilation (FMD; an indicator of vascular endothelial function) [16], [17], [18]. Impaired endothelial function in preeclampsia, which occurs for a short period in young, mostly healthy females, provides persuasive evidence that even short periods of episodic hypertension induce vascular dysfunction. More than a decade ago, Steins et al. [19] proposed that instability in blood pressure could contribute to vascular injury and consequently result in greater risk for arterial disease in individuals with SCI.

Blood pressure regulation at the level of the resistance vessels is achieved via a balance of neural activity, hormonal control, and intrinsic properties of the vascular smooth muscle and endothelium. Spinal cord injury perturbs this balance. We know that SCI triggers plasticity in several divisions of the central and peripheral nervous system that regulate sympathetic tone [20], [21], [22], [23], [24], [25], [26]. Although less is known about effects of SCI on cardiovascular end organs, abnormalities in cardiac and vascular structure and function have been reported in individuals with SCI [27], [28], [29], [30]. Recent experiments in animal models reveal marked vascular dysfunction within the critical splanchnic vascular bed. Mesenteric arteries from rats with chronic high thoracic SCI are hypersensitive to the α1-adrenoreceptor agonist phenylephrine (PE [24]; LMR, NA, JAI, SG, MSR, IL, AVK, unpublished observations, 2009). Hyperresponsiveness to PE in the splanchnic circulation develops over time after SCI and may contribute to the development of AD [24]. Here, we sought to determine whether the opposite is also true; that is, whether recurrent AD might exacerbate vascular dysfunction after SCI.

We therefore examined the effects of recurrent AD on vascular function after SCI. In one group of animals, AD was induced on a daily basis via colorectal distension (CRD) over two weeks after complete transection of the T3 spinal cord. At 1-month after injury, we examined severity of CRD-induced AD in animals exposed to CRD during recovery from SCI and in SCI-only controls. We then characterized vasoactive properties of mesenteric arteries from both groups of animals using in vitro myography.

Section snippets

Material and methods

All experimental procedures conformed with the Guide to the Care and Use of Experimental Animals established by the Canadian Council on Animal Care and were approved by the University of British Columbia Animal Care Committee.

Repetitive CRD exacerbated SCI-induced vascular dysfunction

Using in vitro myography, we examined vasoactive responses in mesenteric arteries from animals exposed to repeated CRD (SCI-CRD, n=5) and from SCI-only controls (n=5). When exposed to cumulative addition of PE (Fig. 1C), mesenteric arteries from SCI-CRD animals exhibited enhanced vasoconstriction compared with arteries from the SCI-only group (Fig. 2, Left). Raw force recorded in response to PE was normalized internally (ie, for each arterial segment) and expressed as percentage of contraction

Discussion

In these experiments, we investigated the effects of recurrent CRD-induced AD on vascular function in animals with SCI. In one group of animals, AD was induced daily via CRD during 2 weeks after T3 transection: this manipulation exacerbated PE hyperresponsiveness in mesenteric arteries examined 1 month after SCI. The effects of recurrent AD were not due to impaired endothelial function because ACh-evoked vasodilation was similar in arteries from SCI-CRD animals and SCI-only controls.

Acknowledgments

We gratefully acknowledge the support of the Heart and Stroke Foundation of Canada (BC & Yukon). We would also like to thank John Byron Ramsey for excellent animal care and technical support.

References (74)

  • E.L. Schiffrin

    Remodeling of resistance arteries in essential hypertension and effects of antihypertensive treatment

    Am J Hypertens

    (2004)
  • D.J. Strauss et al.

    Trends in life expectancy after spinal cord injury

    Arch Phys Med Rehabil

    (2006)
  • T.A. Linsenmeyer et al.

    Silent autonomic dysreflexia during voiding in men with spinal cord injuries

    J Urol

    (1996)
  • A.V. Krassioukov et al.

    The changes in human spinal sympathetic preganglionic neurons after spinal cord injury

    Spinal Cord

    (1999)
  • J.C. Furlan et al.

    Descending vasomotor pathways in humans: correlation between axonal preservation and cardiovascular dysfunction after spinal cord injury

    J Neurotrauma

    (2003)
  • A. Curt et al.

    Assessment of autonomic dysreflexia in patients with spinal cord injury

    J Neurol Neurosurg Psychiatry

    (1997)
  • H. Krum et al.

    Diurnal blood pressure variation in quadriplegic chronic spinal cord injury patients

    Clin Sci (Lond)

    (1991)
  • M. Munakata et al.

    Circadian blood pressure rhythm in patients with higher and lower spinal cord injury: simultaneous evaluation of autonomic nervous activity and physical activity

    J Hypertens

    (1997)
  • R. Lindan et al.

    Incidence and clinical features of autonomic dysreflexia in patients with spinal cord injury

    Paraplegia

    (1980)
  • W.M. Helkowski et al.

    Autonomic dysreflexia: incidence in persons with neurologically complete and incomplete tetraplegia

    J Spinal Cord Med

    (2003)
  • E.V. Sidorov et al.

    Orthostatic hypotension in the first month following acute spinal cord injury

    Spinal Cord

    (2008)
  • A. Illman et al.

    The prevalence of orthostatic hypotension during physiotherapy treatment in patients with an acute spinal cord injury

    Spinal Cord

    (2000)
  • V.E. Claydon et al.

    Orthostatic hypotension and autonomic pathways after spinal cord injury

    J Neurotrauma

    (2006)
  • V.E. Claydon et al.

    Orthostatic hypotension following spinal cord injury: understanding clinical pathophysiology

    Spinal Cord

    (2006)
  • C.J. Mathias

    Orthostatic hypotension: causes, mechanisms, and influencing factors

    Neurology

    (1995)
  • S. Elliott et al.

    Malignant autonomic dysreflexia in spinal cord injured men

    Spinal Cord

    (2006)
  • D.L. Fry

    Acute vascular endothelial changes associated with increased blood velocity gradients

    Circ Res

    (1968)
  • F. Khan et al.

    Changes in endothelial function precede the clinical disease in women in whom preeclampsia develops

    Hypertension

    (2005)
  • J.C. Chambers et al.

    Association of maternal endothelial dysfunction with preeclampsia

    JAMA

    (2001)
  • P.K. Agatisa et al.

    Impairment of endothelial function in women with a history of preeclampsia: an indicator of cardiovascular risk

    Am J Physiol Heart Circ Physiol

    (2004)
  • S.A. Steins et al.

    Cardiac rehabilitation in patients with spinal cord injuries

    Phys Med Rehabil Clin N Am

    (1995)
  • N.R. Krenz et al.

    Neutralizing intraspinal nerve growth factor blocks autonomic dysreflexia caused by spinal cord injury

    J Neurosci

    (1999)
  • J.A. Brock et al.

    Enhanced neurally evoked responses and inhibition of norepinephrine reuptake in rat mesenteric arteries after spinal transection

    Am J Physiol Heart Circ Physiol

    (2006)
  • M. Yeoh et al.

    Tail arteries from chronically spinalized rats have potentiated responses to nerve stimulation in vitro

    J Physiol

    (2004)
  • M.S. Nash et al.

    Reversal of adaptive left ventricular atrophy following electrically-stimulated exercise training in human tetraplegics

    Paraplegia

    (1991)
  • M.T.E. Hopman et al.

    Increased vascular resistance in paralyzed legs after spinal cord injury is reversible by training

    J Appl Physiol

    (2002)
  • J.M.O. Arnold et al.

    Autonomic dysreflexia in tetraplegic patients: evidence for alpha-adrenoceptor hyper-responsiveness

    Clin Auton Res

    (1995)
  • Cited by (0)

    FDA device/drug status: not applicable.

    Author disclosures: none.

    The authors (NA and LMR) have contributed equally to this study.

    View full text