Basic ScienceRecurrent autonomic dysreflexia exacerbates vascular dysfunction after spinal cord injury
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.
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Author disclosures: none.
The authors (NA and LMR) have contributed equally to this study.