Examination of a novel potential therapy for autonomic dysreflexia

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PROJECT SUMMARY/ABSTRACT Autonomic dysreflexia (AD) is a potentially life-threatening hypertensive crisis that predominantly affects individuals with a spinal cord injury (SCI) above T6. AD can be triggered idiopathically or by distention or manipulation of pelvic visceral organs, especially the bladder and bowel, which can occur with catheterization and fecal evacuation procedures that are necessary to manage bladder and bowel emptying. Sensory stimuli arising from the pelvic viscera activate cardiovascular sympathetic preganglionic neurons through an intersegmental spinal reflex that triggers AD. Currently, there are no pharmaceutical agents approved for the prevention of AD. A potential novel therapeutic approach may be to use an antagonist that inhibits a receptor (that is anatomically, physiologically, pharmacologically, and clinically implicated in the spinal control of visceral and cardiovascular function at various points in the reflex pathways responsible for AD) to prevent the occurrence of AD. Our preliminary data indicate that blocking the actions of a specific endogenous neurotransmitter using a selective receptor antagonist inhibits colorectal distension (CRD)-induced hypertension in anesthetized rats with acute SCI. We hypothesize that selective antagonists of this receptor will also reduce or eliminate hypertension induced by CRD in rats with chronic SCI, and that the effect may be greater after a chronic injury because of synaptic plasticity changes and sprouting of fibers in the L6 dorsal horn and sacral parasympathetic nucleus. This hypothesis will be tested by examining the ability of selective antagonists to block AD induced by CRD, and spontaneous AD events, in rats with chronic SCI. In Specific Aim 1, we will examine the effects of antagonists on CRD-induced hypertension in male and female rats with chronic SCI. In Specific Aim 2, we will select the most efficacious antagonist from Aim 1 to determine the effect of daily SC administration for 1 week on resting blood pressure and spontaneous AD events in rats with chronic SCI. As several selective antagonists are approved for clinical use in the US, it is reasonable to expect that a proof of concept clinical trial for the prevention of AD could begin soon after obtaining supportive data from this proposal.