Effects of Hypertension After Spinal Cord Injury

Abstract

Prior work has shown that pain after spinal cord injury (SCI) undermines locomotor recovery and provided evidence that pain increases the area of hemorrhage. We hypothesized that pain may be having this effect because it drives an acute rise in systolic blood pressure. To explore this issue, I sought to test whether pharmacologically inducing a rise in blood pressure is sufficient to increase hemorrhage. I did this by pharmacologically inducing hypertension with norepinephrine. In all experiments, male or female Sprague-Dawley rats received a contusion injury at the T10-T11 spinal level. After treatment locomotor scores and blood pressure were assessed. At the conclusion of the study, a 1-cm section of spinal cord centered on the lesion site was collected and processed for signs of hemorrhage. In the first set of experiments, I found that pharmacologically inducing hypertension after SCI is detrimental to acute and long-term locomotor performance, with norepinephrine treatment increasing lesion volume in our 21-day model. Contrary to my hypothesis, this increase in blood pressure was not sufficient to increase acute hemorrhage. This was true for both males and females, with females exhibiting some protective effects. Further work explored whether the effect of hypertension varies over time after injury. Hypertension induced hemorrhage when treatment was given 30 minutes after injury, but not 1.5, 6, or 24 hours after injury. However, only those animals receiving treatment 1.5, 6, and 24 hours after injury exhibited a decrease in locomotor performance. Finally, I explored whether drug treatment had a local effect and the receptor class involved. I found that local (intrathecal) application of norepinephrine is not sufficient to impact locomotor performance. I then focused on how pharmacologically manipulating the adrenergic receptors with other commonly used vasopressors affects recovery. Agonizing the β and α1 adrenergic receptors with dobutamine and phenylephrine, respectively, to pharmacologically augment blood pressure is sufficient to drive a decrease in locomotor performance. Antagonizing the α1 adrenergic receptor activity with prazosin prior to norepinephrine treatment revealed the receptor is also necessary for norepinephrine to exert it’s detrimental effects on behavioral performance. My work demonstrated that hypertension alone does not explain the effect of nociception-induced hemorrhage. However, hypertension may be driving an adverse effect on locomotor performance. Activation of the adrenergic receptors appear to be mediating these effects. This work has further elucidated how hypertension impacts neurological recovery after SCI.