Mechanistic involvement of noradrenergic neuronal neurotransmitter release in cutaneous vasoconstriction during autonomic dysreflexia in persons with spinal cord injury.

INTRODUCTION: Autonomic dysreflexia (AD) is a potentially life-threatening consequence in high (above T6) spinal cord injury that involves multiple incompletely understood mechanisms. While peripheral arteriolar vasoconstriction, which controls systemic vascular resistance, is documented to be pronounced during AD, the pathophysiological neurovascular junction mechanisms of this vasoconstriction are undefined. One hypothesized mechanism is increased neuronal release of norepinephrine and co-transmitters. We tested this by examining the effects of blockade of pre-synaptic neural release of norepinephrine and co-transmitters on cutaneous vasoconstriction during AD, using a novel non-invasive technique; bretylium (BT) iontophoresis followed by skin blood flow measurements via laser doppler flowmetry (LDF). METHODS: Bretylium, a sympathetic neuronal blocking agent (blocks release of norepinephrine and co-transmitters) was applied iontophoretically to the skin of a sensate (arm) and insensate (leg) area in 8 males with motor complete tetraplegia. An nearby untreated site served as control (CON). Cutaneous vascular conductance (CVC) was measured (CVC = LDF/mean arterial pressure) at normotension before AD was elicited by bladder stimulation. The percent drop in CVC values from pre-AD vs. AD was compared among BT and CON sites in sensate and insensate areas. RESULTS: There was a significant effect of treatment but no significant effect of limb/sensation or interaction of limb x treatment on CVC. The percent drop in CVC between BT and CON treated sites was 25.7±1.75 vs. 39.4±0.87, respectively (P = 0.004). CONCLUSION: Bretylium attenuates, but does not fully abolish vasoconstriction during AD. This suggests release of norepinephrine and cotransmitters from cutaneous sympathetic nerves is involved in cutaneous vasoconstriction during AD.

Elucidating mechanisms of attenuated skin vasodilation during passive heat stress in persons with spinal cord injury.

OBJECTIVE: Persons with spinal cord injury (SCI) are unable to efficiently dissipate heat via thermoregulatory vasodilation as efficiently as able-bodied persons during whole body passive heat stress (PHS). Skin blood flow (SkBF) is controlled by dual sympathetic vasomotor systems: noradrenergic vasoconstrictor (VC) nerves and cholinergic vasodilator (VD) nerves. Thus, impaired vasodilation could result from inappropriate increases in noradrenergic VC tone that compete with cholinergic vasodilation or diminished cholinergic tone. To address this issue, we used bretylium (BR) which selectively blocks neural release of norepinephrine, thereby reducing noradrenergic VC tone. If impaired vasodilation during PHS is due to inappropriate increase in VC tone, BR treatment will improve SkBF responses during PHS. DESIGN: Prospective interventional trial. SETTING: laboratory. PARTICIPANTS: 22 veterans with SCI. INTERVENTIONS: Skin surface areas with previously defined intact vs. impaired thermoregulatory vasodilation were treated with BR iontophoresis with a nearby untreated site serving as control/CON. Participants underwent PHS until core temperature rose 1°C. OUTCOME MEASURES: Laser doppler flowmeters measured SkBF over BR and CON sites in areas with impaired and intact thermoregulatory vasodilation. Cutaneous vascular conductance (CVC) was calculated for all sites. Peak-PHS CVC was normalized to baseline (BL): (CVC peak-PHS/CVC BL) to quantify SkBF change. RESULTS: CVC rise in BR sites was significantly less than CON sites in areas with intact (P = 0.03) and impaired (P = 0.04) thermoregulatory vasodilation. CONCLUSION: Cutaneous blockade of neural release of noradrenergic neurotransmitters affecting vasoconstriction did not enhance thermoregulatory vasodilation during PHS in persons with SCI; rather BR attenuated the response. Cutaneous blockade of neural release of noradrenergic neurotransmitters affecting vasoconstriction did not restore cutaneous active vasodilation during PHS in persons with SCI.

Are Thermoregulatory Sweating and Active Vasodilation in Skin Controlled by Separate Nerves During Passive Heat Stress in Persons With Spinal Cord Injury?

Background: Sudomotor responses (SR) and active vasodilation (AVD) are the primary means of heat dissipation during passive heat stress (PHS). It is unknown if they are controlled by a single or separate set of nerves. Older qualitative studies suggest that persons with spinal cord injury (SCI) have discordant areas of sweating and vasodilation. Objectives: To test the hypothesis that neural control of SR and AVD is through separate nerves by measuring SR and vasodilation in persons with SCI to determine if these areas are concordant or discordant. Methods: Nine persons with tetraplegia, 13 with paraplegia, and nine able-bodied controls underwent PHS (core temperature rise 1°C) twice. Initially, the starch iodine test measured SR post-PHS in skin surface areas surrounding the level of injury. Subsequently, laser Doppler imagery scans measured vasodilation pre- and post-PHS in areas with and without SR. Percent change in red blood cell (RBC) flux was compared in areas with and without SR. Results: Persons with tetraplegia were anhidrotic on all areas; however, the same areas demonstrated minimal RBC flux change significantly less than equivalent able-bodied skin surface areas. In persons with paraplegia, areas of intact SR correlated with areas of RBC flux change quantitatively comparable to able-bodied persons. In anhidrotic areas, RBC flux change was significantly less than areas with SR and likely resulted from non-AVD mechanisms. Conclusion: In persons with SCI under PHS, areas with intact SR and AVD are concordant, suggesting these two aspects of thermoregulation are controlled by a single set of nerves.