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ItemMechanisms that increase vascular reactivity following spinal cord injuryAL DERA, HUSSAIN ( 2013)People with spinal cord injury (SCI) can experience episodes of dangerously high blood pressure, termed autonomic dysreflexia, in response to a range of sensory stimuli. While SCI severs bulbospinal inputs to sympathetic preganglionic neurons, the spinal reflex pathways below the lesion remain intact and are unopposed by inhibitory inputs from the brainstem. As a result, somatosympathetic reflexes can produce pronounced constriction of arterial vessels. Studies in man indicate that SCI not only modifies spinal reflexes but also increases neurovascular transmission in arterial vessels. The objective of this thesis was to gain insight into the mechanisms underlying the augmentation of neurovascular transmission that occurs following SCI. In Chapter 2, I investigated the mechanisms that underlie SCI-induced enhancement of neurovascular transmission in the rat tail artery. Isometric contractions of arterial segments from T11 spinal cord-transected and sham-operated rats were compared 6 weeks postoperatively. SCI more than doubled the amplitudes of contractions evoked by nerve stimulation. In arteries from SCI rats, but not those from sham-operated rats, the L-type Ca2+ channel blocker nifedipine reduced nerve-evoked contractions. Furthermore, while the sensitivity to the agonists phenylephrine (α1-adrenoceptor selective) and clonidine (α2-adrenoceptor selective) was unaffected by SCI, nifedipine had a greater inhibitory effect on contractions to both agents in arteries from SCI rats. In arteries from unoperated rats, the L-type Ca2+ channel agonist Bay K8644 mimicked the effects of SCI. These findings demonstrate that the SCI-induced enhancement of neurovascular transmission in rat tail artery can largely be accounted for by an increased contribution of L-type Ca2+ channels to activation of the vascular muscle. In Chapter 3, the mechanisms underlying the enhancement of neurovascular transmission produced SCI and Bay K8644 were further investigated in rat tail artery. In situ electrochemical detection of noradrenaline and electrophysiological monitoring of purinergic transmission were used to assess if Bay K8644 changed neurotransmitter release. In addition, isometric contractions of arterial segments were used to assess if SCI and Bay K8644 similarly changed the contribution of α1-adrenoceptors to nerve-evoked contractions and if interfering with sarcoplamic reticulum (SR) Ca2+ uptake modified the contribution of L-type Ca2+ channels to activation of tail arteries. Bay K8644 did not change noradrenaline-induced oxidation currents or purinergic excitatory junction potentials. Both SCI and Bay K8644 reduced blockade of nerve-evoked contractions by BMY7378 (α1D-adenoceptor antagonist), but did not change that by RS100329 (α1A-adrenoceptor antagonist). Disruption of the SR Ca2+ stores with ryanodine increased both nerve-evoked contractions and blockade of these responses by nifedipine. The findings demonstrate that SCI and Bay K8644 increase the α1A-adrenoceptor-mediated component of nerve-evoked contractions. The findings also suggest that Ca2+ entering smooth muscle via L-type channels is rapidly sequestered by the SR limiting its access to the contractile mechanism. Studies in individuals with SCI suggest the vasculature is hyperreactive to angiotensin II (Ang II). In Chapter 4, the effects of SCI on the reactivity of rat tail and mesenteric arteries to Ang II were investigated. SCI increased contractions of both vessels evoked by Ang II. In tail arteries, the facilitatory effect of Ang II on neurovascular transmission was greatly increased. In contrast, SCI did not change the facilitatory action of Ang II on neurovascular transmission in mesenteric arteries. These findings provide the first direct evidence that SCI increases the reactivity of arterial vessels to Ang II. In addition, in tail artery, the findings indicate that Ang II may contribute to amplifying spinal reflex activation of this vessel.