Anatomy and Neuroscience - Research Publications
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ItemZinc drives vasorelaxation by acting in sensory nerves, endothelium and smooth muscle(NATURE RESEARCH, 2021-06-01)Zinc, an abundant transition metal, serves as a signalling molecule in several biological systems. Zinc transporters are genetically associated with cardiovascular diseases but the function of zinc in vascular tone regulation is unknown. We found that elevating cytoplasmic zinc using ionophores relaxed rat and human isolated blood vessels and caused hyperpolarization of smooth muscle membrane. Furthermore, zinc ionophores lowered blood pressure in anaesthetized rats and increased blood flow without affecting heart rate. Conversely, intracellular zinc chelation induced contraction of selected vessels from rats and humans and depolarized vascular smooth muscle membrane potential. We demonstrate three mechanisms for zinc-induced vasorelaxation: (1) activation of transient receptor potential ankyrin 1 to increase calcitonin gene-related peptide signalling from perivascular sensory nerves; (2) enhancement of cyclooxygenase-sensitive vasodilatory prostanoid signalling in the endothelium; and (3) inhibition of voltage-gated calcium channels in the smooth muscle. These data introduce zinc as a new target for vascular therapeutics.
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ItemSpinal cord thermosensitivity: An afferent phenomenon?(Informa UK Limited, 2016)We review the evidence for thermoregulatory temperature sensors in the mammalian spinal cord and reach the following conclusions. 1) Spinal cord temperature contributes physiologically to temperature regulation. 2) Parallel anterolateral ascending pathways transmit signals from spinal cooling and spinal warming: they overlap with the respective axon pathways of the dorsal horn neurons that are driven by peripheral cold- and warm-sensitive afferents. 3) We hypothesize that these 'cold' and 'warm' ascending pathways transmit all extracranial thermosensory information to the brain. 4) Cutaneous cold afferents can be activated not only by cooling the skin but also by cooling sites along their axons: we consider that this is functionally insignificant in vivo. 5) By a presynaptic action on their central terminals, local spinal cooling enhances neurotransmission from incoming 'cold' afferent action potentials to second order neurons in the dorsal horn; this effect disappears when the spinal cord is warm. 6) Spinal warm sensitivity is due to warm-sensitive miniature vesicular transmitter release from afferent terminals in the dorsal horn: this effect is powerful enough to excite second order neurons in the 'warm' pathway independently of any incoming sensory traffic. 7) Distinct but related presynaptic mechanisms at cold- and warm-sensitive afferent terminals can thus account for the thermoregulatory actions of spinal cord temperature.
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ItemThe neurochemistry and morphology of functionally identified corneal polymodal nociceptors and cold thermoreceptors(PUBLIC LIBRARY SCIENCE, 2018-03-28)It is generally believed that the unencapsulated sensory nerve terminals of modality specific C- and Aδ-neurons lack structural specialization. Here we determined the morphology of functionally defined polymodal receptors and cold thermoreceptors in the guinea pig corneal epithelium. Polymodal receptors and cold thermoreceptors were identified by extracellular recording at the surface of the corneal epithelium. After marking the recording sites, corneas were processed to reveal immunoreactivity for the transient receptor potential channels TRPV1 (transient receptor potential cation channel, subfamily V, member 1) or TPRM8 (transient receptor potential cation channel subfamily M member 8). Polymodal receptor nerve terminals (n = 6) were TRPV1-immunoreactive and derived from an axon that ascended from the sub-basal plexus to the squamous cell layer where it branched into fibers that ran parallel to the corneal surface and terminated with small bulbar endings (ramifying endings). Cold thermoreceptor nerve terminals were TRPM8-immunoreactive (n = 6) and originated from an axon that branched as it ascended through the wing cell and squamous cell layers and terminated with large bulbar endings (complex endings). These findings indicate that modality specific corneal sensory neurons with unencapsulated nerve endings have distinct nerve terminal morphologies that are likely to relate to their function.
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ItemNo Preview AvailableProminent contribution of L-type Ca2+ channels to cutaneous neurovascular transmission that is revealed after spinal cord injury augments vasoconstriction(AMER PHYSIOLOGICAL SOC, 2012-02)In patients with spinal cord injury (SCI), somatosympathetic reflexes produce exaggerated decreases in skin blood flow below the lesion. This hypoperfusion appears to result from an increased responsiveness of cutaneous arterial vessels to neural activation. Here we investigated the mechanisms that underlie SCI-induced enhancement of neurovascular transmission in a cutaneous vessel, the rat tail artery. Isometric contractions of arterial segments from T11 spinal cord transected and sham-operated rats were compared 6 wk postoperatively. SCI more than doubled the amplitudes of contractions of arteries in response to moderate frequencies of nerve stimulation (0.1 to 1 Hz). In arteries from SCI rats, but not those from sham-operated rats, the L-type Ca(2+) channel blocker nifedipine (1 μM) reduced the amplitudes of nerve-evoked contractions. Furthermore, while the sensitivity to the agonists phenylephrine (α(1)-adrenoceptor selective) and clonidine (α(2)-adrenoceptor selective) did not differ significantly between arteries from SCI and sham-operated rats, nifedipine had a greater inhibitory effect on contractions to both agents in arteries from SCI rats. Although sensitivity to clonidine was unchanged, SCI selectively reduced the contribution of postjunctional α(2)-adenceptors to nerve-evoked contractions. In arteries from unoperated rats, the L-type channel agonist BAY K 8644 (0.1 μM) produced a similar enhancement of nerve-evoked contraction to that produced by SCI and also selectively reduced the contribution of α(2)-adrenceptors to these responses. Together the findings demonstrate that the SCI-induced enhancement of neurovascular transmission in the rat tail artery can largely be accounted for by an increased contribution of L-type Ca(2+) channels to activation of the vascular smooth muscle.
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ItemTransient receptor potential cation channel subfamily V member 1 expressing corneal sensory neurons can be subdivided into at least three subpopulations(FRONTIERS MEDIA SA, 2015-06-08)The cornea is innervated by three main functional classes of sensory neurons: polymodal nociceptors, pure mechano-nociceptors and cold-sensing neurons. Here we explored transient receptor potential cation channel subfamily V member 1 (TRPV1) expression in guinea pig corneal sensory neurons, a widely used molecular marker of polymodal nociceptors. We used retrograde tracing to identify corneal afferent neurons in the trigeminal ganglion (TG) and double label in situ hybridization and/or immunohistochemistry to determine their molecular profile. In addition, we used immunohistochemistry to reveal the neurochemistry and structure of TRPV1 expressing nerve endings in the corneal epithelium. Approximately 45% of corneal afferent neurons expressed TRPV1, 28% expressed Piezo2 (a marker of putative pure mechano-nociceptors) and 8% expressed the transient receptor potential cation channel subfamily M member 8 (TRPM8; a marker of cold-sensing neurons). There was no co-expression of TRPV1 and Piezo2 in corneal afferent neurons, but 6% of TRPV1 neurons co-expressed TRPM8. The TRPV1 expressing corneal afferent neurons could be divided into three subpopulations on the basis of calcitonin gene-related peptide (CGRP) and/or or glial cell line-derived neurotrophic factor family receptor alpha3 (GFRα3) co-expression. In the corneal epithelium, the TRPV1 axons that co-expressed CGRP and GFRα3 ended as simple unbranched endings in the wing cell layer. In contrast, those that only co-expressed GFRα3 had ramifying endings that branched and terminated in the squamous cell layer, whereas those that only co-expressed CGRP had simple endings in the basal epithelium. This study shows that the majority of TRPV1 expressing corneal afferent neurons (>90%) are likely to be polymodal nociceptors. Furthermore, TRPV1 expressing corneal afferent neurons can be subdivided into specific subpopulations based on their molecular phenotype, nerve terminal morphology and distribution in the corneal epithelium.
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ItemAngiotensin II increases nerve-evoked contractions in mouse tail artery by a T-type Ca2+ channel-dependent mechanism(ELSEVIER SCIENCE BV, 2015-08-15)Angiotensin II (Ang II) increases sympathetic nerve-evoked contractions of arterial vessels. Here the mechanisms underlying this effect were investigated in mouse tail artery. Isometrically mounted segments of mouse distal tail artery were used to investigate the effects of endothelium denudation, blocking Ca(2+) channels and inhibiting superoxide signalling on Ang II-induced facilitation of nerve-evoked contractions. In addition, in situ amperometry was used to assess effects of Ang II on noradrenaline release. Ang II (0.1-1nM) increased nerve-evoked contractions but did not change noradrenaline release. Losartan (Ang II type 1 receptor antagonist), but not PD 123319 (Ang II type 2 receptor antagonist), blocked the facilitatory effect of Ang II on nerve-evoked contractions. Ang II increased vascular muscle reactivity to phenylephrine and UK-14304 (α1- and α2-adrenoceptor agonists, respectively). Endothelial denudation increased nerve-evoked contractions and reduced the facilitatory effect of Ang II on these responses. Efonidipine (L- and T-type Ca(2+) channel blocker) and NNC 55-0396 (T-type Ca(2+) channel blocker) also attenuated this effect of Ang II, while nifedipine (L-type Ca(2+) channel blocker) did not. Blockers of superoxide generation/signalling did not change the facilitatory effect of Ang II on nerve-evoked contractions. The findings indicate that Ang II increases the contribution of T-type Ca(2+) channels to neural activation of the vascular muscle. In addition, Ang II appears to reduce the inhibitory influence of the endothelium on nerve-evoked contractions.
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ItemModified Cytoplasmic Ca2+ Sequestration Contributes to Spinal Cord Injury-Induced Augmentation of Nerve-Evoked Contractions in the Rat Tail Artery(PUBLIC LIBRARY SCIENCE, 2014-10-28)In rat tail artery (RTA), spinal cord injury (SCI) increases nerve-evoked contractions and the contribution of L-type Ca2+ channels to these responses. In RTAs from unoperated rats, these channels play a minor role in contractions and Bay K8644 (L-type channel agonist) mimics the effects of SCI. Here we investigated the mechanisms underlying the facilitatory actions of SCI and Bay K8644 on nerve-evoked contractions of RTAs and the hypothesis that Ca2+ entering via L-type Ca2+ channels is rapidly sequestered by the sarcoplasmic reticulum (SR) limiting its role in contraction. In situ electrochemical detection of noradrenaline was used to assess if Bay K8644 increased noradrenaline release. Perforated patch recordings were used to assess if SCI changed the Ca2+ current recorded in RTA myocytes. Wire myography was used to assess if SCI modified the effects of Bay K8644 and of interrupting SR Ca2+ uptake on nerve-evoked contractions. Bay K8644 did not change noradrenaline-induced oxidation currents. Neither the size nor gating of Ca2+ currents differed between myocytes from sham-operated (control) and SCI rats. Bay K8644 increased nerve-evoked contractions in RTAs from both control and SCI rats, but the magnitude of this effect was reduced by SCI. By contrast, depleting SR Ca2+ stores with ryanodine or cyclopiazonic acid selectively increased nerve-evoked contractions in control RTAs. Cyclopiazonic acid also selectively increased the blockade of these responses by nifedipine (L-type channel blocker) in control RTAs, whereas ryanodine increased the blockade produced by nifedipine in both groups of RTAs. These findings suggest that Ca2+ entering via L-type channels is normally rapidly sequestered limiting its access to the contractile mechanism. Furthermore, the findings suggest SCI reduces the role of this mechanism.
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ItemIncreased peripherin in sympathetic axons innervating plantar metatarsal arteries in STZ-induced type I diabetic rats(FRONTIERS MEDIA SA, 2014-05-07)A common characteristic of axonopathy is the abnormal accumulation of cytoskeletal proteins. We recently reported that streptozotocin (STZ)-induced type 1 diabetes produced a change in the morphology of sympathetic nerve fibers supplying rat plantar metatarsal arteries (PMAs). Here we investigated whether these morphological changes are associated with axonal accumulation of the type III intermediate filament peripherin and the microtubule protein β-tubulin III, as both are implicated in axonal remodeling. PMAs from hyperglycemic STZ-treated rats receiving a low dose of insulin (STZ-LI) were compared with those from normoglycemic STZ-treated rats receiving a high dose of insulin (STZ-HI) and vehicle-treated controls. Western blotting revealed an increase in protein expression level for peripherin in PMAs from STZ-LI rats but no change in that for β-tubulin III. In addition, there was an increase in the number of peripherin immunoreactive nerve fibers in the perivascular nerve plexus of PMAs from STZ-LI rats. Co-labeling for peripherin and neuropeptide Y (a marker for sympathetic axons) revealed that peripherin immunoreactivity increased in sympathetic axons. None of these changes were detected in PMAs from STZ-HI rats, indicating that increased peripherin in sympathetic axons of STZ-LI rats is likely due to hyperglycemia and provides a marker of diabetes-induced nerve damage.
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ItemSpinal cord injury increases the reactivity of rat tail artery to angiotensin II(FRONTIERS MEDIA SA, 2015-01-06)Studies in individuals with spinal cord injury (SCI) suggest the vasculature is hyperreactive to angiotensin II (Ang II). In the present study, the effects of SCI on the reactivity of the rat tail and mesenteric arteries to Ang II have been investigated. In addition, the effects of SCI on the facilitatory action of Ang II on nerve-evoked contractions of these vessels were determined. Isometric contractions of artery segments from T11 (tail artery) or T4 (mesenteric arteries) spinal cord-transected rats and sham-operated rats were compared 6-7 weeks postoperatively. In both tail and mesenteric arteries, SCI increased nerve-evoked contractions. In tail arteries, SCI also greatly increased Ang II-evoked contractions and the facilitatory effect of Ang II on nerve-evoked contractions. By contrast, SCI did not detectably change the responses of mesenteric arteries to Ang II. 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 modifying their responses following SCI.
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ItemAnalysis of the ghrelin receptor-independent vascular actions of ulimorelin(ELSEVIER SCIENCE BV, 2015-04-05)Ulimorelin (TZP101) is a ghrelin receptor agonist that stimulates intestinal motility, but also reduces blood pressure in rodents and humans and dilates blood vessels. It has been proposed as a treatment for intestinal motility disorders. Here we investigated the mechanisms through which ulimorelin affects vascular diameter. Actions of ulimorelin on wall tension of rodent arteries were investigated and compared with other ghrelin receptor agonists. Saphenous, mesenteric and basilar arteries were obtained from Sprague-Dawley rats (male, 8 weeks) and saphenous arteries were obtained from wild type or ghrelin receptor null mice. These were mounted in myography chambers to record artery wall tension. Ulimorelin (0.03-30µM) inhibited phenylephrine-induced contractions of rat saphenous (IC50=0.6µM; Imax=66±5%; n=3-6) and mesenteric arteries (IC50=5µM, Imax=113±16%; n=3-4), but not those contracted by U46619, ET-1 or 60mM [K(+)]. Relaxation of phenylephrine-constricted arteries was not observed with ghrelin receptor agonists TZP102, capromorelin or AZP-531. In rat saphenous and basilar arteries, ulimorelin (10-100µM) and TZP102 (10-100µM) constricted arteries (EC50=9.9µM; Emax=50±7% and EC50=8µM; Emax=99±16% respectively), an effect not attenuated by the ghrelin receptor antagonist YIL 781 3µM or mimicked by capromorelin or AZP-531. In mesenteric arteries, ulimorelin, 1-10µM, caused a surmountable rightward shift in the response to phenylephrine (0.01-1000µM; pA2=5.7; n=3-4). Ulimorelin had similar actions in mouse saphenous artery from both wild type and ghrelin receptor null mice. We conclude that ulimorelin causes vasorelaxation through competitive antagonist action at α1-adrenoceptors and a constrictor action not mediated via the ghrelin receptor.