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Alberto J. Kaumann - One of the best experts on this subject based on the ideXlab platform.
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prucalopride is a partial agonist through human and porcine atrial 5 ht4 receptors comparison with recombinant human 5 ht4 splice variants
2005Co-Authors: Kurt A. Krobert, Trond Brattelid, Finn Olav Levy, Alberto J. KaumannAbstract:Prucalopride is a gastrointestinal prokinetic drug that acts through 5-HT4 receptors, but its potential effects on cardiac atrial function are unknown. We investigated the effects of prucalopride on human right atrium, piglet left atrium, and piglet sinoatrial node. The effects of prucalopride on 5-HT4 receptor splice variants a, b, g and i, known to be expressed in human atrium, were studied for comparison. Prucalopride was an inotropic partial agonist, compared with 5-HT, on paced human atrial trabeculae (−logEC50M=7.4) and porcine left atria (−logEC50M=7.2), with intrinsic activity of 0.77 and 0.63 respectively. Prucalopride (1 μM) surmountably antagonized the positive inotropic effects of 5-HT on human (pKP=7.2) and porcine (pKP=7.1) atrium. Prucalopride was also a chronotropic partial agonist (−logEC50M=7.4, intrinsic activity=0.72 with respect to 5-HT) on spontaneously beating piglet atria. The cardiostimulant effects of prucalopride were prevented by GR113808 (1 μM), consistent with mediation through 5-HT4 receptors. Prucalopride bound to recombinant 5-HT4(a), 5-HT4(b), 5-HT4(g), and 5-HT4(i) receptors, labeled by [3H]GR113808, with pKi values of 7.6, 7.5, 7.4, and 7.8 respectively. Prucalopride stimulated adenylyl cyclase as a partial agonist on 5-HT4(a), 5-HT4(b), and 5-HT4(i) receptors with intrinsic activities of 0.82, 0.86, and 0.78 and −logEC50 values of 7.2, 7.3, and 7.2 respectively. At the 5-HT4(g) receptor prucalopride acted as a full agonist (−logEC50M=8.0) compared with 5-HT in the cell line tested, which was probably due to high receptor expression levels. We conclude that prucalopride is a cardiostimulatory partial agonist through human and porcine 5-HT4 receptors. Since prucalopride acts similarly through 5-HT4(a), 5-HT4(b), 5-HT4(g), and 5-HT4(i) receptors, any of these variants could be involved in the mediation of cardiostimulation.
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Appearance of a ventricular 5-HT4 receptor-mediated inotropic response to serotonin in heart failure
2005Co-Authors: Eirik Qvigstad, Trond Brattelid, Kurt A. Krobert, Jon Arne Kro Birkeland, Alberto J. Kaumann, Tor Skomedal, Ole M. Sejersted, Kjetil Wessel Andressen, Ivar Sjaastad, Jan-bjørn OsnesAbstract:Background : Current pharmacological treatment of congestive heart failure (CHF) addresses changes in neurohumoral stimulation or cardiac responsiveness to such stimulation. Yet, undiscovered neurohumoral changes, adaptive or maladaptive, may occur in CHF and suggest novel pharmacological treatment. Serotonin [5-hydroxytryptamine (5-HT)] enhances contractility and causes arrhythmias through 5-HT4 receptors in human atrium and ventricle but not through rat ventricular 5-HT4 receptors. Objective : We investigated whether CHF could induce ventricular responsiveness to serotonin. Methods : Postinfarction CHF was induced in male Wistar rats by coronary artery ligation. Contractility was measured in left ventricular papillary muscles 6 weeks after infarction. Messenger RNA was quantified by RT-PCR and cAMP by RIA. Results : Serotonin caused positive inotropic (−logEC50=7.5) and lusitropic effects in CHF but not Sham papillary muscles. The inotropic effect of 10 μM serotonin in CHF (31.3 ± 2.2%) was of similar size as the effect of 10 μM isoproterenol (34.0 ± 1.7%). The effects of serotonin were antagonised by GR113808 (0.5–5 nM), consistent with mediation through 5-HT4 receptors. This was further supported by positive inotropic effects of the 5-HT4-selective partial agonist RS67506. Carbachol blunted the serotonin responses and serotonin increased ventricular and cardiomyocyte cAMP, consistent with coupling to Gs and adenylyl cyclase. Quantitative RT-PCR revealed fourfold increased 5-HT4(b) mRNA expression in CHF vs. Sham ventricles. Conclusion : Functional ventricular 5-HT4 receptors are induced by myocardial infarction and CHF of the rat heart. We propose that they are a model for ventricular 5-HT4 receptors of human failing heart and may play a pathophysiological role in heart failure.
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cgp 12177 increases contractile force and hastens relaxation of human myocardial preparations through a propranolol resistant state of the β1 adrenoceptor
2003Co-Authors: Doreen Sarsero, Alberto J. Kaumann, Fraser D Russell, James A Lynham, G C Rabnott, Ian A Yang, Kwun M Fong, Peter C M MolenaarAbstract:Two forms of the activated β1-adrenoceptor exist, one that is stabilized by (-)-noradrenaline and is sensitive to blockade by (-)-propranolol and another which is stabilized by partial agonists such as (-)-pindolol and (-)-CGP 12177 but is relatively insensitive to (-)-propranolol. We investigated the effects of stimulation of the propranolol-resistant β1-adrenoceptor in the human heart. Myocardium from non-failing and failing human hearts were set up to contract at 1 Hz. In right atrium from non-failing hearts in the presence of 200 nM (-)-propranolol, (-)-CGP 12177 caused concentration-dependent increases in contractile force (–logEC50[M] 7.3±0.1, Emax 23±1% relative to maximal (-)-isoprenaline stimulation of β1- and β2-adrenoceptors, n=86 patients), shortening of the time to reach peak force (–logEC50[M] 7.4±0.1, Emax 37±5%, n=61 patients) and shortening of the time to reach 50% relaxation (t50%, –logEC50[M] 7.3±0.1, Emax 33±2%, n=61 patients). The potency and maxima of the positive inotropic effects were independent of Ser49Gly- and Gly389Arg-β1-adrenoceptor polymorphisms but were potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (–logEC50[M] 7.7±0.1, Emax 68±6%, n=6 patients, P<0.0001). In the presence of (-)-propranolol and 3-isobutyl-1-methylxanthine, the potency (–logEC50[M] 7.4±0.1, P=0.0013, n=9 patients) but not the maximal effect of (-)-CGP 12177 was reduced in right atrium from failing hearts, which was associated with 64% and 52% reductions in the densities of low-affinity and high-affinity (-)-[3H]CGP 12177 binding sites. In the presence of (-)-propanolol and 3-isobutyl-1-methylxanthine, (-)-CGP 12177 increased atrial cyclic AMP levels and activated cyclic AMP-dependent protein kinase in right atrium from non-failing hearts. In right ventricle from failing hearts (-)-CGP 12177 increased contractile force (–logEC50[M] 7.4±0.1, Emax 34±3%, n=13 patients) and hastened the time to peak force (–logEC50[M] 7.6±0.1) and time to reach 50% relaxation (–logEC50[M] 7.4±0.1) in the presence of (-)-propranolol and 3-isobutyl-1-methylxanthine. Our results show that (-)-CGP 12177 increases contractility and hastens relaxation through a cyclic AMP pathway in human myocardium, consistent with mediation through a (-)-propranolol-resistant state of the β1-adrenoceptor. The reduction in heart failure of atrial inotropic potency of (-)-CGP 12177, as well as of the high-affinity and low-affinity binding sites for (-)-[3H]CGP 12177, is consistent with the β1-adrenoceptor nature of these sites.
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cgp 12177 increases contractile force and hastens relaxation of human myocardial preparations through a propranolol resistant state of the β adrenoceptor
2003Co-Authors: Doreen Sarsero, Alberto J. Kaumann, Fraser D Russell, James A Lynham, G C Rabnott, Ian A Yang, Kwun M Fong, P MolenaarAbstract:Two forms of the activated #1-adrenoceptor exist, one that is stabilized by (-)-noradrenaline and is sensitive to blockade by (-)-propranolol and another which is stabilized by partial agonists such as (-)-pindolol and (-)-CGP 12177 but is relatively insensitive to (-)-propranolol. We investigated the effects of stimulation of the propranolol-resistant #1-adrenoceptor in the human heart. Myocardium from non-failing and failing human hearts were set up to contract at 1 Hz. In right atrium from non-failing hearts in the presence of 200 nM (-)-propranolol, (-)-CGP 12177 caused concentration-dependent increases in contractile force (-logEC50[M] 7.3-0.1, Emax 23-1% relative to maximal (-)-isoprenaline stimulation of #1- and #2-adrenoceptors, n=86 patients), shortening of the time to reach peak force (-logEC50[M] 7.4-0.1, Emax 37-5%, n=61 patients) and shortening of the time to reach 50% relaxation (t50%, -logEC50[M] 7.3-0.1, Emax 33-2%, n=61 patients). The potency and maxima of the positive inotropic effects were independent of Ser49Gly- and Gly389Arg-#1-adrenoceptor polymorphisms but were potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (-logEC50[M] 7.7-0.1, Emax 68-6%, n=6 patients, P less than 0.0001). In the presence of (-)-propranolol and 3-isobutyl-1-methylxanthine, the potency (-logEC50[M] 7.4-0.1, P=0.0013, n=9 patients) but not the maximal effect of (-)-CGP 12177 was reduced in right atrium from failing hearts, which was associated with 64% and 52% reductions in the densities of low-affinity and high-affinity (-)-[3H]CGP 12177 binding sites. In the presence of (-)-propanolol and 3-isobutyl-1-methylxanthine, (-)-CGP 12177 increased atrial cyclic AMP levels and activated cyclic AMP-dependent protein kinase in right atrium from non-failing hearts. In right ventricle from failing hearts (-)-CGP 12177 increased contractile force (-logEC50[M] 7.4-0.1, Emax 34-3%, n=13 patients) and hastened the time to peak force (-logEC50[M] 7.6-0.1) and time to reach 50% relaxation (-logEC50[M] 7.4-0.1) in the presence of (-)-propranolol and 3-isobutyl-1-methylxanthine. Our results show that (-)-CGP 12177 increases contractility and hastens relaxation through a cyclic AMP pathway in human myocardium, consistent with mediation through a (-)-propranolol-resistant state of the #1-adrenoceptor. The reduction in heart failure of atrial inotropic potency of (-)-CGP 12177, as well as of the high-affinity and low-affinity binding sites for (-)-[3H]CGP 12177, is consistent with the #1-adrenoceptor nature of these sites.
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bibn4096bs is a potent competitive antagonist of the relaxant effects of α cgrp on human temporal artery comparison with cgrp 8 37
2002Co-Authors: Raphaela Verheggen, Katja Bumann, Alberto J. KaumannAbstract:Release of CGRP during migraine may produce harmful dilatation of cranial arteries, thereby possibly causing pain. We have compared the antagonism by BIBN4096BS and CGRP(8-37) of the relaxant effects of α-CGRP on rings of human temporal artery. α-CGRP relaxed the arteries precontracted with 9 – 24 mM KCl (−logEC50=9.4) nearly as efficaciously as sodium nitroprusside (10 μM). BIBN4096BS (0.1 – 100 nM) antagonized the effects of α-CGRP in surmountable manner with slopes of Schild-plots not different from unity. −LogKB values of 10.1 and 10.4 were estimated for BIBN4096BS when administered before or during the KCl-contracture respectively. BIBN4096BS (1 μM) did not modify the relaxant effects of papaverine and sodium nitroprusside. CGRP(8-37) (1 – 10 μM) antagonized the effects of α-CGRP in a surmountable manner with slopes of Schild-plots not different from unity. −LogKB values of 6.6 and 6.7 were estimated for CGRP(8-37) administered before or during the KCl-contracture respectively. The high affinity of BIBN4096BS for CGRP receptors of human temporal artery makes it an excellent tool to explore the hypothesis of CGRP-evoked cerebral vasodilation in migraine. British Journal of Pharmacology (2002) 136, 120–126; doi:10.1038/sj.bjp.0704682
Domenico Pratico - One of the best experts on this subject based on the ideXlab platform.
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Medicine Address for Correspondence:
2013Co-Authors: Polina Fenik, Guanxia Zhan, Domenico Pratico, Ph. D, Sigrid C VeaseyAbstract:Humans with long-standing sleep apnea show mixed responses to serotonergic therapies for obstructive sleep apnea. We hypothesize that long-term intermittent hypoxia may result in oxidative injury to upper airway motoneurons, thereby diminishing serotonergic motoneuronal excitation. Unilateral serotonin and glutamate agonist and antagonist microinjections into the hypoglossal motor nuclei in adult rats exposed to three weeks of intermittent hypoxia showed reduced hypoglossal nerve responsiveness (logEC50) for serotonin and N-methyl-D-aspartate. However, long-term intermittent hypoxia did not appear to alter hypoglossal response to-amino-3-hydroxy-methylisoxazole-4-propionic acid injections. There was no reduction in hypoglossal motoneuron soma number or in serotonergic post-synaptic receptor mRNA copy numbers within single-cells; in contrast, there was an increase in isoprostanes in the dorsal medulla. Systemic 4-hydroxyl-2,2,6,6-tetramethylpiperidin-1-oxyl (tempol) throughout exposure to intermittent hypoxia improved the EC50 for serotonin to a larger extent than glutamate and normalized medullary isoprostanes. Protein kinase C activity within the hypoglossal nucleus was increased following long-term intermittent hypoxia. These results suggest that long-term intermittent hypoxia reduces serotonergic and N-methyl-D-aspartate excitatory output of hypoglossal nerves, and that reduced excitatory responsiveness and lipid peroxidation are largely prevented with superoxide dismutase treatment throughout hypoxia/reoxygenation
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Long-Term Intermittent Hypoxia Reduced Excitatory Hypoglossal Nerve Output
2013Co-Authors: Sigrid C Veasey, Guanxia Zhan, Polina Fenik, Domenico PraticoAbstract:Humans with long-standing sleep apnea show mixed responses to serotonergic therapies for obstructive sleep apnea. We hypothesize that long-term intermittent hypoxia may result in oxidative injury to upper airway motoneurons, thereby diminishing serotonergic motoneuronal excitation. Unilateral serotonin and glutamate agonist and antagonist microinjections into the hypoglossal motor nuclei in adult rats exposed to 3 weeks of intermittent hypoxia showed reduced hypoglossal nerve responsiveness (logEC50) for serotonin and N-methyl-D-aspartate. However, long-term intermittent hypoxia did not appear to alter hypoglossal response to �-amino-3-hydroxy-methylisoxazole-4-propionic acid injections. There was no reduction in hypoglossal motoneuron soma number or in serotonergic postsynaptic receptor mRNA copy numbers within singlecells; in contrast, there was an increase in isoprostanes in the dorsal medulla. Systemic 4-hydroxyl-2,2,6,6-tetramethylpiperidin-1-oxyl (tempol) throughout exposure to intermittent hypoxia improved the EC50 for serotonin to a larger extent than glutamate and normalized medullary isoprostanes. Protein kinase C activity within the hypoglossal nucleus was increased after long-term intermittent hypoxia. These results suggest that long-term intermittent hypoxia reduces serotonergic and N-methyl-D-aspartate excitatory output of hypoglossal nerves, and that reduced excitatory responsiveness and lipid peroxidation are largely prevented with superoxide dismutase treatment throughout hypoxia/reoxygenation. Similar alterations in neurochemical responsiveness may occur in select persons with obstructive sleep apnea
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long term intermittent hypoxia reduced excitatory hypoglossal nerve output
2004Co-Authors: Sigrid C Veasey, Guanxia Zhan, Polina Fenik, Domenico PraticoAbstract:Humans with long-standing sleep apnea show mixed responses to serotonergic therapies for obstructive sleep apnea. We hypothesize that long-term intermittent hypoxia may result in oxidative injury to upper airway motoneurons, thereby diminishing serotonergic motoneuronal excitation. Unilateral serotonin and glutamate agonist and antagonist microinjections into the hypoglossal motor nuclei in adult rats exposed to 3 weeks of intermittent hypoxia showed reduced hypoglossal nerve responsiveness (logEC50) for serotonin and N-methyl-D-aspartate. However, long-term intermittent hypoxia did not appear to alter hypoglossal response to α-amino-3-hydroxy-methylisoxazole-4-propionic acid injections. There was no reduction in hypoglossal motoneuron soma number or in serotonergic postsynaptic receptor mRNA copy numbers within single-cells; in contrast, there was an increase in isoprostanes in the dorsal medulla. Systemic 4-hydroxyl-2,2,6,6-tetramethylpiperidin-1-oxyl (tempol) throughout exposure to intermittent hypoxia...
Lacy M Alexander - One of the best experts on this subject based on the ideXlab platform.
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impaired increases in skin sympathetic nerve activity contribute to age related decrements in reflex cutaneous vasoconstriction
2015Co-Authors: Jody L Greaney, Anna E Stanhewicz, Larry W Kenney, Lacy M AlexanderAbstract:Key points The reduction in skin blood flow during whole-body cooling is impaired in healthy older adults. However, the relative contributions of altered skin sympathetic nerve activity (SSNA), transduction of this efferent neural outflow to the cutaneous vasculature, and peripheral vascular responsiveness to adrenergic stimuli to the impaired reflex vasoconstrictor response to whole-body cooling in human ageing remain unclear. We report that the SSNA response to whole-body cooling is blunted in healthy older adults, and this attenuated sympathetic response is related to a marked impairment in reflex cutaneous vasoconstriction. Further, the reflex SSNA response to a non-thermoregulatory stimulus was preserved in older adults during cooling. We additionally show that cutaneous vascular responsiveness to adrenergic stimuli is not reduced in older adults. These results further our understanding of the physiological mechanisms underlying impaired thermal-cardiovascular integration in healthy ageing. Abstract Reflex cutaneous vasoconstriction is impaired in older adults; however, the relative roles of altered skin sympathetic nerve activity (SSNA) and end-organ peripheral vascular responsiveness are unclear. We hypothesized that in older adults whole-body cooling would elicit a blunted SSNA response and cutaneous adrenergic responsiveness would be reduced. Twelve young adults (Y; 24 ± 1 years) and 12 older adults (O; 57 ± 2 years) participated in two protocols. In Protocol 1, SSNA (peroneal microneurography) and red cell flux in the affected dermatome (laser Doppler flowmetry; dorsum of foot) were measured during whole-body cooling (mean skin temperature (Tsk) 30.5°C; water-perfused suit). Mental stress was performed at mean Tsk 34.0°C (thermoneutral) and at 30.5°C. In Protocol 2, an intradermal microdialysis fibre was placed in the skin of the lateral calf for graded infusions of noradrenaline (norepinephrine) (NA; 10−12 to 10−2 m). Cutaneous vascular conductance (CVC = flux/mean arterial pressure) was expressed as a change from baseline (ΔCVCbase). Vasoconstriction was attenuated in O. SSNA increased significantly during cooling in Y (+184 ± 37%; P 0.05). Mental stress at Tsk 30.5°C further increased SSNA in both groups. There was no age-related difference in adrenergic responsiveness to exogenous NA (logEC50: −6.41 ± 0.24 in Y, −6.37 ± 0.25 in O; P > 0.05). While the SSNA response to whole-body cooling is impaired with ageing, SSNA can be further increased by a non-thermoregulatory stimulus. Cutaneous adrenergic sensitivity is not reduced in O. These findings suggest that alterations in afferent signalling or central processing likely contribute to blunted SSNA responses to cooling and subsequent impairments in reflex cutaneous vasoconstriction in ageing.
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impaired increases in skin sympathetic nerve activity contribute to age related decrements in reflex cutaneous vasoconstriction
2015Co-Authors: Jody L Greaney, Anna E Stanhewicz, Larry W Kenney, Lacy M AlexanderAbstract:Key points The reduction in skin blood flow during whole-body cooling is impaired in healthy older adults. However, the relative contributions of altered skin sympathetic nerve activity (SSNA), transduction of this efferent neural outflow to the cutaneous vasculature, and peripheral vascular responsiveness to adrenergic stimuli to the impaired reflex vasoconstrictor response to whole-body cooling in human ageing remain unclear. We report that the SSNA response to whole-body cooling is blunted in healthy older adults, and this attenuated sympathetic response is related to a marked impairment in reflex cutaneous vasoconstriction. Further, the reflex SSNA response to a non-thermoregulatory stimulus was preserved in older adults during cooling. We additionally show that cutaneous vascular responsiveness to adrenergic stimuli is not reduced in older adults. These results further our understanding of the physiological mechanisms underlying impaired thermal-cardiovascular integration in healthy ageing. Abstract Reflex cutaneous vasoconstriction is impaired in older adults; however, the relative roles of altered skin sympathetic nerve activity (SSNA) and end-organ peripheral vascular responsiveness are unclear. We hypothesized that in older adults whole-body cooling would elicit a blunted SSNA response and cutaneous adrenergic responsiveness would be reduced. Twelve young adults (Y; 24 ± 1 years) and 12 older adults (O; 57 ± 2 years) participated in two protocols. In Protocol 1, SSNA (peroneal microneurography) and red cell flux in the affected dermatome (laser Doppler flowmetry; dorsum of foot) were measured during whole-body cooling (mean skin temperature (Tsk) 30.5°C; water-perfused suit). Mental stress was performed at mean Tsk 34.0°C (thermoneutral) and at 30.5°C. In Protocol 2, an intradermal microdialysis fibre was placed in the skin of the lateral calf for graded infusions of noradrenaline (norepinephrine) (NA; 10−12 to 10−2 m). Cutaneous vascular conductance (CVC = flux/mean arterial pressure) was expressed as a change from baseline (ΔCVCbase). Vasoconstriction was attenuated in O. SSNA increased significantly during cooling in Y (+184 ± 37%; P 0.05). Mental stress at Tsk 30.5°C further increased SSNA in both groups. There was no age-related difference in adrenergic responsiveness to exogenous NA (logEC50: −6.41 ± 0.24 in Y, −6.37 ± 0.25 in O; P > 0.05). While the SSNA response to whole-body cooling is impaired with ageing, SSNA can be further increased by a non-thermoregulatory stimulus. Cutaneous adrenergic sensitivity is not reduced in O. These findings suggest that alterations in afferent signalling or central processing likely contribute to blunted SSNA responses to cooling and subsequent impairments in reflex cutaneous vasoconstriction in ageing.
Sigrid C Veasey - One of the best experts on this subject based on the ideXlab platform.
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Medicine Address for Correspondence:
2013Co-Authors: Polina Fenik, Guanxia Zhan, Domenico Pratico, Ph. D, Sigrid C VeaseyAbstract:Humans with long-standing sleep apnea show mixed responses to serotonergic therapies for obstructive sleep apnea. We hypothesize that long-term intermittent hypoxia may result in oxidative injury to upper airway motoneurons, thereby diminishing serotonergic motoneuronal excitation. Unilateral serotonin and glutamate agonist and antagonist microinjections into the hypoglossal motor nuclei in adult rats exposed to three weeks of intermittent hypoxia showed reduced hypoglossal nerve responsiveness (logEC50) for serotonin and N-methyl-D-aspartate. However, long-term intermittent hypoxia did not appear to alter hypoglossal response to-amino-3-hydroxy-methylisoxazole-4-propionic acid injections. There was no reduction in hypoglossal motoneuron soma number or in serotonergic post-synaptic receptor mRNA copy numbers within single-cells; in contrast, there was an increase in isoprostanes in the dorsal medulla. Systemic 4-hydroxyl-2,2,6,6-tetramethylpiperidin-1-oxyl (tempol) throughout exposure to intermittent hypoxia improved the EC50 for serotonin to a larger extent than glutamate and normalized medullary isoprostanes. Protein kinase C activity within the hypoglossal nucleus was increased following long-term intermittent hypoxia. These results suggest that long-term intermittent hypoxia reduces serotonergic and N-methyl-D-aspartate excitatory output of hypoglossal nerves, and that reduced excitatory responsiveness and lipid peroxidation are largely prevented with superoxide dismutase treatment throughout hypoxia/reoxygenation
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Long-Term Intermittent Hypoxia Reduced Excitatory Hypoglossal Nerve Output
2013Co-Authors: Sigrid C Veasey, Guanxia Zhan, Polina Fenik, Domenico PraticoAbstract:Humans with long-standing sleep apnea show mixed responses to serotonergic therapies for obstructive sleep apnea. We hypothesize that long-term intermittent hypoxia may result in oxidative injury to upper airway motoneurons, thereby diminishing serotonergic motoneuronal excitation. Unilateral serotonin and glutamate agonist and antagonist microinjections into the hypoglossal motor nuclei in adult rats exposed to 3 weeks of intermittent hypoxia showed reduced hypoglossal nerve responsiveness (logEC50) for serotonin and N-methyl-D-aspartate. However, long-term intermittent hypoxia did not appear to alter hypoglossal response to �-amino-3-hydroxy-methylisoxazole-4-propionic acid injections. There was no reduction in hypoglossal motoneuron soma number or in serotonergic postsynaptic receptor mRNA copy numbers within singlecells; in contrast, there was an increase in isoprostanes in the dorsal medulla. Systemic 4-hydroxyl-2,2,6,6-tetramethylpiperidin-1-oxyl (tempol) throughout exposure to intermittent hypoxia improved the EC50 for serotonin to a larger extent than glutamate and normalized medullary isoprostanes. Protein kinase C activity within the hypoglossal nucleus was increased after long-term intermittent hypoxia. These results suggest that long-term intermittent hypoxia reduces serotonergic and N-methyl-D-aspartate excitatory output of hypoglossal nerves, and that reduced excitatory responsiveness and lipid peroxidation are largely prevented with superoxide dismutase treatment throughout hypoxia/reoxygenation. Similar alterations in neurochemical responsiveness may occur in select persons with obstructive sleep apnea
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long term intermittent hypoxia reduced excitatory hypoglossal nerve output
2004Co-Authors: Sigrid C Veasey, Guanxia Zhan, Polina Fenik, Domenico PraticoAbstract:Humans with long-standing sleep apnea show mixed responses to serotonergic therapies for obstructive sleep apnea. We hypothesize that long-term intermittent hypoxia may result in oxidative injury to upper airway motoneurons, thereby diminishing serotonergic motoneuronal excitation. Unilateral serotonin and glutamate agonist and antagonist microinjections into the hypoglossal motor nuclei in adult rats exposed to 3 weeks of intermittent hypoxia showed reduced hypoglossal nerve responsiveness (logEC50) for serotonin and N-methyl-D-aspartate. However, long-term intermittent hypoxia did not appear to alter hypoglossal response to α-amino-3-hydroxy-methylisoxazole-4-propionic acid injections. There was no reduction in hypoglossal motoneuron soma number or in serotonergic postsynaptic receptor mRNA copy numbers within single-cells; in contrast, there was an increase in isoprostanes in the dorsal medulla. Systemic 4-hydroxyl-2,2,6,6-tetramethylpiperidin-1-oxyl (tempol) throughout exposure to intermittent hypoxia...
Jody L Greaney - One of the best experts on this subject based on the ideXlab platform.
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impaired increases in skin sympathetic nerve activity contribute to age related decrements in reflex cutaneous vasoconstriction
2015Co-Authors: Jody L Greaney, Anna E Stanhewicz, Larry W Kenney, Lacy M AlexanderAbstract:Key points The reduction in skin blood flow during whole-body cooling is impaired in healthy older adults. However, the relative contributions of altered skin sympathetic nerve activity (SSNA), transduction of this efferent neural outflow to the cutaneous vasculature, and peripheral vascular responsiveness to adrenergic stimuli to the impaired reflex vasoconstrictor response to whole-body cooling in human ageing remain unclear. We report that the SSNA response to whole-body cooling is blunted in healthy older adults, and this attenuated sympathetic response is related to a marked impairment in reflex cutaneous vasoconstriction. Further, the reflex SSNA response to a non-thermoregulatory stimulus was preserved in older adults during cooling. We additionally show that cutaneous vascular responsiveness to adrenergic stimuli is not reduced in older adults. These results further our understanding of the physiological mechanisms underlying impaired thermal-cardiovascular integration in healthy ageing. Abstract Reflex cutaneous vasoconstriction is impaired in older adults; however, the relative roles of altered skin sympathetic nerve activity (SSNA) and end-organ peripheral vascular responsiveness are unclear. We hypothesized that in older adults whole-body cooling would elicit a blunted SSNA response and cutaneous adrenergic responsiveness would be reduced. Twelve young adults (Y; 24 ± 1 years) and 12 older adults (O; 57 ± 2 years) participated in two protocols. In Protocol 1, SSNA (peroneal microneurography) and red cell flux in the affected dermatome (laser Doppler flowmetry; dorsum of foot) were measured during whole-body cooling (mean skin temperature (Tsk) 30.5°C; water-perfused suit). Mental stress was performed at mean Tsk 34.0°C (thermoneutral) and at 30.5°C. In Protocol 2, an intradermal microdialysis fibre was placed in the skin of the lateral calf for graded infusions of noradrenaline (norepinephrine) (NA; 10−12 to 10−2 m). Cutaneous vascular conductance (CVC = flux/mean arterial pressure) was expressed as a change from baseline (ΔCVCbase). Vasoconstriction was attenuated in O. SSNA increased significantly during cooling in Y (+184 ± 37%; P 0.05). Mental stress at Tsk 30.5°C further increased SSNA in both groups. There was no age-related difference in adrenergic responsiveness to exogenous NA (logEC50: −6.41 ± 0.24 in Y, −6.37 ± 0.25 in O; P > 0.05). While the SSNA response to whole-body cooling is impaired with ageing, SSNA can be further increased by a non-thermoregulatory stimulus. Cutaneous adrenergic sensitivity is not reduced in O. These findings suggest that alterations in afferent signalling or central processing likely contribute to blunted SSNA responses to cooling and subsequent impairments in reflex cutaneous vasoconstriction in ageing.
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impaired increases in skin sympathetic nerve activity contribute to age related decrements in reflex cutaneous vasoconstriction
2015Co-Authors: Jody L Greaney, Anna E Stanhewicz, Larry W Kenney, Lacy M AlexanderAbstract:Key points The reduction in skin blood flow during whole-body cooling is impaired in healthy older adults. However, the relative contributions of altered skin sympathetic nerve activity (SSNA), transduction of this efferent neural outflow to the cutaneous vasculature, and peripheral vascular responsiveness to adrenergic stimuli to the impaired reflex vasoconstrictor response to whole-body cooling in human ageing remain unclear. We report that the SSNA response to whole-body cooling is blunted in healthy older adults, and this attenuated sympathetic response is related to a marked impairment in reflex cutaneous vasoconstriction. Further, the reflex SSNA response to a non-thermoregulatory stimulus was preserved in older adults during cooling. We additionally show that cutaneous vascular responsiveness to adrenergic stimuli is not reduced in older adults. These results further our understanding of the physiological mechanisms underlying impaired thermal-cardiovascular integration in healthy ageing. Abstract Reflex cutaneous vasoconstriction is impaired in older adults; however, the relative roles of altered skin sympathetic nerve activity (SSNA) and end-organ peripheral vascular responsiveness are unclear. We hypothesized that in older adults whole-body cooling would elicit a blunted SSNA response and cutaneous adrenergic responsiveness would be reduced. Twelve young adults (Y; 24 ± 1 years) and 12 older adults (O; 57 ± 2 years) participated in two protocols. In Protocol 1, SSNA (peroneal microneurography) and red cell flux in the affected dermatome (laser Doppler flowmetry; dorsum of foot) were measured during whole-body cooling (mean skin temperature (Tsk) 30.5°C; water-perfused suit). Mental stress was performed at mean Tsk 34.0°C (thermoneutral) and at 30.5°C. In Protocol 2, an intradermal microdialysis fibre was placed in the skin of the lateral calf for graded infusions of noradrenaline (norepinephrine) (NA; 10−12 to 10−2 m). Cutaneous vascular conductance (CVC = flux/mean arterial pressure) was expressed as a change from baseline (ΔCVCbase). Vasoconstriction was attenuated in O. SSNA increased significantly during cooling in Y (+184 ± 37%; P 0.05). Mental stress at Tsk 30.5°C further increased SSNA in both groups. There was no age-related difference in adrenergic responsiveness to exogenous NA (logEC50: −6.41 ± 0.24 in Y, −6.37 ± 0.25 in O; P > 0.05). While the SSNA response to whole-body cooling is impaired with ageing, SSNA can be further increased by a non-thermoregulatory stimulus. Cutaneous adrenergic sensitivity is not reduced in O. These findings suggest that alterations in afferent signalling or central processing likely contribute to blunted SSNA responses to cooling and subsequent impairments in reflex cutaneous vasoconstriction in ageing.
