- Email: [email protected]
Differential cardiovascular reflexes evoked by activation of nociceptive airway sensory nerves in healthy and cardiovascular-diseased rats
66
Abstracts / Autonomic Neuroscience: Basic and Clinical 192 (2015) 56–141
teleost fish, but little is known about the ventilatory and cardiovascular effects of GRP in these vertebrates. The goal of this study was to compare the central and peripheral actions of trout GRP on ventilatory and cardiovascular variables in the unanesthetized rainbow trout. Compared to vehicle only, intracerebroventricular injection of GRP (1- 50 pmol) significantly (P b 0.05) elevated the ventilation frequency (VF) and the ventilation amplitude (VA) and consequently the total ventilation (VTOT). The maximum hyperventilatory effect of GRP (VTOT: + 225 %), observed at a dose of 50 pmol, was mostly due to its stimulatory action on VA (+170 %) rather than VF (+ 20%). In addition, GRP produced a significant increase in mean dorsal aortic blood pressure (PDA) (50 pmol; + 35 %) and heart rate (HR) (50 pmol; + 25 %). Intra-arterial (IA) injections of GRP (5-100 pmol) were without consistent effect on the ventilatory variables. The doses of 50 and 100 pmol GRP elevated PDA by the same amount (+ 20 %) (P b 0.05) but only the 50 pmol dose significantly increased HR (+ 15 %). In conclusion, our study suggests that endogenous GRP within the brain of the trout may act as a potent neurotransmitter and/or neuromodulator in the regulation of cardio-ventilatory functions. In the periphery, endogenous GRP may act as local and/or circulating hormone with an involvement in vasoregulatory mechanisms. doi:10.1016/j.autneu.2015.07.040
P4.2 Transient acute lung injury induces activation and proliferation of a selective cell population in the neuroepithelial body microenvironment L. Verckist, C. Rottiers, R. Lembrechts, I. Pintelon, J.-P. Timmermans, I. Brouns, D. Adriaensen Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Belgium Epithelial cells of intrapulmonary conductive airways show a very low turn-over rate in postnatal lungs. The airway epithelium harbors innervated groups of neuroendocrine cells that are surrounded by Clara-like cells (CLCs), which together compose the socalled neuroepithelial body microenvironment (NEB-ME). Literature data and own recent results strongly suggest that the NEB-ME should be regarded as a unique airway stem cell niche. Transient acute lung injury (ALI) was induced in mice via a single intratracheal instillation of lipopolysaccharide (LPS; 10 mg/kg bw). In one experiment, broncho-alveolar lavage fluid (BALF) was collected 24 h after LPS instillation, and was used to challenge the NEB-ME in ex vivo lung slices of control mice. In another experiment, BrdU (10 mg/kg bw), as a marker for cells that divide during the observation window, was injected intraperitoneally at the time of LPS instillation and after 24 h, the animals were euthanized after 48 h, and the lungs were processed for freeze sectioning and BrdU immunostaining. Challenge of lung slices with BALF of ALI mice was shown to induce a reversible and reproducible selective Ca2 +-mediated activation of CLCs in the NEB-ME of control mice. Lung sections of ALI mice, 48 h after LPS challenge, revealed a remarkable increase in BrdU-labeled cells that surround the NEB-ME, as compared to control lungs. In conclusion, ALI appears to result in the production of soluble mediators in the airways that selectively activate, and induce proliferation of, a stem cell population in the NEB-ME. Support: Hercules Foundation grant AUAH-09-001 (DA); UA grant GOA BOF 2015 (DA).
doi:10.1016/j.autneu.2015.07.041
P4.3 Differential cardiovascular reflexes evoked by activation of nociceptive airway sensory nerves in healthy and cardiovascular-diseased rats J.S. Hooper, K.F. Morris, J.B. Dean, T.E. Taylor-Clark Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South FL, USA Background/Aims: Inhalation of pollutants causes significant increases in acute cardiovascular morbidity/mortality, in part via the modulation of autonomic function following the activation of airway sensory nerve reflexes. Pollutants selectively activate sensory nerves termed ‘nociceptors’ via the activation of the TRPA1 ion channel. However, inhalation of pollutants causes sympathetic-like effects disproportionately in patients with cardiovascular disease (CVD) but not in healthy individuals. We hypothesize that preexisting CVD alters cardiovascular reflexes evoked from the airways, and that this switch negatively impacts the effect of pollution on the clinical population. Methods: ECG were recorded in conscious and freely-moving rats (Healthy groups: Sprague Dawley (SD) and Wistar-Kyoto (WK); CVD group: Spontaneously Hypertensive (SH)) using radiotelemetry. To selectively activate pollutant-sensitive airway reflexes rats were exposed to the TRPA1 selective agonist allyl isothiocyanate (AITC). ECGs were recorded during exposure to nebulized vehicle and AITC (30 mM). Results: AITC caused bradycardia in SD and WK rats. Bradycardia was associated with elongated PR intervals and AV block. AITC-evoked responses in SD and WK were abolished by pretreatment with the muscarinic antagonist atropine, indicating a dominant role of parasympathetic reflexes. AITC caused complex brady-tachy arrhythmias in SH rats. In addition to evoking some AV block, AITC evoked significant premature ventricular contractions (PVCs) in SH rats. Atropine abolished the bradycardic/ AV components of AITC-evoked ECG responses. Pretreatment with the beta1 adrenoceptor antagonist atenolol abolished the AITCevoked PVCs, suggesting that this component was dependent on an increase in sympathetic responses. Conclusions: Pre-existing CVD switches pollution-sensitive airway reflexes from parasympathetic to sympathetic.
doi:10.1016/j.autneu.2015.07.042
P4.4 Muscle Sympathetic Nerve Activity during Hypercapnia in Young and Older Adults J.N. Barnesa,b, R.E. Harveyb, M.J. Joynerb a Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, USA b Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA Aging reduces the cerebrovascular response to hypercapnia, although the exact mechanism is unknown. During hypercapnia, chemoreflexmediated sympathoexcitation may influence the cerebrovascular response. Currently, it is unknown if aging influences the muscle sympathetic nerve activity (MSNA) response to hypercapnia and whether this MSNA response is associated with the cerebrovascular response. Our objective was to compare MSNA changes during hypercapnia in young and older adults. Cerebral blood flow velocity, mean arterial pressure (MAP) and MSNA were measured in 15 young (20-35 yr) and 10 older (56-76 yr) healthy adults during room air (baseline) and while breathing 6% CO2. At baseline, older adults had lower cerebral blood flow velocity compared with young adults (54 ± 5
Abstracts / Autonomic Neuroscience: Basic and Clinical 192 (2015) 56–141
teleost fish, but little is known about the ventilatory and cardiovascular effects of GRP in these vertebrates. The goal of this study was to compare the central and peripheral actions of trout GRP on ventilatory and cardiovascular variables in the unanesthetized rainbow trout. Compared to vehicle only, intracerebroventricular injection of GRP (1- 50 pmol) significantly (P b 0.05) elevated the ventilation frequency (VF) and the ventilation amplitude (VA) and consequently the total ventilation (VTOT). The maximum hyperventilatory effect of GRP (VTOT: + 225 %), observed at a dose of 50 pmol, was mostly due to its stimulatory action on VA (+170 %) rather than VF (+ 20%). In addition, GRP produced a significant increase in mean dorsal aortic blood pressure (PDA) (50 pmol; + 35 %) and heart rate (HR) (50 pmol; + 25 %). Intra-arterial (IA) injections of GRP (5-100 pmol) were without consistent effect on the ventilatory variables. The doses of 50 and 100 pmol GRP elevated PDA by the same amount (+ 20 %) (P b 0.05) but only the 50 pmol dose significantly increased HR (+ 15 %). In conclusion, our study suggests that endogenous GRP within the brain of the trout may act as a potent neurotransmitter and/or neuromodulator in the regulation of cardio-ventilatory functions. In the periphery, endogenous GRP may act as local and/or circulating hormone with an involvement in vasoregulatory mechanisms. doi:10.1016/j.autneu.2015.07.040
P4.2 Transient acute lung injury induces activation and proliferation of a selective cell population in the neuroepithelial body microenvironment L. Verckist, C. Rottiers, R. Lembrechts, I. Pintelon, J.-P. Timmermans, I. Brouns, D. Adriaensen Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Belgium Epithelial cells of intrapulmonary conductive airways show a very low turn-over rate in postnatal lungs. The airway epithelium harbors innervated groups of neuroendocrine cells that are surrounded by Clara-like cells (CLCs), which together compose the socalled neuroepithelial body microenvironment (NEB-ME). Literature data and own recent results strongly suggest that the NEB-ME should be regarded as a unique airway stem cell niche. Transient acute lung injury (ALI) was induced in mice via a single intratracheal instillation of lipopolysaccharide (LPS; 10 mg/kg bw). In one experiment, broncho-alveolar lavage fluid (BALF) was collected 24 h after LPS instillation, and was used to challenge the NEB-ME in ex vivo lung slices of control mice. In another experiment, BrdU (10 mg/kg bw), as a marker for cells that divide during the observation window, was injected intraperitoneally at the time of LPS instillation and after 24 h, the animals were euthanized after 48 h, and the lungs were processed for freeze sectioning and BrdU immunostaining. Challenge of lung slices with BALF of ALI mice was shown to induce a reversible and reproducible selective Ca2 +-mediated activation of CLCs in the NEB-ME of control mice. Lung sections of ALI mice, 48 h after LPS challenge, revealed a remarkable increase in BrdU-labeled cells that surround the NEB-ME, as compared to control lungs. In conclusion, ALI appears to result in the production of soluble mediators in the airways that selectively activate, and induce proliferation of, a stem cell population in the NEB-ME. Support: Hercules Foundation grant AUAH-09-001 (DA); UA grant GOA BOF 2015 (DA).
doi:10.1016/j.autneu.2015.07.041
P4.3 Differential cardiovascular reflexes evoked by activation of nociceptive airway sensory nerves in healthy and cardiovascular-diseased rats J.S. Hooper, K.F. Morris, J.B. Dean, T.E. Taylor-Clark Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South FL, USA Background/Aims: Inhalation of pollutants causes significant increases in acute cardiovascular morbidity/mortality, in part via the modulation of autonomic function following the activation of airway sensory nerve reflexes. Pollutants selectively activate sensory nerves termed ‘nociceptors’ via the activation of the TRPA1 ion channel. However, inhalation of pollutants causes sympathetic-like effects disproportionately in patients with cardiovascular disease (CVD) but not in healthy individuals. We hypothesize that preexisting CVD alters cardiovascular reflexes evoked from the airways, and that this switch negatively impacts the effect of pollution on the clinical population. Methods: ECG were recorded in conscious and freely-moving rats (Healthy groups: Sprague Dawley (SD) and Wistar-Kyoto (WK); CVD group: Spontaneously Hypertensive (SH)) using radiotelemetry. To selectively activate pollutant-sensitive airway reflexes rats were exposed to the TRPA1 selective agonist allyl isothiocyanate (AITC). ECGs were recorded during exposure to nebulized vehicle and AITC (30 mM). Results: AITC caused bradycardia in SD and WK rats. Bradycardia was associated with elongated PR intervals and AV block. AITC-evoked responses in SD and WK were abolished by pretreatment with the muscarinic antagonist atropine, indicating a dominant role of parasympathetic reflexes. AITC caused complex brady-tachy arrhythmias in SH rats. In addition to evoking some AV block, AITC evoked significant premature ventricular contractions (PVCs) in SH rats. Atropine abolished the bradycardic/ AV components of AITC-evoked ECG responses. Pretreatment with the beta1 adrenoceptor antagonist atenolol abolished the AITCevoked PVCs, suggesting that this component was dependent on an increase in sympathetic responses. Conclusions: Pre-existing CVD switches pollution-sensitive airway reflexes from parasympathetic to sympathetic.
doi:10.1016/j.autneu.2015.07.042
P4.4 Muscle Sympathetic Nerve Activity during Hypercapnia in Young and Older Adults J.N. Barnesa,b, R.E. Harveyb, M.J. Joynerb a Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, USA b Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA Aging reduces the cerebrovascular response to hypercapnia, although the exact mechanism is unknown. During hypercapnia, chemoreflexmediated sympathoexcitation may influence the cerebrovascular response. Currently, it is unknown if aging influences the muscle sympathetic nerve activity (MSNA) response to hypercapnia and whether this MSNA response is associated with the cerebrovascular response. Our objective was to compare MSNA changes during hypercapnia in young and older adults. Cerebral blood flow velocity, mean arterial pressure (MAP) and MSNA were measured in 15 young (20-35 yr) and 10 older (56-76 yr) healthy adults during room air (baseline) and while breathing 6% CO2. At baseline, older adults had lower cerebral blood flow velocity compared with young adults (54 ± 5