The Experts below are selected from a list of 63 Experts worldwide ranked by ideXlab platform
Charles W Emala - One of the best experts on this subject based on the ideXlab platform.
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low voltage vagal nerve stimulation reduces Bronchoconstriction in guinea pigs through catecholamine release
Neuromodulation, 2012Co-Authors: Thomas J. Hoffmann, Bruce Simon, Charles W EmalaAbstract:Objective: Electrical stimulation of the vagus nerve at relatively high voltages (e.g., >10 V) can induce Bronchoconstriction. However, low voltage (≤2 V) vagus nerve stimulation (VNS) can attenuate histamine-invoked Bronchoconstriction. Here, we identify the mechanism for this inhibition. Methods: In urethanea-nesthetized guinea pigs, bipolar electrodes were attached to both vagus nerves and changes in pulmonary inflation pressure were recorded in response to i.v. histamine and during VNS. The attenuation of the histamine response by low-voltage VNS was then examined in the presence of pharmacologic inhibitors or nerve ligation. Results: Low-voltage VNS attenuated Histamine-Induced Bronchoconstriction (4.4 ± 0.3 vs. 3.2 ± 0.2 cm H2O, p < 0.01) and remained effective following administration of a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester, and after sympathetic nerve depletion with guanethidine, but not after the β-adrenoceptor antagonist propranolol. Nerve ligation caudal to the electrodes did not block the inhibition but cephalic nerve ligation did. Low-voltage VNS increased circulating epinephrine and norepinephrine without but not with cephalic nerve ligation. Conclusion: These results indicate that low-voltage VNS attenuates Histamine-Induced Bronchoconstriction via activation of afferent nerves, resulting in a systemic increase in catecholamines likely arising from the adrenal medulla.
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inhibition of histamine induced Bronchoconstriction in guinea pig and swine by pulsed electrical vagus nerve stimulation
Neuromodulation, 2009Co-Authors: Thomas J. Hoffmann, Steven Mendez, Peter S Staats, Charles W EmalaAbstract:Objective. Smooth muscle help regulate the diameter of the airways and their constriction can contribute to the pathology of acute asthma attacks. This study sought to determine if applying a specific electrical signal to the vagus nerve (VN) could minimize Histamine-Induced Bronchoconstriction. Methods. Sixteen guinea pigs and three swine were anesthetized and had bipolar electrodes positioned on the cervical VNs. After the animals stabilized, i.v. histamine was titrated to elicit a moderate 2–4 cm H2O increase in pulmonary inflation pressure (Ppi). Histamine was then dosed with or without concurrent low voltage VN stimulation. Results. The peak change in Ppi following a histamine challenge was reduced in the guinea pig by VN stimulation (3.4 ± 0.4 vs. 2.1 ± 0.2 cm H2O, p < 0.001). The results were confirmed in a limited study in swine and indicate VN treatment is applicable to larger animals. Conclusion. This study suggests that VN stimulation can reduce Bronchoconstriction and may prove useful as a rescue therapy in the treatment of acute asthma.
Thomas J. Hoffmann - One of the best experts on this subject based on the ideXlab platform.
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low voltage vagal nerve stimulation reduces Bronchoconstriction in guinea pigs through catecholamine release
Neuromodulation, 2012Co-Authors: Thomas J. Hoffmann, Bruce Simon, Charles W EmalaAbstract:Objective: Electrical stimulation of the vagus nerve at relatively high voltages (e.g., >10 V) can induce Bronchoconstriction. However, low voltage (≤2 V) vagus nerve stimulation (VNS) can attenuate histamine-invoked Bronchoconstriction. Here, we identify the mechanism for this inhibition. Methods: In urethanea-nesthetized guinea pigs, bipolar electrodes were attached to both vagus nerves and changes in pulmonary inflation pressure were recorded in response to i.v. histamine and during VNS. The attenuation of the histamine response by low-voltage VNS was then examined in the presence of pharmacologic inhibitors or nerve ligation. Results: Low-voltage VNS attenuated Histamine-Induced Bronchoconstriction (4.4 ± 0.3 vs. 3.2 ± 0.2 cm H2O, p < 0.01) and remained effective following administration of a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester, and after sympathetic nerve depletion with guanethidine, but not after the β-adrenoceptor antagonist propranolol. Nerve ligation caudal to the electrodes did not block the inhibition but cephalic nerve ligation did. Low-voltage VNS increased circulating epinephrine and norepinephrine without but not with cephalic nerve ligation. Conclusion: These results indicate that low-voltage VNS attenuates Histamine-Induced Bronchoconstriction via activation of afferent nerves, resulting in a systemic increase in catecholamines likely arising from the adrenal medulla.
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inhibition of histamine induced Bronchoconstriction in guinea pig and swine by pulsed electrical vagus nerve stimulation
Neuromodulation, 2009Co-Authors: Thomas J. Hoffmann, Steven Mendez, Peter S Staats, Charles W EmalaAbstract:Objective. Smooth muscle help regulate the diameter of the airways and their constriction can contribute to the pathology of acute asthma attacks. This study sought to determine if applying a specific electrical signal to the vagus nerve (VN) could minimize Histamine-Induced Bronchoconstriction. Methods. Sixteen guinea pigs and three swine were anesthetized and had bipolar electrodes positioned on the cervical VNs. After the animals stabilized, i.v. histamine was titrated to elicit a moderate 2–4 cm H2O increase in pulmonary inflation pressure (Ppi). Histamine was then dosed with or without concurrent low voltage VN stimulation. Results. The peak change in Ppi following a histamine challenge was reduced in the guinea pig by VN stimulation (3.4 ± 0.4 vs. 2.1 ± 0.2 cm H2O, p < 0.001). The results were confirmed in a limited study in swine and indicate VN treatment is applicable to larger animals. Conclusion. This study suggests that VN stimulation can reduce Bronchoconstriction and may prove useful as a rescue therapy in the treatment of acute asthma.
David R Adams - One of the best experts on this subject based on the ideXlab platform.
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phosphodiesterase inhibitors part 5 hybrid pde3 4 inhibitors as dual bronchorelaxant anti inflammatory agents for inhaled administration
Bioorganic & Medicinal Chemistry Letters, 2013Co-Authors: Koji Ochiai, Satoshi Takita, Tomohiko Eiraku, Akihiko Kojima, Kazuhiko Iwase, Tetsuya Kishi, Tokutaro Yasue, Akira Ohinata, Yuichi Yageta, David R AdamsAbstract:(-)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (KCA-1490) exhibits moderate dual PDE3/4-inhibitory activity and promises as a combined bronchodilatory/anti-inflammatory agent. N-alkylation of the pyridazinone ring markedly enhances potency against PDE4 but suppresses PDE3 inhibition. Addition of a 6-aryl-4,5-dihydropyridazin-3(2H)-one extension to the N-alkyl group facilitates both enhancement of PDE4-inhibitory activity and restoration of potent PDE3 inhibition. Both dihydropyridazinone rings, in the core and extension, can be replaced by achiral 4,4-dimethylpyrazolone subunits and the core pyrazolopyridine by isosteric bicyclic heteroaromatics. In combination, these modifications afford potent dual PDE3/4 inhibitors that suppress Histamine-Induced Bronchoconstriction in vivo and exhibit promising anti-inflammatory activity via intratracheal administration.
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phosphodiesterase inhibitors part 3 design synthesis and structure activity relationships of dual pde3 4 inhibitory fused bicyclic heteroaromatic dihydropyridazinones with anti inflammatory and bronchodilatory activity
Bioorganic & Medicinal Chemistry, 2012Co-Authors: Koji Ochiai, Satoshi Takita, Tomohiko Eiraku, Akihiko Kojima, Kazuhiko Iwase, Tetsuya Kishi, Kazunori Fukuchi, Tokutaro Yasue, David R Adams, Robert W AllcockAbstract:Abstract (−)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. A survey of potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of KCA-1490 has identified the 4-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl and 8-methoxy-2-(trifluoromethyl)quinolin-5-yl analogues as dual PDE3/4-inhibitory compounds that potently suppress Histamine-Induced Bronchoconstriction and exhibit anti-inflammatory activity in vivo.
Koji Ochiai - One of the best experts on this subject based on the ideXlab platform.
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phosphodiesterase inhibitors part 5 hybrid pde3 4 inhibitors as dual bronchorelaxant anti inflammatory agents for inhaled administration
Bioorganic & Medicinal Chemistry Letters, 2013Co-Authors: Koji Ochiai, Satoshi Takita, Tomohiko Eiraku, Akihiko Kojima, Kazuhiko Iwase, Tetsuya Kishi, Tokutaro Yasue, Akira Ohinata, Yuichi Yageta, David R AdamsAbstract:(-)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (KCA-1490) exhibits moderate dual PDE3/4-inhibitory activity and promises as a combined bronchodilatory/anti-inflammatory agent. N-alkylation of the pyridazinone ring markedly enhances potency against PDE4 but suppresses PDE3 inhibition. Addition of a 6-aryl-4,5-dihydropyridazin-3(2H)-one extension to the N-alkyl group facilitates both enhancement of PDE4-inhibitory activity and restoration of potent PDE3 inhibition. Both dihydropyridazinone rings, in the core and extension, can be replaced by achiral 4,4-dimethylpyrazolone subunits and the core pyrazolopyridine by isosteric bicyclic heteroaromatics. In combination, these modifications afford potent dual PDE3/4 inhibitors that suppress Histamine-Induced Bronchoconstriction in vivo and exhibit promising anti-inflammatory activity via intratracheal administration.
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phosphodiesterase inhibitors part 3 design synthesis and structure activity relationships of dual pde3 4 inhibitory fused bicyclic heteroaromatic dihydropyridazinones with anti inflammatory and bronchodilatory activity
Bioorganic & Medicinal Chemistry, 2012Co-Authors: Koji Ochiai, Satoshi Takita, Tomohiko Eiraku, Akihiko Kojima, Kazuhiko Iwase, Tetsuya Kishi, Kazunori Fukuchi, Tokutaro Yasue, David R Adams, Robert W AllcockAbstract:Abstract (−)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. A survey of potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of KCA-1490 has identified the 4-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl and 8-methoxy-2-(trifluoromethyl)quinolin-5-yl analogues as dual PDE3/4-inhibitory compounds that potently suppress Histamine-Induced Bronchoconstriction and exhibit anti-inflammatory activity in vivo.
William M Abraham - One of the best experts on this subject based on the ideXlab platform.
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inhaled tryptase causes Bronchoconstriction in sheep via histamine release
American Journal of Respiratory and Critical Care Medicine, 1996Co-Authors: Jussara F. Molinari, William R. Moore, Richard D. Tanaka, Mario Scuri, James M Clark, William M AbrahamAbstract:Allergen-induced Bronchoconstriction involves mast cell activation. Tryptase is a mast cell serine protease that is released during this process, but little is known about the action of tryptase in the airway. The purpose of this study was to determine: (1) if aerosolized tryptase causes Bronchoconstriction, and (2) the mechanism by which this occurs. We measured mean pulmonary flow resistance (RL) in five allergic sheep before and after consecutive inhalations of 100 and 500 ng tryptase (in 2 ml total volume). Inhaled tryptase at 100 and 500 ng increased RL (mean +/- SE) by 33 +/- 12 and 122 +/- 8% (p < 0.05) over baseline. The response was reproducible upon repeat challenges. These studies were repeated in the same animals after pretreatment with aerosolized APC 366 (9 mg/3 ml), a specific tryptase inhibitor. In APC-366-treated sheep, tryptase increased RL by 10 +/- 3 and 6 +/- 2% (p < 0.05 versus control values) at 100 and 500 ng, respectively. The response to tryptase was also blocked by pretreating the sheep intravenously with the histamine H1-antagonist chlorpheniramine (2 mg/kg), in which RL increased only 5 +/- 4 and 7 +/- 6% after 100 and 500 ng tryptase. APC 366, however, did not block Histamine-Induced Bronchoconstriction. Consistent with these findings was the observation that segmental bronchial challenge with tryptase (1 microgram) resulted in a significant increase in histamine levels in bronchoalveolar lavage. Inhaled tryptase (500 ng) also caused airway hyperresponsiveness to aerosolized carbachol 2 h after tryptase challenge. This tryptase-induced airway hyperresponsiveness could be blocked either by pretreating the sheep with APC 366 (30 min before challenge) or by treating the sheep 30 min after challenge. These results indicate that inhaled tryptase causes Bronchoconstriction and airway hyperresponsiveness in allergic sheep by an event that may involve mast cell activation.