The mechanisms of chronic nadolol treatment on the regulation of bronchial tone in a murine model of asthma

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Title: The mechanisms of chronic nadolol treatment on the regulation of bronchial tone in a murine model of asthma
Author: Lin, Rui
Abstract: Statement of the problem : Using a murine model of asthma , chronic beta blocker treatment was found to improve airway hyperresponsiveness (AHR ) . This finding completed a paradigm shift in the treatment of asthma using β adrenoceptor (AR ) ligands , which was an analogy of the paradigm shift that occurred in congestive heart failure . Therefore , we hypothesized that chronic beta blocker treatment altered the cellular signaling modulating airway smooth muscle tone . Procedure or methods : Radioligand binding assays were used to measure β AR number and further identify the subtype of β AR regulated by chronic beta blocker treatment . To evaluate the effect of chronic nadolol treatment on Gs signaling pathways , cAMP accumulation in the lung homogenates was measured by direct enzyme immunoassay ; the cAMP -PKA dependent signaling was evaluated by isoproterenol induced tracheal relaxation ; Gs , GRK2 , GRK3 , PDE4D and β arrestin 2 , important proteins regulating the Gs signaling and playing important roles in lung physiology were measured by immunoblotting . To evaluate the effect of chronic nadolol treatment on Gi and Gq signaling pathways , Gαi3 , Gαi2 , Gq , GRK5 , PLCβ1 , PKCα were also measured by immunoblotting . To evaluate the effect of chronic nadolol treatment on arachidonic acid metabolism , cysteinyl leukotrines were measured in bronchoalveolar lavage fluid (BALF ) , while cPLA2 , COX2 and 5 -LO were also measured by immunoblotting . In addition , β2 AR knockout mice were treated with the same protocol as the wildtype mice to confirm that the effects of chronic nadolol treatment on PDE4D , Gαi3 and PLCβ1 were β2 AR dependent . Results : Chronic beta blocker treatment increased β2 AR density and decreased PDE4D expression . Although chronic beta blocker treatment showed no effect on cAMP -PKA dependent airway smooth muscle relaxation , the regulation of Gi expression and Gi signaling in airway smooth muscle were found to be altered with chronic nadolol treatment . Also , chronic nadolol treatment decreased PLCβ1 expression and PKCα , 5 - LO translocation . While a reduction in AHR , mucous metaplasia , and inflammatory cell counts in bronchoalveolar lavage fluid (BALF ) was observed in wildtype mice , chronic nadolol treatment had no effect on PDE4D , Gi3 and PLCβ1 expression in β2 AR null mice . Conclusion : Chronic nadolol treatment decreased airway tone in a murine model of asthma by decreasing cAMP breakdown and Gi , Gq signaling . These effects are possibly dependent on its chronic blockade of β2 AR .
URI: http : / /hdl .handle .net /10657 /6
Date: 2010-03-24

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The mechanisms of chronic nadolol treatment on the regulation of bronchial tone in a murine model of asthma. Available electronically from http : / /hdl .handle .net /10657 /6 .

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