Tetramethylpyrazine stimulates cystic fibrosis transmembrane conductance regulator-mediated anion secretion in distal colon of rodents

AIM： To investigate the effect of tetramethylpyrazine （TMP）, an active compound from Ligustium Wollichii Franchat, on electrolyte transport across the distal colon of rodents and the mechanism involved.METHODS： The short-circuit current （Isc） technique in conjunction with pharmacological agents and specific inhibitors were used in analyzing the electrolyte transport across the distal colon of rodents. The underlying cellular signaling mechanism was investigated by radioimmunoassay analysis （RIA） and a special mouse model of cystic fibrosis.RESULTS： IMP stimulated a conoentration-dependent rise in ISCl, which was dependent on both Cl^- and HCO3^-, and inhibited by apical application of diphenylamine-2,2＇-dicarboxylic acid （DPC） and glibenclamide, but resistant to 4,4＇-diisothiocyanatostilbene-2,2＇-disulfonic acid disodium salt hydrate （DIDS）. Removal of Na^＋ from basolateral solution almost completely abolished the Isc response to TMP, but it was insensitive to apical Na^＋ replacement or apical Na^＋ channel blocker, amiloride. Pretreatment of colonic mucosa with BAPTA-AM, a membrane-permeable selective Ca2＋ chelator, did not significantly alter the TMP-induced Iso No additive effect of forskolin and 3-isobutyl-l-methylxanthine （[BMX） was observed on the TMP-induced Isc, but it was significantly reduced by a protein kinase A inhibitor, H89.RIA results showed that TMP （1 mmol/L） elicited a significant increase in cellular cAMP production, which was similar to that elicited by the adenylate cyclase activator, forskolin （10μmol/L）. The TMP-elicited Isc as well as forskolin- or IBMX-induced Isc were abolished in mice with homozygous mutation of the cystic fibrosis transmembrane conductance regulator （CFTR） presenting defective CFTR functions and secretions.CONCLUSION： TMP may stimulate cAMP-dependent and CFTR-mediated Cl^- and HCO3^- secretion. This may have implications in the future development of alternative treatment for constipation.

Transient occult cardiotoxicity in children receiving continuous beta-agonist therapy

Background:Continuous beta-agonist therapy,typically in the form of inhaled albuterol,is the first line therapy for the treatment of acute and severe bronchospasm in children.Although this treatment is commonly used,concerns about cardiotoxicity have been raised.We aimed to investigate the cardiotoxic effects of continuous beta-agonist therapy in children.Methods:We conducted a retrospective review of children admitted to the intensive care unit(ICU)between May 2008 and April 2009,who were treated with continuous beta-agonist therapy(intravenous and nebulized).Results:Twenty of the 36 children treated with continuous albuterol had repeated serum troponin-T and lactate levels measured.Eleven patients(55%)were also treated with continuous intravenous terbutaline.Elevated levels of troponin-T levels were found in 25%of children,and elevated lactate levels were found in 60%.However,all returned to normal levels within 48 hours of ICU admission,despite continued beta-agonist therapy.No children experienced arrhythmias during therapy.There was no association between intravenous terbutaline use and elevated troponin-T[odds ratio(OR),1.3;95%CI,0.2-10.3]or with elevated serum lactate(OR,0.6;95%CI,0.1-3.7).There was also no association between elevated troponin-T or lactate and ICU or hospital length of stay.Conclusions:In this small study,a significant proportion of children had elevated serum troponin-T and lactate levels while receiving inhaled continuous beta-agonist therapy,irrespective of intravenous therapy.However,these abnormal values all returned to normal within 48 hours of ICU admission and were not associated with increased duration of hospitalization.