Aim and Method A novel three-dimensional quantitative structure-activityrelationship (3D-QSAR) method, self-organizing molecular field analysis (SOMFA) , was used toinvestigate the correlation between the molecular pr...Aim and Method A novel three-dimensional quantitative structure-activityrelationship (3D-QSAR) method, self-organizing molecular field analysis (SOMFA) , was used toinvestigate the correlation between the molecular properties and a class of chromanol analogs asI_(Ks) blockers. Results The cross-validated correlation coefficient q^2 values (0.698) and noncross-validated correlation coefficient r^2 values (0.701) proved a good conventional statisticalcorrelation. Conclusion The final SOMFA model has therefore good predictive activity for the furthermolecular design of chromanol I_(Ks) potassium channel blockers.展开更多
Potassium (K+) ions are critical for the activation and catalytic cycle of the gastric H+,K+-ATPase, resulting in the secretion of hydrochloric acid into the parietal cell canaliculus. As both symptom, severity and es...Potassium (K+) ions are critical for the activation and catalytic cycle of the gastric H+,K+-ATPase, resulting in the secretion of hydrochloric acid into the parietal cell canaliculus. As both symptom, severity and esophageal mucosal damage in gastro-esophageal reflux disease (GERD) are related to the degree of acid exposure, K+ is a logical target for approaches to inhibit acid production.The probable K+ binding site on the gastric H+,K+-ATPase has recently been described and studies are elucidating how K+ activates the enzyme. K+ channels in the apical membrane of the parietal cell are implicated in the recycling of K+ and, to date, three potential K+ channels (KCNQ1, Kir2.1 and Kir4.1) have been identified. The channels represent theoretical sites for agents to control acid secretion but it will be difficult to develop selective blockers. An alternative strategy is to prevent K+ from activating gastric H+,K+-ATPase; the potassiumcompetitive acid blocker (P-CAB) class inhibits acidsecretion by binding at or near the K+ binding site.Ongoing research is further defining the role of K+ in the functioning of the gastric H+,K+-ATPase, as well as determining the clinical utility of agents directed toward this important cation.展开更多
Background Many studies have indicated that hyperpolarizing cardioplegia is responsible for myocardial preservation and researchers have suggested that the adenosine triphosphate-sensitive potassium channels （KATe） ...Background Many studies have indicated that hyperpolarizing cardioplegia is responsible for myocardial preservation and researchers have suggested that the adenosine triphosphate-sensitive potassium channels （KATe） were the end effectors of cardio-protection. But whether mitochondrial KATe plays an important role in hyperpolarizing cardioplegia is not apparent. The present study investigated the effect of hyperpolarizing cardioplegia containing pinacidil （a nonselective KATe opener） on ischemia/repeffusion injury in rat hearts, especially the role of mitochondrial KATe in pinacidil hyperpolarizing cardioplegia. Methods Sprague-Dawley rat hearts were Langendorff-perfused for 20 minutes with Krebs-Henseleit buffer at 37℃ before equilibration. Cardiac arrest was then induced in different treatments： there was no arrest and ischemia in the normal group, the control group were arrested by clamping the aorta, depolarizing caidioplegia （St. Thomas solution containing 16 mmol/L KCI） and hyperpolarizing cardioplegia groups used St. Thomas solution containing 0.05 mmol/L pinacidil and 5 mmol/L KCI to induce cardiac arrest in group hyperkalemic and group pinacidil, in group hyperkalemic ＋ 5-hydroxydecanote （5HD） and Pinacidil ＋ 5HD, 5HD （0.1 retool/L） was added to the above two solutions to block mitochondria KATe channels. Global ischemia was then administrated for 40 minutes at 37℃, followed by 30 minutes of reperfusion. At the end of equilibration and reperfusion, hemodynamics, ultrastructure, and mitochondrial function were measured. Results In the control group, ischemia/reperfusion decreased the left ventricular developed pressure, heart rate, coronary flow, mitochondrial membrane potential, impaired mitochondrial respiratory function, increased reactive oxygen species and left ventricular end diastolic pressure. Damage to myocardial ultrastructure was also evident. Both depolarized arrest and especially hyperpolarized cardioplegia significantly reduced these lesions. 5HD partially blocked the beneficial effects of pinacidil cardioplegia but showing no effects on hyperkalemic arrest. Conclusions Pinacidil cardioplegia provides better cardioprotection with preservation of hemodynamics, ultrastructure, and mitochondrial function than traditional cardioplegia. The mitochondria KATe channels may play an important role in the protection mechanism.展开更多
文摘Aim and Method A novel three-dimensional quantitative structure-activityrelationship (3D-QSAR) method, self-organizing molecular field analysis (SOMFA) , was used toinvestigate the correlation between the molecular properties and a class of chromanol analogs asI_(Ks) blockers. Results The cross-validated correlation coefficient q^2 values (0.698) and noncross-validated correlation coefficient r^2 values (0.701) proved a good conventional statisticalcorrelation. Conclusion The final SOMFA model has therefore good predictive activity for the furthermolecular design of chromanol I_(Ks) potassium channel blockers.
文摘Potassium (K+) ions are critical for the activation and catalytic cycle of the gastric H+,K+-ATPase, resulting in the secretion of hydrochloric acid into the parietal cell canaliculus. As both symptom, severity and esophageal mucosal damage in gastro-esophageal reflux disease (GERD) are related to the degree of acid exposure, K+ is a logical target for approaches to inhibit acid production.The probable K+ binding site on the gastric H+,K+-ATPase has recently been described and studies are elucidating how K+ activates the enzyme. K+ channels in the apical membrane of the parietal cell are implicated in the recycling of K+ and, to date, three potential K+ channels (KCNQ1, Kir2.1 and Kir4.1) have been identified. The channels represent theoretical sites for agents to control acid secretion but it will be difficult to develop selective blockers. An alternative strategy is to prevent K+ from activating gastric H+,K+-ATPase; the potassiumcompetitive acid blocker (P-CAB) class inhibits acidsecretion by binding at or near the K+ binding site.Ongoing research is further defining the role of K+ in the functioning of the gastric H+,K+-ATPase, as well as determining the clinical utility of agents directed toward this important cation.
基金This project was supported by a grant from the National Natural Science Foundation of China （No. 30460132）.
文摘Background Many studies have indicated that hyperpolarizing cardioplegia is responsible for myocardial preservation and researchers have suggested that the adenosine triphosphate-sensitive potassium channels （KATe） were the end effectors of cardio-protection. But whether mitochondrial KATe plays an important role in hyperpolarizing cardioplegia is not apparent. The present study investigated the effect of hyperpolarizing cardioplegia containing pinacidil （a nonselective KATe opener） on ischemia/repeffusion injury in rat hearts, especially the role of mitochondrial KATe in pinacidil hyperpolarizing cardioplegia. Methods Sprague-Dawley rat hearts were Langendorff-perfused for 20 minutes with Krebs-Henseleit buffer at 37℃ before equilibration. Cardiac arrest was then induced in different treatments： there was no arrest and ischemia in the normal group, the control group were arrested by clamping the aorta, depolarizing caidioplegia （St. Thomas solution containing 16 mmol/L KCI） and hyperpolarizing cardioplegia groups used St. Thomas solution containing 0.05 mmol/L pinacidil and 5 mmol/L KCI to induce cardiac arrest in group hyperkalemic and group pinacidil, in group hyperkalemic ＋ 5-hydroxydecanote （5HD） and Pinacidil ＋ 5HD, 5HD （0.1 retool/L） was added to the above two solutions to block mitochondria KATe channels. Global ischemia was then administrated for 40 minutes at 37℃, followed by 30 minutes of reperfusion. At the end of equilibration and reperfusion, hemodynamics, ultrastructure, and mitochondrial function were measured. Results In the control group, ischemia/reperfusion decreased the left ventricular developed pressure, heart rate, coronary flow, mitochondrial membrane potential, impaired mitochondrial respiratory function, increased reactive oxygen species and left ventricular end diastolic pressure. Damage to myocardial ultrastructure was also evident. Both depolarized arrest and especially hyperpolarized cardioplegia significantly reduced these lesions. 5HD partially blocked the beneficial effects of pinacidil cardioplegia but showing no effects on hyperkalemic arrest. Conclusions Pinacidil cardioplegia provides better cardioprotection with preservation of hemodynamics, ultrastructure, and mitochondrial function than traditional cardioplegia. The mitochondria KATe channels may play an important role in the protection mechanism.
