Y-26763 protects the canine heart from a stunning injury through opening of the KATP channels

Fukunari, Atsushi; Miyai, Hisato; Shinagawa, Kenji; Kawahara, Kiminori; Nakajima, Tohru

doi:10.1016/s0014-2999(97)00035-6

Cited by 4 publications

(7 citation statements)

References 31 publications

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“…Pharmacologically, K ATP + channels are antagonized by sulfonylurea derivatives, with GLIB (glyburide) reported to unspecifically block all receptor isoforms, SUR-1, SUR-2A, and SUR-2B. GLIB has been reported to be effective as a K ATP + channel antagonist in dogs before, in similar dosages as applied in the present study [26–30]. Activity of GLIB in our model is suggested by the hypoglycemic response after GLIB pretreatment (SUR-1 effect), with arterial glucose decreased from baseline values of ~100 to ~50 mg dL −1 (end of experiments).…”

Section: Discussionmentioning

confidence: 66%

“…While the first hypoxic episode served to elucidate the effect of LEVO pretreatment, the second hypoxic episode served to elucidate the role of K ATP + channels (by subsequently adding GLIB pretreatment, reported to block GLIB-sensitive K ATP + channels [26–30]). Between the two hypoxic episodes, an extended normoxic period was interposed to allow complete recovery of measured variables.…”

Section: Discussionmentioning

confidence: 99%

“…This dose was derived from previous canine studies addressing the contribution of K ATP + channels to the effects of LEVO and other cardiovascular modulators [26–30]. …”

Section: Methodsmentioning

confidence: 99%

“…In this context, GLIB pretreatment has previously been published as a research tool to study the contribution of GLIB-sensitive K ATP + channels to the effects of LEVO and other cardiovascular challenges [26–30]. Thus, to elucidate the contribution of K ATP + channels in the present study, we tested if K ATP + channel blockade by GLIB pretreatment would alter the (circulatory) condition during hypoxia, both with and without a LEVO pretreatment.…”

Section: Introductionmentioning

confidence: 97%

“…These K ATP + channels, activated by LEVO or hypoxia, are pharmacologically blocked by glibenclamide (GLIB) [26–30]. In this context, GLIB pretreatment has previously been published as a research tool to study the contribution of GLIB-sensitive K ATP + channels to the effects of LEVO and other cardiovascular challenges [26–30].…”

Section: Introductionmentioning

confidence: 99%

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The effects of levosimendan and glibenclamide on circulatory and metabolic variables in a canine model of acute hypoxia

et al. 2011

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PurposeTo study the effects of pretreatment with levosimendan (LEVO, a Ca2+-sensitizer and KATP+ channel opener) and/or the KATP+ channel antagonist glibenclamide (GLIB) on systemic hemodynamics, metabolism, and regional gastromucosal oxygenation during hypoxic hypoxemia.MethodsChronically instrumented, healthy dogs (24–32 kg, n = 6 per group, randomized cross-over design) were repeatedly sedated, mechanically ventilated (FiO2 ~0.3) and subjected to the following interventions: no pretreatment, LEVO pretreatment, GLIB pretreatment, or combined LEVO + GLIB pretreatment, each followed by hypoxic hypoxemia (FiO2 ~0.1). We measured cardiac output (CO, ultrasonic flow probes), oxygen consumption (VO2, indirect calorimetry), and gastromucosal microvascular hemoglobin oxygenation (μHbO2, spectrophotometry). Statistics: data are presented as mean ± SEM and compared by one-way ANOVA (direct drug effects within group) and two-way ANOVA (between all hypoxic conditions) both with Bonferroni corrections; p < 0.05.ResultsIn LEVO-pretreated hypoxemia, CO was significantly higher compared to unpretreated hypoxemia. The increased CO was neither associated with an increased VO2 nor with markers of aggravated anaerobiosis (pH, BE, lactate). In addition, LEVO pretreatment did not further compromise gastromucosal μHbO2 in hypoxemia. After combined LEVO + GLIB pretreatment, systemic effects of GLIB were apparent, however, CO was significantly higher than during unpretreated and GLIB-pretreated hypoxemia, but equal to LEVO-pretreated hypoxemia, indicating that GLIB did not prevent the increased CO in LEVO-pretreated hypoxia.ConclusionsLEVO pretreatment resulted in improved systemic circulation (CO) during hypoxemia without fueling systemic VO2, without aggravating systemic anaerobiosis markers, and without further compromising microvascular gastromucosal oxygenation. Thus, LEVO pretreatment may be an option to support the systemic circulation during hypoxia.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

“…This dose was derived from previous canine studies addressing the contribution of K ATP + channels to the effects of LEVO and other cardiovascular modulators [26–30]. …”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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The effects of levosimendan and glibenclamide on circulatory and metabolic variables in a canine model of acute hypoxia

et al. 2011

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Y-26763: ATP-sensitive K+ channel activation and the inhibition of insulin release from human pancreatic β-cells

Cosgrove

Straub

Barnes

et al. 2004

European Journal of Pharmacology

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Drug-likeness Analysis of Traditional Chinese Medicines: Prediction of Drug-likeness Using Machine Learning Approaches

Tian¹,

Wang

Li³

et al. 2012

Mol. Pharmaceutics

101

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Quantitative or qualitative characterization of the drug-like features of known drugs may help medicinal and computational chemists to select higher quality drug leads from a huge pool of compounds and to improve the efficiency of drug design pipelines. For this purpose, the theoretical models for drug-likeness to discriminate between drug-like and non-drug-like based on molecular physicochemical properties and structural fingerprints were developed by using the naive Bayesian classification (NBC) and recursive partitioning (RP) techniques, and then the drug-likeness of the compounds from the Traditional Chinese Medicine Compound Database (TCMCD) was evaluated. First, the impact of molecular physicochemical properties and structural fingerprints on the prediction accuracy of drug-likeness was examined. We found that, compared with simple molecular properties, structural fingerprints were more essential for the accurate prediction of drug-likeness. Then, a variety of Bayesian classifiers were constructed by changing the ratio of drug-like to non-drug-like molecules and the size of the training set. The results indicate that the prediction accuracy of the Bayesian classifiers was closely related to the size and the degree of the balance of the training set. When a balanced training set was used, the best Bayesian classifier based on 21 physicochemical properties and the LCFP_6 fingerprint set yielded an overall leave-one-out (LOO) cross-validated accuracy of 91.4% for the 140,000 molecules in the training set and 90.9% for the 40,000 molecules in the test set. In addition, the RP classifiers with different maximum depth were constructed and compared with the Bayesian classifiers, and we found that the best Bayesian classifier outperformed the best RP model with respect to overall prediction accuracy. Moreover, the Bayesian classifier employing structural fingerprints highlights the important substructures favorable or unfavorable for drug-likeness, offering extra valuable information for getting high quality lead compounds in the early stage of the drug design/discovery process. Finally, the best Bayesian classifier was used to predict the drug-likeness of 33,961 compounds in TCMCD. Our calculations show that 59.37% of the molecules in TCMCD were identified as drug-like molecules, indicating that traditional Chinese medicines (TCMs) are therefore an excellent source of drug-like molecules. Furthermore, the important structural fingerprints in TCMCD were detected and analyzed. Considering that the pharmacology of TCMCD and MDDR (MDL Drug Data Report) was linked by the important common structural features, the potential pharmacology of the compounds in TCMCD may therefore be annotated by these important structural signatures identified from Bayesian analysis, which may be valuable to promote the development of TCMs.

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Y-26763 protects the canine heart from a stunning injury through opening of the KATP channels

Cited by 4 publications

References 31 publications

The effects of levosimendan and glibenclamide on circulatory and metabolic variables in a canine model of acute hypoxia

The effects of levosimendan and glibenclamide on circulatory and metabolic variables in a canine model of acute hypoxia

Y-26763: ATP-sensitive K+ channel activation and the inhibition of insulin release from human pancreatic β-cells

Drug-likeness Analysis of Traditional Chinese Medicines: Prediction of Drug-likeness Using Machine Learning Approaches

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