Potent Cardioprotective Effect of the 4-Anilinoquinazoline Derivative PD153035: Involvement of Mitochondrial KATP Channel Activation

Background: The aim of the present study was to evaluate the protective effects of the 4-anilinoquinazoline derivative PD153035 on cardiac ischemia/reperfusion and mitochondrial function. Methodology/Principal Findings: Perfused rat hearts and cardiac HL-1 cells were used to determine cardioprotective effects of PD153035. Isolated rat heart mitochondria were studied to uncover mechanisms of cardioprotection. Nanomolar doses of PD153035 strongly protect against heart and cardiomyocyte damage induced by ischemia/reperfusion and cyanide/aglycemia. PD153035 did not alter oxidative phosphorylation, nor directly prevent Ca(2+) induced mitochondrial membrane permeability transition. The protective effect of PD153035 on HL-1 cells was also independent of AKT phosphorylation state. Interestingly, PD153035 activated K(+) transport in isolated mitochondria, in a manner prevented by ATP and 5-hydroxydecanoate, inhibitors of mitochondrial ATP-sensitive K(+) channels (mitoK(ATP)). 5-Hydroxydecanoate also inhibited the cardioprotective effect of PD153035 in cardiac HL-1 cells, demonstrating that this protection is dependent on mitoK(ATP) activation. Conclusions/Significance: We conclude that PD153035 is a potent cardioprotective compound and acts in a mechanism involving mitoK(ATP) activation

SLO-2 Is Cytoprotective and Contributes to Mitochondrial Potassium Transport

Mitochondrial potassium channels are important mediators of cell protection against stress. The mitochondrial large-conductance “big” K+ channel (mBK) mediates the evolutionarily-conserved process of anesthetic preconditioning (APC), wherein exposure to volatile anesthetics initiates protection against ischemic injury. Despite the role of the mBK in cardioprotection, the molecular identity of the channel remains unknown. We investigated the attributes of the mBK using C. elegans and mouse genetic models coupled with measurements of mitochondrial K+ transport and APC. The canonical Ca2+-activated BK (or “maxi-K”) channel SLO1 was dispensable for both mitochondrial K+ transport and APC in both organisms. Instead, we found that the related but physiologically-distinct K+ channel SLO2 was required, and that SLO2-dependent mitochondrial K+ transport was triggered directly by volatile anesthetics. In addition, a SLO2 channel activator mimicked the protective effects of volatile anesthetics. These findings suggest that SLO2 contributes to protection from hypoxic injury by increasing the permeability of the mitochondrial inner membrane to K+

Essential oils of leaves of Piper species display larvicidal activity against the dengue vector, Aedes aegypti (Diptera: Culicidae)

The mosquito Aedes aegypti is the vector of the dengue virus, an endemic arbovirus from tropical and subtropical regions of the world. The increasing resistance of mosquitoes to commercial insecticides impairs regular control programs; therefore, chemical prospecting originating from the Amazonian flora is promising for potential new insecticides. Several Piper species are, notably, rich in phenylpropanoids and terpenoids, substances with proven insecticidal activity. The composition and the larvicidal activity of three Piper species against A. aegypti were evaluated. Essential oils were extracted by hydrodistillation in a modified Clevenger apparatus and analyzed by GC/MS. The major components found in Piper arboreum were germacrene D (31.83%) and bicyclogermacrene (21.40%); in Piper marginatum: (E)-methyl isoeugenol (27.08%), (E)-anethole (23.98%) and (Z)-methyl isoeugenol (12.01%); and in Piper aduncum: (E)-isocroweacin (29.52%) and apiole (28.62%) and elemicin (7.82%). Essential oils from the Piperaceae species studied resulted in Lethal Concentrations (LC50) of 34-55 ppm, while LC90 was higher than 100 ppm, except for P. marginatum (85 ppm)