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Potent cardioprotective effect of the 4-anilinoquinazoline derivative PD153035: involvement of mitochondrial K(ATP) channel activation.

Cavalheiro RA, Marin RM, Rocco SA, Cerqueira FM, da Silva CC, Rittner R, Kowaltowski AJ, Vercesi AE, Franchini KG, Castilho RF - PLoS ONE (2010)

Bottom Line: 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.We conclude that PD153035 is a potent cardioprotective compound and acts in a mechanism involving mitoK(ATP) activation.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, Brazil.

ABSTRACT

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.

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PD153035 improves cardiac function after ischemia/reperfusion.Panels A–D: Perfused rat hearts were submitted to left ventricular pressure measurements after 15 min stabilizing perfusion, as described in the Methods section. PD153035 was present at 10 pM, 1 nM or 100 nM (Panels B, C and D, respectively) during the full experimental period. Panel A shows hearts in the absence of PD153035. After 10 min, the hearts were submitted to 40 min ischemia by interruption of coronary flow, followed by 35 min reperfusion. Data are representative traces of 3 similar repetitions. LVP: Left ventricular pressure. Panels E–F: Averages±SEM of 3 experiments conducted under the conditions of Panels A–D. DLVP: developed left ventricular pressure; DP: diastolic pressure. Values for 10 pM, 1 nM and 100 nM PD153035 concentrations were significantly different from controls at 85 min (p<0.05).
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pone-0010666-g001: PD153035 improves cardiac function after ischemia/reperfusion.Panels A–D: Perfused rat hearts were submitted to left ventricular pressure measurements after 15 min stabilizing perfusion, as described in the Methods section. PD153035 was present at 10 pM, 1 nM or 100 nM (Panels B, C and D, respectively) during the full experimental period. Panel A shows hearts in the absence of PD153035. After 10 min, the hearts were submitted to 40 min ischemia by interruption of coronary flow, followed by 35 min reperfusion. Data are representative traces of 3 similar repetitions. LVP: Left ventricular pressure. Panels E–F: Averages±SEM of 3 experiments conducted under the conditions of Panels A–D. DLVP: developed left ventricular pressure; DP: diastolic pressure. Values for 10 pM, 1 nM and 100 nM PD153035 concentrations were significantly different from controls at 85 min (p<0.05).

Mentions: Perfused rat hearts were pre-treated with different concentrations of PD153035 and submitted to 40 min ischemia followed by reperfusion. Figures 1A–D show representative left ventricular pressure measurements in these perfused hearts. Upon global ischemia, the contractile function of the isolated rat hearts ceased within a few cycles (Panel A). Following reperfusion, spontaneous beating is resumed, but with increases in diastolic pressures and decreased systolic performance, as indicated by the marked reduction in the developed pressure. On the other hand, hearts pre-treated with increasing PD153035 concentrations (10 pM, Panel B; 1 nM, Panel C or 100 nM, Panel D) presented significantly less increases in the diastolic pressure and reductions in the systolic performance. Figures 1E–F shows average left ventricular developed pressures (Panel E) and diastolic pressures (Panel F) in hearts submitted to ischemia/reperfusion in the presence of 10 pM (▴), 1 nM (○) or 100 nM PD153035 (♦). Compared to controls (□), PD153035 treatment strikingly improved cardiac function, with a maximal effect observed at 1 nM.


Potent cardioprotective effect of the 4-anilinoquinazoline derivative PD153035: involvement of mitochondrial K(ATP) channel activation.

Cavalheiro RA, Marin RM, Rocco SA, Cerqueira FM, da Silva CC, Rittner R, Kowaltowski AJ, Vercesi AE, Franchini KG, Castilho RF - PLoS ONE (2010)

PD153035 improves cardiac function after ischemia/reperfusion.Panels A–D: Perfused rat hearts were submitted to left ventricular pressure measurements after 15 min stabilizing perfusion, as described in the Methods section. PD153035 was present at 10 pM, 1 nM or 100 nM (Panels B, C and D, respectively) during the full experimental period. Panel A shows hearts in the absence of PD153035. After 10 min, the hearts were submitted to 40 min ischemia by interruption of coronary flow, followed by 35 min reperfusion. Data are representative traces of 3 similar repetitions. LVP: Left ventricular pressure. Panels E–F: Averages±SEM of 3 experiments conducted under the conditions of Panels A–D. DLVP: developed left ventricular pressure; DP: diastolic pressure. Values for 10 pM, 1 nM and 100 nM PD153035 concentrations were significantly different from controls at 85 min (p<0.05).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2871796&req=5

pone-0010666-g001: PD153035 improves cardiac function after ischemia/reperfusion.Panels A–D: Perfused rat hearts were submitted to left ventricular pressure measurements after 15 min stabilizing perfusion, as described in the Methods section. PD153035 was present at 10 pM, 1 nM or 100 nM (Panels B, C and D, respectively) during the full experimental period. Panel A shows hearts in the absence of PD153035. After 10 min, the hearts were submitted to 40 min ischemia by interruption of coronary flow, followed by 35 min reperfusion. Data are representative traces of 3 similar repetitions. LVP: Left ventricular pressure. Panels E–F: Averages±SEM of 3 experiments conducted under the conditions of Panels A–D. DLVP: developed left ventricular pressure; DP: diastolic pressure. Values for 10 pM, 1 nM and 100 nM PD153035 concentrations were significantly different from controls at 85 min (p<0.05).
Mentions: Perfused rat hearts were pre-treated with different concentrations of PD153035 and submitted to 40 min ischemia followed by reperfusion. Figures 1A–D show representative left ventricular pressure measurements in these perfused hearts. Upon global ischemia, the contractile function of the isolated rat hearts ceased within a few cycles (Panel A). Following reperfusion, spontaneous beating is resumed, but with increases in diastolic pressures and decreased systolic performance, as indicated by the marked reduction in the developed pressure. On the other hand, hearts pre-treated with increasing PD153035 concentrations (10 pM, Panel B; 1 nM, Panel C or 100 nM, Panel D) presented significantly less increases in the diastolic pressure and reductions in the systolic performance. Figures 1E–F shows average left ventricular developed pressures (Panel E) and diastolic pressures (Panel F) in hearts submitted to ischemia/reperfusion in the presence of 10 pM (▴), 1 nM (○) or 100 nM PD153035 (♦). Compared to controls (□), PD153035 treatment strikingly improved cardiac function, with a maximal effect observed at 1 nM.

Bottom Line: 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.We conclude that PD153035 is a potent cardioprotective compound and acts in a mechanism involving mitoK(ATP) activation.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, Brazil.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus