CARDIAC role of the mitochondrial Ca2+ transporters in the high-[K+](o) cardioprotection of rat hearts under ischemia and reperfusion: a mechano-energetic study.
The role of mitochondrial transporters in the cardioprotection of rat hearts exposed to high [K+]-low [Ca2+]-cardioplegia (CPG) and ischemia and reperfusion (I/R) was studied through the mechano-energetic consequences of target drugs. The total heat rate (Ht) and the left intraventricular pressure (LVP) were simultaneously measured in isolated perfused hearts (30 degrees C and 1 Hz) inside a flow-calorimeter during 45 minutes of no-flow I and 45 minutes of R. After stabilization (C) they were pretreated with CPG and 100 microM 5-hydroxidecanoate (5HD, selective mKATP blocker) without and with 10 or 30 microM clonazepam (Clzp, mNCX inhibitor), 30 microM diazoxide (Dzx, selective mKATP opener), 1 microM Ru360 (selective Ca-uniporter blocker), and 0.2 microM cyclosporine-A, (mPTP inhibitor, before I and during R). Before I, 5-hydroxydecanoate in CPG increased the resting heat rate (17.83 +/- 3.55 mW/g) without changing the stunning. Clzp 30 microM + CPG + 5-hydroxydecanoate reduced the postischemic P with diastolic contracture and high Ht. Dzx protected C-hearts from stunning but increased it in CPG hearts with low economy (P/Ht) as well as Ru360. Cyclosporine-A did not modify the stunning of C or CPG ischemic hearts, suggesting that the mPTP was not opened.


CONCLUSIONS
Mitochondria have a precise role for determining cardioprotection or stunning in high-K+ cardioplegic rat hearts under I/R. Known protective drugs, such as Dzx and Ru360, which reduce the mitochondrial Ca2+-uptake, increased the stunning of CPG-rat hearts and reduced muscle economy, whereas 5-hydroxydecanoate and Clzp together increased the stunning by inducing mitochondrial Ca2+ overload.
Ragone
María Inés
MI
Cátedra de Farmacología, Area Farmacia, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata (UNLP), Argentina.
Consolini
Alicia E
AE
D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D002314:Cardioplegic Solutions; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006324:Heart Arrest, Induced; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D017682:Myocardial Stunning / Q000139:chemically induced; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors; D013997:Time Factors; D017725:Ventricular Pressure / Q000187:drug effects
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002314:Cardioplegic Solutions; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D019831:Sodium-Calcium Exchanger; C034703:mitochondrial calcium uniporter