Preservation of mitochondrial function during ischemia as a possible mechanism for cardioprotection of diltiazem against ischemia/reperfusion injury.
A possible mechanism for D-cis-diltiazem (diltiazem)-mediated improvement of the contractile function of ischemic/reperfused hearts was examined. Thirty-five-min ischemia/60-min reperfusion recovered little the left ventricular developed pressure (LVDP) and decreased myocardial high-energy phosphates (HEPs). Ischemia induced an accumulation of tissue Na+ content, an increase in cytochrome c in the cytosolic fraction, and a decrease in the oxygen consumption rate (OCR) in perfused hearts. Treatment of the heart with 1 microM diltiazem for the last 3-min of pre-ischemia did not affect the decrease in HEPs during ischemia, whereas that with 3 microM partially attenuated the decrease in ATP, suggesting that 3 microM diltiazem exerted energy-sparing effect. Treatment with 1 microM diltiazem enhanced the post-ischemic recovery of LVDP associated with attenuation of the ischemia-induced accumulation of tissue Na+, increase in cytochrome c in the cytosolic fraction, and decrease in myocardial OCR, and restoration of the myocardial HEPs during reperfusion. Combined treatment with diltiazem and a Na+/H+ exchange inhibitor, but not a Na+ channel blocker, facilitated the attenuation of Na+ accumulation in the ischemic heart and the enhancement of the post-ischemic recovery of LVDP. Sodium lactate, a possible metabolite in ischemic hearts, and sodium chloride increased the Na+ concentration in mitochondria, released cytochrome c into incubation medium, and reduced the mitochondrial respiration. Treatment of isolated mitochondria with diltiazem failed to attenuate the sodium lactate- and sodium chloride-induced alterations. These results suggest that the cardioprotection of diltiazem may be exerted via attenuating cytosolic Na+ overload through Na+ channels in the ischemic heart, leading to preservation of mitochondrial functional ability during ischemia, followed by improvement of post-ischemic energy production and contractile recovery.
Takeo
Satoshi
S
Department of Pharmacology, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. takeos@ps.toyaku.ac.jp
Tanonaka
Kouichi
K
Iwai
Takeshi
T
Motegi
Kanataka
K
Hirota
Yuko
Y
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D002317:Cardiovascular Agents; D045304:Cytochromes c / Q000378:metabolism; D004110:Diltiazem / Q000627:therapeutic use*; D004347:Drug Interactions; D007511:Ischemia / Q000150:complications*; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010710:Phosphates / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D012119:Respiration; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors
D002316:Cardiotonic Agents; D002317:Cardiovascular Agents; D010710:Phosphates; D026941:Sodium Channel Blockers; D017923:Sodium-Hydrogen Exchangers; D045304:Cytochromes c; D012964:Sodium; D004110:Diltiazem; D002118:Calcium