Different effects of optical isomers of the 5-HT1A receptor antagonist pyrapyridolol against postischemic guinea-pig myocardial dysfunction and apoptosis through the mitochondrial permeability transition pore.
The recovery (%) of the left ventricular developed pressure by (S)-(-)-pyrapyridolol (5 x 10(-8) M) (90.7%), an optical isomer of a new 5-HT1A receptor antagonist, was greater than that by (R)-(+)-pyrapyridolol (66.2%, control: 34.4%) against ischemia-reperfusion injury in perfused Langendorff guinea-pig hearts. In the perfused mitochondrial preparation, (S)-(-)-pyrapyridolol inhibited the mitochondrial Ca2+ (Cam) elevation that was brought about by the change of Ca2+ content or pH of perfusate, similar to findings with cyclosporin A, well known to be an inhibitor of the mitochondrial permeability transition pore (MPTP). The mitochondrial K(ATP) channel opener, diazoxide, also inhibited the Cam elevation, but the mitochondrial K(ATP) channel antagonist, 5-hydroxydecanoic acid, attenuated it. There were significantly fewer numbers of TUNEL-positive cells in these (S)-(-)-pyrapyridolol-treated hearts than the control or (R)-(+)-pyrapyridolol, with decreases of the caspase-3 activity. Therefore, these results suggest that (S)-(-)-pyrapyridolol likely inhibits the opening of the MPTP by preventing the Cam overload induced apoptosis related to endogenous 5-HT accumulation in ischemia-reperfusion hearts.
Huang
Lei
L
Department of Anesthesiology, Nagoya University School of Medicine, Nagoya, Aichi 466-8550, Japan.
Hotta
Yoshihiro
Y
Miyazeki
Kunihiro
K
Ishikawa
Naohisa
N
Miki
Yasuyoshi
Y
Sugimoto
Yumi
Y
Yamada
Jun
J
Nakano
Akinobu
A
Hishiwaki
Kimitoshi
K
Shimada
Yasuhiro
Y
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013237:Stereoisomerism; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017725:Ventricular Pressure / Q000187:drug effects
D002227:Carbazoles; D016166:Free Radical Scavengers; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; C510716:pyrapyridolol; D044282:Receptor, Serotonin, 5-HT1A; D009569:Nitric Oxide; D012701:Serotonin; D000255:Adenosine Triphosphate; D002118:Calcium