Protective effects of sarpogrelate, a 5-HT2A antagonist, against postischemic myocardial dysfunction in guinea-pig hearts.
The protective effects of sarpogrelate (SG), a 5-HT2A antagonist, were investigated in perfused guinea-pig Langendorff hearts subjected to ischemia and reperfusion. Changes in cellular levels of high phosphorous energy, NO and Ca2+ in the heart together with simultaneous recordings of left ventricular developed pressure (LVDP) were monitored using an nitric oxide (NO) electrode, fluorometry and 31P-NMR. The recovery of LVDP from ischemia by reperfusion was 30.1% in the control, while the treatment with SG (5 x 10(-7) M) in pre- and post-ischemia hearts produced a gradual increase to 73.1 and 53.6%, respectively. At the final stage of ischemia, the intracellular concentration of Ca2+ ([Ca2+]i) and release of NO increased with no twitching and remained at a high steady level. The addition of SG increased the transient NO signal (TNO) level at the end of ischemia compared with the control, but [Ca2+]i during ischemia decreased. Meanwhile, mitochondrial Ca2+ uptake on acidification or Ca2+ content changes of the perfusate was suppressed by pre-treatment with SG or the KATP channel opener diazoxide, but not the KATP channel blocker 5-HD. The myocardial NO elevated with 5-HT in normal Langendorff hearts was suppressed by the treatment with SG. Therefore, the existence of the 5HT2A receptor in a Langendorff heart was anticipated. By in vitro EPR, SG was found to directly quench the hydroxy radical. Thus, these findings suggested that the 5-HT2A receptor induced in ischemia-reperfusion plays an important role in the mitochondrial KATP channel of hearts in close relation with NO and active oxygen radicals.
Muto
Tatsuya
T
Department of Pharmacology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
Hotta
Yoshihiro
Y
Miyazeki
Kunihiro
K
Ando
Hiroaki
H
Ishikawa
Naohisa
N
Hasegawa
Takaaki
T
Sugimoto
Yumi
Y
Yamada
Jun
J
Miki
Yasuyoshi
Y
D000818:Animals; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D020013:Calcium Signaling; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D016257:Fura-2 / Q000031:analogs & derivatives / Q000032:analysis; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008929:Mitochondria, Heart / Q000737:chemistry / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism; D010758:Phosphorus / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D013386:Succinates / Q000494:pharmacology / Q000627:therapeutic use*
D002316:Cardiotonic Agents; D016166:Free Radical Scavengers; D005609:Free Radicals; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D013386:Succinates; C049925:fura-2-am; C064294:sarpogrelate; D010758:Phosphorus; D009569:Nitric Oxide; D002118:Calcium; D016257:Fura-2