1P223 Protective effects of 5-HT antagonists, against postischemic nryocardial dysfunction in guinea pig hearts

We reported that sarpogrelate (SG), a 5-HT2A antagonist, has a beneficial effect against ischemia-reperfusion injury (Jpn.J.Pharmacol.2001). In the present experiment, the effects of (±)-pyrapyridolol (PY), a new 5-HT1A antagonist(Yamada et al.,Pharmacol.Rev.Comm.2002), against ischemia-reperfusion injury were investigated in perfused Langendorff guinea pig hearts. NO electrode, fluorometry and 31P-NMR were used to monitor changes in the cellular high phosphorous energy and NO and Ca2. content in the heart, together with simultaneous recordings of LVDP. The recovery rate of LVDP from ischemia by reperfusion was 30.1% in the control experiments, while in the presence of PY (5xl0-8M) a gradual increase to 78.2% was observed (SG 5x10^-7M: 73.1%). In nonischemic hearts, 5-HT IA or 2Aagonist (10^-6M-10^-4M) increased the basal level of transient NO in a manner similar to administration of 5HT (10^-6M-10^-4M), with increases in the diastolic level of transient Ca2+ signals. The NO increases induced by 5HT were reduced by SG or PY. Thus, these findings suggested that 5HTIA and 2Areceptors induced during ischemia and reperfusion might play an important role in injured hearts in close relation to NO.