Protective effects of sarpogrelate, a 5-HT2A antagonist, against postischemic myocardial dysfunction in guinea-pig hearts

The protective effects of sarpogrelate (SG), a 5-HT_2A 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 (5×10^-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 (T_NO) 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 K_ATP channel opener diazoxide, but not the K_ATP 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 5HT_2A 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-HT_2A receptor induced in ischemia–reperfusion plays an important role in the mitochondrial K_ATP channel of hearts in close relation with NO and active oxygen radicals.