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.