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

European Journal of Pharmacology
Lei HuangYasuhiro Shimada

Abstract

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.

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Citations

Apr 9, 2010·Clinical and Experimental Pharmacology & Physiology·Chong-Feng BaiMing-Gao Zhao
Mar 5, 2011·Biological & Pharmaceutical Bulletin·Kumiko Mitsui-SaitohYoshiaki Takaya
May 3, 2014·Biological & Pharmaceutical Bulletin·Tatsuya MutoYoshihiro Hotta
Jun 28, 2007·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Sabzali Javadov, Morris Karmazyn

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