Discovery of Efficient Hypoxia-Targeted NO Donor Compounds to Alleviate Hypoxia Cardiac Disease.

In order to obtain efficient NO donor drugs to treat hypoxic cardiac disease, a series of hypoxia-targeted NO donor compounds were prepared and screened. Among them, a representative compound H3 was found to selectively release NO under hypoxia with a higher ratio than isosorbide dinitrate (ISDN). In vitro study indicated that H3 had a strong capability of alleviating vascular dilation and reducing myocardial hypoxic injury due to its effective regulation of vascular dilatation and myocardial injury-related proteins in H9c2 cells even at low concentrations. By intraperitoneal injection or intragastric administration, in vivo animal tests revealed that H3 possessed a potent antimyocardial hypoxic injury effect superior to ISDN. These findings suggest that H3 has a better effect on alleviating hypoxic cardiac disease than the conventional drug, owing to its hypoxia-targeted release of NO.

A hypoxia-activated NO donor for the treatment of myocardial hypoxia injury.

As present NO donor drugs cannot localize to release NO at the hypoxic site, along with the short half-life and bidirectional regulation of NO, they are unable to overcome low bioavailability and side effects in the treatment of myocardial hypoxia injury. In this study, we designed and prepared a novel hypoxia-activated NO donor (Hano) by hybridization of a known NO donor compound (Nno) with a hypoxia-activated group. Hano and isosorbide dinitrate were compared in terms of NO release and anti-myocardial hypoxia injury. Furthermore, the effects of Hano and Nno on releasing NO, dilating blood vessels, and preventing myocardial hypoxia injury were studied and compared in smooth muscle cells, cardiomyocytes and mice. The results showed that the NO release by Hano increased either in smooth muscle cells or in myocardial cells under hypoxia conditions. Significantly, Hano was found capable of dilating blood vessels and attenuating hypoxia injury both in vitro and in vivo, and has great potential as a hypoxia-activated NO donor drug to treat hypoxic heart diseases.