Chest pain is the major symptom of patients with coronary heart disease. Agents that release nitric oxide (NO) within the body can help to treat such angina pectoris attacks because NO dilates arteries thereby improving blood circulation. To date, NO release from nitrovasodilators like glyceryltrinitrate is not fully understood.
Pharmacologists in Bochum and Graz gained new insights into this process by analyzing the enzyme responsible for NO release. The results of this study have been published in the Journal of Biological Chemistry.
The reaction causing bioactivation is not well understood
So-called nitrovasodilators such as nitroglycerin have been used effectively in the treatment of angina pectoris in coronary heart disease for more than century. Within the human body, nitric oxide (NO) is released from the nitroglycerin and in turn stimulates an enzyme that dilates the arteries and thus improves blood circulation. In 1998, Robert F. Furchgott, Ferid Murad and Louis Ignarro were awarded the Nobel Prize for Medicine for their discoveries that nitric oxide is not only released from drugs but is being produced endogenously in the body and has an important function as a signalling molecule in the cardiovascular system.
The molecular mechanism of NO release
The positive effect of nitrovasodilators entirely depends on the release of NO or chemically related molecules within the vascular smooth muscle cells, the so called bioactivation. In 2002, Stamler and coworkers were able to identify mitochondrial aldehyde dehydrogenase-2 (ALDH2) as the enzyme responsible for bioactivation of nitroglycerin. ALDH2 is also involved in the decomposition of toxic metabolites of alcohol.
Researchers from Bochum and Graz investigated the ALDH2-catalyzed bioactivation of nitroglycerin by exchanging amino acids to identify residues essential for NO release, thereby gaining insight into the catalyzed reaction. Dr. Michael Russwurm pointed out that a better understanding of bioactivation of nitrovasodilators at the molecular level is not only important for the therapeutic use of known NO donors, but also for the possible development of new NO-releasing agents. E.g. an altered bioactivation could reduce the well-known phenomenon of tolerance, i.e. the loss in efficacy of nitrovasodilators.
- Wenzl et al. Role of the General Base Glu-268 in Nitroglycerin Bioactivation and Superoxide Formation by Aldehyde Dehydrogenase-2. Journal of Biological Chemistry, 2009; 284 (30): 19878 DOI: 10.1074/jbc.M109.005652
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