Aldehyde dehydrogenase-independent bioactivation of nitroglycerin in porcine and bovine blood vessels.
Bottom Line: ALDH2 mRNA expression and the rates of GTN denitration were similarly low, excluding a significant contribution of ALDH2 to the bioactivation of GTN in these vessels.Attempts to identify the responsible pathway with enzyme inhibitors did not provide conclusive evidence for the involvement of ALDH3A1, cytochrome P450, or GSH-S-transferase.If present in the human vasculature, this pathway might contribute to the therapeutic effects of organic nitrates that are not metabolized by ALDH2.
Affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Austria.Show MeSH
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Mentions: Fig. 1 shows the relaxation of porcine (A) and bovine (B) coronary arteries to GTN with EC50 values of 146 ± 14 and 32 ± 7 nM, respectively. Surprisingly, relaxation was not affected by the non-selective ALDH inhibitor chloral hydrate or DPI, which we have recently described as potent ALDH2 inhibitor . Relaxation to GTN of porcine coronary arteries which had been precontracted with 30 mM KCl instead of U-46619 was also insensitive to chloral hydrate (data not shown). Since these results suggested that ALDH2 does not contribute to GTN bioactivation in these vessels, we tested for the potential involvement of endogenous NO  or a pathway unrelated to sGC activation. However, the NO synthase inhibitor l-NNA did not antagonize but even slightly potentiated the effect of GTN (EC50 = 40 ± 8 and 14 ± 4 nM in porcine and bovine vessels, respectively). Complete inhibition of relaxation by the sGC inhibitor ODQ  strongly indicates that activation of sGC by GTN-derived NO or a related species is essentially involved. The direct NO donor DEA/NO caused relaxation of porcine and bovine coronary arteries with EC50 values of 38 ± 4 and 18 ± 4 nM, respectively (panels C and D). Again, chloral hydrate and DPI had no effect, relaxation was slightly potentiated by l-NNA and blocked by ODQ.
Affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Austria.