Explanation of the discrepancy between the degree of organic nitrate decomposition, nitrite formation and guanylate cyclase stimulation
Feelisch, Martin, Noack, E. and Schröder, H. (1988) Explanation of the discrepancy between the degree of organic nitrate decomposition, nitrite formation and guanylate cyclase stimulation. European Heart Journal, 9 , supplement A, 57-62. (doi:10.1093/eurheartj/9.suppl_A.57 ). (PMID:2900766).
We continuously studied the quantitative formation of nitric oxide (NO), nitrite and nitrate ions from several organic nitrate esters in the presence of various thiol-containing compounds by spectroscopy and HPLC. The results indicate that there are different pathways of decomposition depending on the chemical nature of the mercaptan tested. The amino acid cysteine is known to function as an essential cofactor for guanylate cyclase activation by organic nitrates in vitro. For comparison we investigated several structural analogues with respect to their nitric oxide or nitrite ion releasing potency. Both were found to represent the main products resulting from nitrate ester breakdown besides the respective alcohols. We found that only those compounds were able to activate the enzyme in the presence of nitroglycerin (GTN) which induce the release of NO as well. On the other hand, nearly all other thiols tested caused an in vitro decomposition of organic nitrates by producing excess nitrite and the corresponding disulfide without the formation of NO. Thus, the decomposition of organic nitrates to nitrite ions does not contribute at all to activation of guanylate cyclase. Our results confirm that the liberation of nitric oxide is the common principle of action for all nitrovasodilators. In addition, our results suggest that the thiol consuming transformation of organic nitrates into nitrite ions (ratio NO/nitrite 1:10) may lead to a depletion of cysteine stores, resulting in a decreased formation of NO and, consequently, in a decrease of guanylate cyclase activation, clinically arising as nitrate tolerance.
|Keywords:||guanylate cyclase, cyclic GMP, organic nitrates, molsidomine, nitric oxide, nitrite, haemoglobin, cysteine|
|Subjects:||R Medicine > R Medicine (General)
R Medicine > RM Therapeutics. Pharmacology
|Divisions:||Faculty of Medicine > Infection, Inflammation and Immunity
|Date Deposited:||17 May 2012 15:17|
|Last Modified:||09 Jan 2013 14:17|
|RDF:||RDF+N-Triples, RDF+N3, RDF+XML, Browse.|
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