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Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase

Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase
Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase
Organic nitrates develop their vasodilating potency by stimulating the enzyme guanylate cyclase. There are still several theories concerning the molecular mechanism of enzyme activation, the most likely of which sees nitric oxide (NO.) as the true modulator of the soluble guanylate cyclase. We therefore examined the release of nitric oxide from organic nitrates by means of a difference-spectrophotometric method and found that our results correlated well with the extent of enzyme activation. The more NO. was liberated from the compounds in question, the higher was the enzyme activation observed. When the examined nitrates were used in a concentration which caused a half-maximal enzyme stimulation, the result was a NO. liberation of striking uniformity. This correlation also applied to SIN-1 for which it has been assumed up to now that the intact molecule itself is able to stimulate the enzyme and not the nitric oxide released from it. We found the reaction between organic nitrates and cysteine to be highly dependent on temperature, while the extent of the observed enhancement increased with the number of nitrate groups per molecule. We also studied the potential effects of certain compounds on non-enzymatic NO. release and found that, in addition to methylene blue, thionine and brilliantcresyl blue, but not ferricyanide, were also effective inhibitors. So it seems likely that both an enzymatic and a non-enzymatic mode of inhibition of enzyme activity does exist. Since oxyhemoglobin is an effective scavenger of nitric oxide, its addition can inhibit enzyme activation by nitrovasodilators. Our results stress the important role of the non-enzymatic liberation of NO. from organic nitrates and related compounds as possible, perhaps even as the principal mode of activation of soluble guanylate cyclase by nitrovasodilators.
guanylatecyclase, cyclic gmp, nitrovasodilators, nitricoxide, hemoglobin, methylene blue, cysteine
0014-2999
19-30
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Noack, Eike A.
177a1f42-a3a2-4503-aa97-9b24040736e0
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Noack, Eike A.
177a1f42-a3a2-4503-aa97-9b24040736e0

Feelisch, Martin and Noack, Eike A. (1987) Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase. European Journal of Pharmacology, 139 (1), 19-30. (PMID:2888663)

Record type: Article

Abstract

Organic nitrates develop their vasodilating potency by stimulating the enzyme guanylate cyclase. There are still several theories concerning the molecular mechanism of enzyme activation, the most likely of which sees nitric oxide (NO.) as the true modulator of the soluble guanylate cyclase. We therefore examined the release of nitric oxide from organic nitrates by means of a difference-spectrophotometric method and found that our results correlated well with the extent of enzyme activation. The more NO. was liberated from the compounds in question, the higher was the enzyme activation observed. When the examined nitrates were used in a concentration which caused a half-maximal enzyme stimulation, the result was a NO. liberation of striking uniformity. This correlation also applied to SIN-1 for which it has been assumed up to now that the intact molecule itself is able to stimulate the enzyme and not the nitric oxide released from it. We found the reaction between organic nitrates and cysteine to be highly dependent on temperature, while the extent of the observed enhancement increased with the number of nitrate groups per molecule. We also studied the potential effects of certain compounds on non-enzymatic NO. release and found that, in addition to methylene blue, thionine and brilliantcresyl blue, but not ferricyanide, were also effective inhibitors. So it seems likely that both an enzymatic and a non-enzymatic mode of inhibition of enzyme activity does exist. Since oxyhemoglobin is an effective scavenger of nitric oxide, its addition can inhibit enzyme activation by nitrovasodilators. Our results stress the important role of the non-enzymatic liberation of NO. from organic nitrates and related compounds as possible, perhaps even as the principal mode of activation of soluble guanylate cyclase by nitrovasodilators.

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More information

Published date: 2 July 1987
Keywords: guanylatecyclase, cyclic gmp, nitrovasodilators, nitricoxide, hemoglobin, methylene blue, cysteine
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 337928
URI: https://eprints.soton.ac.uk/id/eprint/337928
ISSN: 0014-2999
PURE UUID: 56b913fe-5cdc-4bfd-9d6a-9bbd051bf7f4
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 08 May 2012 15:08
Last modified: 06 Jun 2018 12:29

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