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Enhanced inhibition of the EDHF phenomenon by a phenyl methoxyalaninyl phosphoramidate derivative of dideoxyadenosine

Griffith, Tudor M., Chaytor, Andrew T., Edwards, David Hughes, Daverio, Felice and McGuigan, Christopher 2004. Enhanced inhibition of the EDHF phenomenon by a phenyl methoxyalaninyl phosphoramidate derivative of dideoxyadenosine. British Journal of Pharmacology 142 (1) , pp. 27-30. 10.1038/sj.bjp.0705782

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Abstract

In rabbit arteries endogenous production of cAMP facilitates electrotonic signalling via gap junctions, thus explaining the ability of P-site inhibitors of adenylyl cyclase to attenuate EDHF-type responses. In the present study, we show that a lipophilic phosphoramidate pronucleotide derivative of dideoxyadenosine, 2′,3′-ddA-PMAPh, exhibits enhanced activity as an inhibitor of EDHF-type smooth muscle hyperpolarizations induced by acetylcholine (ACh) compared to the parent nucleoside 2′,3′-ddA, and that the effects of both compounds can be reversed by the cAMP phosphodiesterase inhibitor IBMX. Neither 2′,3′-ddA nor 2′,3′-ddA-PMAPh depress ACh-evoked endothelial hyperpolarization directly. Modifications in the lipophilicity of dideoxyadenosine and its direct intracellular delivery as a mononucleotide may thus enhance the ability to inhibit adenylyl cyclase and depress electrotonic signalling via myoendothelial gap junctions.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: cAMP; adenylyl cyclase; gap junctions; connexin
Publisher: Nature Publishing Group
ISSN: 0007-1188
Last Modified: 22 Oct 2017 21:22
URI: http://orca-mwe.cf.ac.uk/id/eprint/71260

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