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 ORCID: https://orcid.org/0000-0001-8409-710X 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:	28 Oct 2022 08:34
URI:	https://orca.cardiff.ac.uk/id/eprint/71260

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