title: Enhanced inhibition of the EDHF phenomenon by a phenyl methoxyalaninyl phosphoramidate derivative of dideoxyadenosine.
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.
authors.affiliation: Department of Diagnostic Radiology, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN. griffith@cardiff.ac.uk
authors.forename: Tudor M
authors.initials: TM
authors.lastname: Griffith
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chaytor
authors.forename: David H
authors.initials: DH
authors.lastname: Edwards
authors.forename: Felice
authors.initials: F
authors.lastname: Daverio
authors.forename: Christopher
authors.initials: C
authors.lastname: McGuigan
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001685:Biological Factors / Q000037:antagonists & inhibitors* / Q000502:physiology; D016048:Dideoxyadenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007083:Iliac Artery / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D010756:Phosphoric Acids / Q000494:pharmacology*; D011817:Rabbits
chemical_list: D000577:Amides; D001685:Biological Factors; D010756:Phosphoric Acids; C067410:endothelium-dependent hyperpolarization factor; D016048:Dideoxyadenosine; C011067:phosphoramidic acid