Pivotal role of phosphate chain length in vasoconstrictor versus vasodilator actions of adenine dinucleotides in rat mesenteric arteries.
1. The isolated perfused rat mesenteric arterial bed was used to examine the activity of the adenine dinucleotides: beta-nicotinamide adenine dinucleotide (NAD); beta-nicotinamide adenine dinucleotide phosphate (NADP); flavin adenine dinucleotide (FAD); and of the alpha,omega-diadenosine polyphosphates: adenylyl adenosine (AP1A); P1,P2-diadenosine pyrophosphate (AP2A); P1,P3-diadenosine triphosphate (AP3A); P1,P4-diadenosine tetraphosphate (AP4A); P1,P5-diadenosine pentaphosphate (AP5A); P1,P6-diadenosine hexaphosphate (AP6A). Responses were compared with those of ADP, ATP, 2-methylthio-ATP (2-meSATP) and alpha,beta-methylene ATP (alpha,beta-meATP). 2. In basal tone preparations mono- and dinucleotides elicited vasoconstriction with the order of potency: alpha,beta-meATP > or = AP5A > or = AP6A > or = AP4A > or = 2-meSATP >> ATP >> ADP. The dinucleotides NAD, NADP, FAD, AP1A, AP2A and AP3A had no effect. 3. The P2X-purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (30 microM) virtually abolished vasoconstrictor responses to AP4A, AP5A and AP6A. 4. Auto- and cross-desensitization of vasoconstrictor responses to AP4A, AP5A, AP6A, ATP and alpha,beta-meATP were observed. 5. In raised tone preparations nucleotides elicited endothelium-dependent vasodilatation with the order of potency: 2-meSATP = ADP > ATP > AP3A > AP2A > AP1A = NADP = FAD > NAD. The nucleotides AP4A, AP5A, AP6A and alpha,beta-meATP had no vasodilator effects. 6. It is concluded that the alpha,omega-adenine dinucleotides AP4A, AP5A and AP6A elicit vasoconstriction, but not vasodilatation, in the rat mesenteric arterial bed via P2x-purinoceptors. In contrast, the dinucleotides NADP, FAD, AP1A, AP2A and AP3A elicit vasodilatation, but not vasoconstriction, via endothelial P2Y-purinoceptors. 7. It is suggested that there is a crucial relationship between the structure of the alpha,omega-diadenosine polyphosphates and their activity at P2X- and P2Y-purinoceptors with a pivotal role played by the polyphosphate chain. Molecules with four or more phosphates are vasoconstrictors, while those with three or less phosphates are vasodilators.
Ralevic
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V
Department of Anatomy and Developmental Biology, University College London, UK.
Hoyle
C H
CH
Burnstock
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D000227:Adenine Nucleotides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D010710:Phosphates / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D000227:Adenine Nucleotides; D010710:Phosphates; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents