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 (AP(1)A); P-1,P-2-diadenosine pyrophosphate (AP(2)A); P-1,P-3-diadenosine triphosphate (AP(3)A); P-1,P-4-diadenosine tetraphosphate (AP(4)A); P-1,P-5-diadenosine pentaphosphate (AP(5)A); P-1,P-6-diadenosine hexaphosphate (AP(6)A). 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 greater than or equal to AP(5)A greater than or equal to AP(6)A greater than or equal to AP(4)A greater than or equal to 2-meSATP much greater than ATP much greater than ADP. The dinucleotides NAD, NADP, FAD, AP(1)A, AP(2)A and AP(3)A had no effect. 3. The P-2X-purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (30 mu M) virtually abolished vasoconstrictor responses to AP(4)A, AP(5)A and AP(6)A. 4. Auto- and cross-desensitization of vasoconstrictor responses to AP(4)A, AP(5)A, AP(6)A, 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 > AP(3)A > AP(2)A > AP(1)A = NADP = FAD > NAD. The nucleotides AP(4)A, AP(5)A, AP(6)A and alpha,beta-meATP had no vasodilator effects. 6. It is concluded that the alpha,omega-adenine dinucleotides AP(4)A, AP(5)A and AP(6)A elicit vasoconstriction, but not vasodilatation, in the rat mesenteric arterial bed via P-2X-purinoceptors. In contrast, the dinucleotides NADP, FAD, AP(1)A, AP(2)A and AP(3)A elicit vasodilatation, but not vasoconstriction, via endothelial P-2Y-purinoceptors. 7. It is suggested that there is a crucial relationship between the structure of the alpha,omega-diadenosine polyphosphates and their activity at P-2X- and P-2Y-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.