Relative contribution of P2U- and P2Y-purinoceptors to endothelium-dependent vasodilatation in the golden hamster isolated mesenteric arterial bed.
1. P2-purinoceptors were characterized pharmacologically in the constantly perfused isolated mesenteric arterial vascular bed of the golden hamster. Vasoconstrictor and vasodilator responses to the nucleotides ATP, ADP, 2 methylthio ATP (2MeSATP), alpha,beta-methylene ATP (alpha,beta-meATP) and uridine 5'-triphosphate (UTP) and a role for ATP in sympathetic constriction were examined. 2. At basal tone nucleotides elicited dose-dependent vasoconstriction with an observed rank order of potency of alpha,beta-meATP >> 2MeSATP > ATP = ADP > UTP (based on the doses required to elicit constrictor responses of 25 mmHg). Adenosine had no vasoconstrictor action at doses up to 5 mumol. After application of a single dose (0.5 mumol) of alpha,beta-meATP preparations were desensitized to constriction by subsequent application of nucleotides. 3. Electrical field stimulation (4-64 Hz, 90 V, 1 ms, 30 s) elicited frequency-dependent constrictions which were abolished by guanethidine (5 microM) and by prazosin (1 microM). 4. The non-selective P2-purinoceptor antagonist suramin (100 microM) did not significantly affect vasoconstrictor responses to ATP. The P2X-selective purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 3 microM), virtually abolished responses to ATP. When the endothelium was removed vasoconstrictor responses to ATP and noradrenaline were augmented. 5. In preparations with tone raised with methoxamine (10-80 microM) nucleotides elicited vasodilatation with an observed potency order of ATP = UTP > ADP >> adenosine. 2MeSATP had relatively minor vasodilator effects and at the highest dose tested (50 nmol) elicited only vasoconstriction. alpha,beta-meATP did not elicit vasodilatation but produced further constriction of the raised tone preparation. At the highest doses of ATP and ADP (0.5 microM) responses were biphasic with vasoconstriction preceding vasodilatation. After removal of the endothelium, with the exception of adenosine, vasodilator responses to purines and to UTP were abolished; vasoconstriction to ATP, ADP, UTP and 2MeSATP was evident at the highest doses. 6. Suramin (100 microM) inhibited vasodilatation to both ATP and UTP and abolished responses to 2MeSATP. PPADS (3 microM) inhibited relaxation to 2MeSATP but did not affect relaxation to ATP, UTP, adenosine and acetylcholine and ADP. 7. Reactive blue 2 (30 microM) blocked vasodilator responses to ATP, UTP, 2MeSATP and acetylcholine; it was without effect when used at 3 microM. 8. The results of this study show that ATP elicits vasoconstriction of mesenteric arteries of the golden hamster via P2X-purinoceptors located on the smooth muscle, and vasodilatation via P2U-receptors which are located on the endothelium. 2MeSATP has marginal vasodilator activity, suggesting that P2Y-purinoceptors contribute minimally to relaxation to ATP in hamster mesenteric arteries.
Ralevic
V
V
Department of Anatomy and Developmental Biology, University College London.
Burnstock
G
G
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000502:physiology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D008729:Methoxamine; D009119:Muscle Contraction / Q000187:drug effects; D009129:Muscle Tonus / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000502:physiology*; D013498:Suramin / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D018048:Receptors, Purinergic P2; D014662:Vasoconstrictor Agents; D013498:Suramin; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D008729:Methoxamine; D014544:Uridine Triphosphate