title: Spreading dilatation to luminal perfusion of ATP and UTP in rat isolated small mesenteric arteries.
abstract: Levels of ATP achieved within the lumen of vessels suggest a key autacoid role. P2Y receptors on the endothelium may represent the target for ATP, leading to hyperpolarization and associated relaxation of vascular smooth muscle through the endothelium-dependent hyperpolarizing factor (EDHF) pathway. EDHF signals radially from the endothelium to cause dilatation, and appears mechanistically distinct from the axial spread of dilatation, which we showed occurs independently of a change in endothelial cell Ca2+ in rat mesenteric arteries. Here we have investigated the potential of P2Y receptor stimulation to evoke spreading dilatation in rat resistance small arteries under physiological pressure and flow. Triple cannulation of isolated arteries enables focal application of purine and pyrimidine nucleotides to the endothelium, avoiding potential complicating actions of these agents on the smooth muscle. Nucleotides were locally infused through one branch of a bifurcation, causing near maximal local dilatation attributable to EDHF. Dilatation then spread rapidly into the adjacent feed artery and upstream against the direction of luminal flow, sufficient to increase flow into the feed artery. The rate of decay of this spreading dilatation was identical between nucleotides, and matched that to ACh, which acts only on the endothelium. In contrast, focal abluminal application of either ATP or UTP at the downstream end of cannulated arteries evoked constriction, which only in the case of ATP was also associated with modest spread of dilatation. The non-hydrolysable ADP analogue, ADPbetaS, acting at P2Y1 receptors, caused robust local and spreading dilatation responses whether applied to the luminal or abluminal surface of pressurized arteries. Dilatation to nucleotides was sensitive to inhibition with apamin and TRAM-34, selective blockers of small- and intermediate-conductance Ca2+-activated K+ channels, respectively. These data demonstrate that direct luminal stimulation of P2Y receptor on the endothelium of rat mesenteric arteries leads to marked spreading dilatation and thus suggests that circulating purines and pyrimidines may act as important regulators of blood flow.
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Polly
authors.initials: P
authors.lastname: Winter
authors.forename: Kim A
authors.initials: KA
authors.lastname: Dora
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001685:Biological Factors / Q000378:metabolism; D001783:Blood Flow Velocity; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D017538:Mesenteric Artery, Superior / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010477:Perfusion; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011312:Pressure; D058910:Purinergic P2 Receptor Agonists; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058472:Receptors, Purinergic P2Y1; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D013152:Splanchnic Circulation; D013873:Thionucleotides / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000378:metabolism* / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D001685:Biological Factors; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C546384:P2ry1 protein, rat; D026902:Potassium Channel Blockers; D058910:Purinergic P2 Receptor Agonists; D011720:Pyrazoles; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D051640:Small-Conductance Calcium-Activated Potassium Channels; C411671:TRAM 34; D013873:Thionucleotides; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D001030:Apamin; D009569:Nitric Oxide; C030812:adenosine 5'-O-(2-thiodiphosphate); D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000109:Acetylcholine; D014544:Uridine Triphosphate