Comparison of P2 receptor subtypes producing dilation in rat intracerebral arterioles.
OBJECTIVE
P2 receptors are important regulators of cerebrovascular tone. However, there is functional heterogeneity of P2Y receptors along the vascular tree, and the functionality of P2Y receptors in small arterioles has not been studied in detail. We investigated the effects of activating P2Y1 and P2Y2 receptors and their underlying dilator mechanisms in rat intracerebral arterioles.


METHODS
We used computer-aided videomicroscopy to measure diameter responses from isolated and pressurized rat penetrating arterioles (39.9+/-1.2 microm) to the natural P2 receptor agonist ATP in addition to ADP-beta-S (P2Y1-selective) and ATP-gamma-S (P2Y2-selective) and inhibitors of signaling pathways.


RESULTS
Extraluminal application of ATP-gamma-S and ADP-beta-S initiated a biphasic response (initial constriction followed by the secondary dilation) similar to ATP-induced responses. Pyridoxal phosphate-6-azophenyl-2',4'-disulphonic acid (0.1 mmol/L; a P2Y1 receptor antagonist) blocked ADP-beta-S- but not ATP-gamma-S-induced dilation and affected the ATP-mediated dilation at low concentrations. Nomega-Monomethyl-l-arginine partially inhibited the dilation of ATP and ADP-beta-S but not ATP-gamma-S. High K+ saline suppressed the dilation of all agonists. Indomethacin had no effect.


CONCLUSIONS
Both P2Y1 and P2Y2 receptors are functionally present in cerebral arterioles. ATP stimulates P2Y1 receptors at low concentrations, while high concentrations of ATP activate P2Y2 in addition to P2Y1 receptors. Nitric oxide is involved in P2Y1 but not P2Y2 receptor activation. Potassium channels play an important role in the regulation of P2Y receptor-mediated dilation.
Department of Neurosurgery, Washington University School of Medicine, Box 8057, 660 S Euclid Ave, St Louis, Mo 63110, USA.
Tetsuyoshi
T
Horiuchi
Hans H
HH
Dietrich
Kazuhiro
K
Hongo
Ralph G
RG
Dacey
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000098:blood supply*; D002560:Cerebrovascular Circulation / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D018715:Microscopy, Video; D009569:Nitric Oxide / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2; D013873:Thionucleotides / Q000494:pharmacology; D014654:Vascular Patency / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; C546384:P2ry1 protein, rat; C546387:P2ry2 protein, rat; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2; D013873:Thionucleotides; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C030812:adenosine 5'-O-(2-thiodiphosphate); C022571:adenosine 5'-O-(3-thiotriphosphate); D011732:Pyridoxal Phosphate; D000244:Adenosine Diphosphate; D011189:Potassium Chloride; D000255:Adenosine Triphosphate; D007213:Indomethacin