title: P2u receptor-mediated release of endothelium-derived relaxing factor/nitric oxide and endothelium-derived hyperpolarizing factor from cerebrovascular endothelium in rats.
abstract: OBJECTIVE
  Stimulation of P2u purinoceptors by UTP on endothelium dilates the rat middle cerebral artery (MCA) through the release of endothelium-derived relaxing factor/nitric oxide (EDRF/NO) and an unknown relaxing factor. The purpose of this study was to determine whether this unknown relaxing factor is endothelium-derived hyperpolarizing factor (EDHF).
  
  
  METHODS
  Rat MCAs were isolated, cannulated, pressurized, and luminally perfused. UTP was added to the luminal perfusate to elicit dilations.
  
  
  RESULTS
  Resting outside diameter of the MCAs in one study was 209+/-7 micrometer (n=10). The MCAs showed concentration-dependent dilations with UTP administration. Inhibition of NO synthase with NG-nitro-L-arginine methyl ester (L-NAME) (1 micromol/L to 1 mmol/L) did not diminish the maximum response to UTP but did shift the concentration-response curve to the right. Scavenging NO with hemoglobin (1 or 10 micromol/L) or inhibition of guanylate cyclase with ODQ (1 or 10 micromol/L) had effects on the UTP-mediated dilations similar to those of L-NAME. In the presence of L-NAME, dilations induced by 10 micromol/L UTP were accompanied by 13+/-2 mV (P<0.009) hyperpolarization of the vascular smooth muscle membrane potential (-28+/-2 to -41+/-1 mV). Iberiotoxin (100 nmol/L), blocker of the large-conductance calcium-activated K channels, sometimes blocked the dilation, but its effects were variable. Charybdotoxin (100 nmol/L), also a blocker of the large-conductance calcium-activated K channels, abolished the L-NAME-insensitive component of the dilation to UTP.
  
  
  CONCLUSIONS
  Stimulation of P2u purinoceptors on the endothelium of the rat MCA released EDHF, in addition to EDRF/NO, and dilated the rat MCA by opening an atypical calcium-activated K channel.
authors.affiliation: Department of Anesthesiology, Graduate Program in Cardiovascular Sciences of the DeBakey Heart Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: J
authors.initials: J
authors.lastname: You
authors.forename: T D
authors.initials: TD
authors.lastname: Johnson
authors.forename: S P
authors.initials: SP
authors.lastname: Marrelli
authors.forename: J V
authors.initials: JV
authors.lastname: Mombouli
authors.forename: R M
authors.initials: RM
authors.lastname: Bryan
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D017609:Barium Compounds / Q000494:pharmacology; D002536:Cerebral Arteries / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000502:physiology; D018999:Charybdotoxin / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058473:Receptors, Purinergic P2Y2; D019789:Tetraethylammonium / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D017609:Barium Compounds; D002712:Chlorides; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D010069:Oxadiazoles; C546387:P2ry2 protein, rat; D010455:Peptides; D015221:Potassium Channels; D011810:Quinoxalines; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; C024986:barium chloride; D018999:Charybdotoxin; D001030:Apamin; D009569:Nitric Oxide; D019789:Tetraethylammonium; D011189:Potassium Chloride; C064719:iberiotoxin; D015761:4-Aminopyridine; D005905:Glyburide; D014544:Uridine Triphosphate; D019331:NG-Nitroarginine Methyl Ester