title: Agonist-specific differences in mechanisms mediating eNOS-dependent pial arteriolar dilation in rats.
abstract: Nitric oxide (NO), derived from the endothelial isoform of NO synthase (eNOS), is a vital mediator of cerebral vasodilation. In the present study, we addressed the issue of whether the mechanisms responsible for agonist-induced eNOS activation differ according to the specific receptor being stimulated. Thus we examined whether heat shock protein 90 (HSP90), phosphatidylinositol-3-kinase (PI3K), and tyrosine kinase participate in ACh- versus ADP-induced eNOS activation in cerebral arterioles in vivo. Pial arteriolar diameter changes in anesthetized male rats were measured during sequential applications of ACh and ADP in the absence and presence of the nonselective NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME), the neuronal NOS (nNOS)-selective inhibitor ARR-17477, the HSP90 blocker 17-(allylamino)-17-demethoxygeldanamycin (AAG), the PI3K inhibitor wortmannin (Wort), or the tyrosine kinase blocker tyrphostin 47 (T-47). Only NOS inhibition with L-NAME (not ARR-17477) reduced ACh and ADP responses (by 65-75%), which suggests that all of the NO dependence in the vasodilating actions of those agonists derived from eNOS. Suffusions of AAG, Wort, and T-47 were accompanied by substantial reductions in ACh-induced dilations but no changes in the responses to ADP. These findings suggest that muscarinic (ACh) and purinergic (ADP) receptor-mediated eNOS activation in cerebral arterioles involve distinctly different signal transduction pathways.
authors.affiliation: Neuroanesthesia Research Laboratory, University of Illinois at Chicago, MBRB (M/C 513), 900 South Ashland Ave., Chicago, IL 60607, USA.
authors.forename: H-L
authors.initials: HL
authors.lastname: Xu
authors.forename: D L
authors.initials: DL
authors.lastname: Feinstein
authors.forename: R A
authors.initials: RA
authors.lastname: Santizo
authors.forename: H M
authors.initials: HM
authors.lastname: Koenig
authors.forename: D A
authors.initials: DA
authors.lastname: Pelligrino
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology*; D001794:Blood Pressure; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010841:Pia Mater / Q000098:blood supply*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D058913:Purinergic Agonists; D051381:Rats; D014664:Vasodilation / Q000502:physiology*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D058913:Purinergic Agonists; D000244:Adenosine Diphosphate; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D000077191:Wortmannin