title: Hypersensitivity to thromboxane receptor mediated cerebral vasomotion and CBF oscillations during acute NO-deficiency in rats.
abstract: BACKGROUND
  Low frequency (4-12 cpm) spontaneous fluctuations of the cerebrovascular tone (vasomotion) and oscillations of the cerebral blood flow (CBF) have been reported in diseases associated with endothelial dysfunction. Since endothelium-derived nitric oxide (NO) suppresses constitutively the release and vascular effects of thromboxane A(2) (TXA(2)), NO-deficiency is often associated with activation of thromboxane receptors (TP). In the present study we hypothesized that in the absence of NO, overactivation of the TP-receptor mediated cerebrovascular signaling pathway contributes to the development of vasomotion and CBF oscillations.
  
  
  RESULTS
  Effects of pharmacological modulation of TP-receptor activation and its downstream signaling pathway have been investigated on CBF oscillations (measured by laser-Doppler flowmetry in anesthetized rats) and vasomotion (measured by isometric tension recording in isolated rat middle cerebral arteries, MCAs) both under physiological conditions and after acute inhibition of NO synthesis. Administration of the TP-receptor agonist U-46619 (1 µg/kg i.v.) to control animals failed to induce any changes of the systemic or cerebral circulatory parameters. Inhibition of the NO synthesis by nitro-L-arginine methyl ester (L-NAME, 100 mg/kg i.v.) resulted in increased mean arterial blood pressure and a decreased CBF accompanied by appearance of CBF-oscillations with a dominant frequency of 148±2 mHz. U-46619 significantly augmented the CBF-oscillations induced by L-NAME while inhibition of endogenous TXA(2) synthesis by ozagrel (10 mg/kg i.v.) attenuated it. In isolated MCAs U-46619 in a concentration of 100 nM, which induced weak and stable contraction under physiological conditions, evoked sustained vasomotion in the absence of NO, which effect could be completely reversed by inhibition of Rho-kinase by 10 µM Y-27632.
  
  
  CONCLUSIONS
  These results suggest that hypersensitivity of the TP-receptor-Rho-kinase signaling pathway contributes to the development of low frequency cerebral vasomotion which may propagate to vasospasm in pathophysiological states associated with NO-deficiency.
authors.affiliation: Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary. bela.horvath@nih.gov
authors.forename: Béla
authors.initials: B
authors.lastname: Horváth
authors.forename: Gábor
authors.initials: G
authors.lastname: Lenzsér
authors.forename: Balázs
authors.initials: B
authors.lastname: Benyó
authors.forename: Tamás
authors.initials: T
authors.lastname: Németh
authors.forename: Rita
authors.initials: R
authors.lastname: Benko
authors.forename: András
authors.initials: A
authors.lastname: Iring
authors.forename: Péter
authors.initials: P
authors.lastname: Hermán
authors.forename: Katalin
authors.initials: K
authors.lastname: Komjáti
authors.forename: Zsombor
authors.initials: Z
authors.lastname: Lacza
authors.forename: Péter
authors.initials: P
authors.lastname: Sándor
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Benyó
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006967:Hypersensitivity; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008297:Male; D020768:Middle Cerebral Artery / Q000473:pathology; D009038:Motion; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000172:deficiency / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000378:metabolism*; D015398:Signal Transduction; D013928:Thromboxane A2 / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D004791:Enzyme Inhibitors; D017482:Receptors, Thromboxane; D009569:Nitric Oxide; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D054460:rho-Associated Kinases; D019331:NG-Nitroarginine Methyl Ester