title: The dose-related effects of nitric oxide synthase inhibition on cerebral blood flow during isoflurane and pentobarbital anesthesia.
abstract: BACKGROUND
  Recent work in animals suggests that nitric oxide may play a role in the cerebral blood flow (CBF) changes produced by anesthetics, particularly the vasodilation seen with volatile anesthetics. It is not clear, however, whether nitric oxide causes the flow increase or simply plays some constitutive role. To distinguish between these possibilities, we studied the dose-related effects of nitric oxide synthase inhibition in rabbits with varying baseline CBFs, produced by anesthesia with isoflurane, low-dose pentobarbital, or high-dose pentobarbital.
  
  
  METHODS
  New Zealand White rabbits were anesthetized with 1 MAC isoflurane, low-dose pentobarbital (50-mg/kg load, 7.5-mg.kg-1.h-1 infusion), or high-dose pentobarbital (50-mg/kg load, 20-mg.kg-1.h-1, deep burst-suppression on the electroencephalogram), and prepared for the measurement of CBF using radioactive microspheres. The confluence of sinuses was also exposed to permit sampling of cerebral venous blood and the determination of cerebral metabolic rate for O2 (CMRO2). Normocapnia and normothermia were maintained throughout. After baseline measurements, animals were sequentially given a cumulative total of 3, 13, and 43 mg/kg intravenous N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase. CBF and CMRO2 were recorded approximately 10 min after each dose.
  
  
  RESULTS
  L-NAME produced a dose-related reduction in CBF in all three anesthetic groups. Statistical examination indicated that the dose response curves were parallel. For example, in isoflurane-anesthetized rabbits, CBF decreased from 77 +/- 19 to 47 +/- 11 ml.100 g-1.min-1 after the 43 mg/kg L-NAME, whereas in high-dose pentobarbital animals, CBF decreased from 42 +/- 15 to 26 +/- 8 ml.100 g-1.min-1 (all values mean +/- SD). Decreases in CMRO2 did not quite achieve significance (P = 0.08), and the CBF/CMRO2 ratio decreased in all animals, suggesting that the CBF reductions were due primarily to direct vasoconstriction. There were no electroencephalographic changes. In separate groups of isoflurane-anesthetized rabbits given 3 mg/kg L-NAME, treatment with 300 mg/kg L-arginine partially reversed the decreases in CBF. By contrast, the effects of 43 mg/kg L-NAME were not reversible with 430 mg/kg L-arginine.
  
  
  CONCLUSIONS
  Although L-NAME reduced CBF in all three anesthetic conditions, it did not alter the relative differences among them: CBF in the presence of isoflurane remained much higher than that seen with the barbiturates. This suggests that nitric oxide may not the primary mediator of anesthetic CBF effects, but rather acts to influence background vascular tone in these anesthetized animals.
authors.affiliation: Department of Anesthesia, University of Iowa College of Medicine, Iowa City 52242.
authors.forename: M M
authors.initials: MM
authors.lastname: Todd
authors.forename: B
authors.initials: B
authors.lastname: Wu
authors.forename: D S
authors.initials: DS
authors.lastname: Warner
authors.forename: M
authors.initials: M
authors.lastname: Maktabi
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000768:Anesthesia, General; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002245:Carbon Dioxide / Q000097:blood; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption / Q000187:drug effects; D010313:Partial Pressure; D010424:Pentobarbital / Q000494:pharmacology*; D011817:Rabbits
chemical_list: D002245:Carbon Dioxide; D001120:Arginine; D007530:Isoflurane; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D010424:Pentobarbital; D010100:Oxygen; D019331:NG-Nitroarginine Methyl Ester