The purpose of this proposal is to determine the mechanism by which volatile anesthetics affect cerebrovascular control. We will test the hypothesis that volatile anesthetics causes cerebral vasodilation by interfering with cerebral vasoconstriction mediated by an alpha2-adrenoreceptor linked by G protein to cyclic AMP. In project 1, we will test the hypothesis that alpha2 receptors located in or adjacent to the cerebrospinal fluid space affect global cerebral blood flow during volatile anesthesia. We will compare injection at different intrathecal locations with intravenous injection of an alpha2 agonist, compare distribution of a radiolabelled alpha2 agonist with regional cerebrovascular changes, and assess cerebrovascular effects of a specific alpha2 antagonist during volatile anesthesia. In project 2, we will test the hypothesis that alpha2 receptor action requires a G protein for transduction to a cAMP effector. We will assess blockade of G protein function (pertussis toxin pretreatment) and direct manipulation of cAMP levels (forskolin ) on cerebral blood flow during volatile anesthesia and on the effect of an alpha2 agonist administered during volatile anesthesia. In project 3, we will test the hypothesis that alpha2 receptor stimulation during volatile anesthesia affects cerebrovascular responsivity. We will assess cerebrovascular responsivity to perfusion pressure and blood gas changes before and after administration of a highly specific alpha2 agonist during volatile anesthesia. In project 4, we will test the hypothesis that pial arterioles respond directly to an alpha2 agonist, alpha2 antagonist, forskolin and pertussis toxin, and thereby differentiate central neurogenic alpha2 mechanisms versus direct vascular alpha2 adrenergic mechanisms. This proposal will improve understanding of the mechanism of cerebrovascular control during volatile anesthesia and will allow prediction of interactions with drugs and diseases which alter alpha2-- adrenoreceptor or G protein function.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM046764-02
Application #
3306219
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1992-02-01
Project End
1996-01-31
Budget Start
1993-02-01
Budget End
1994-01-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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McPherson, R W; Koehler, R C; Kirsch, J R et al. (1997) Intraventricular dexmedetomidine decreases cerebral blood flow during normoxia and hypoxia in dogs. Anesth Analg 84:139-47
McPherson, R W; Kirsch, J R; Ghaly, R F et al. (1995) Effect of nitric oxide synthase inhibition on the cerebral vascular response to hypercapnia in primates. Stroke 26:682-7
McPherson, R W; Kirsch, J R; Tobin, J R et al. (1994) Cerebral blood flow in primates is increased by isoflurane over time and is decreased by nitric oxide synthase inhibition. Anesthesiology 80:1320-7
Sturaitis, M K; Moore, L E; Kirsch, J R et al. (1994) A cholinergic agonist induces cerebral hyperemia in isoflurane- but not pentobarbital-anesthetized dogs. Anesth Analg 78:876-83
McPherson, R W; Koehler, R C; Traystman, R J (1994) Hypoxia, alpha 2-adrenergic, and nitric oxide-dependent interactions on canine cerebral blood flow. Am J Physiol 266:H476-82
Fale, A; Kirsch, J R; McPherson, R W (1994) Alpha 2-adrenergic agonist effects on normocapnic and hypercapnic cerebral blood flow in the dog are anesthetic dependent. Anesth Analg 79:892-8
McPherson, R W; Kirsch, J R; Traystman, R J (1994) Inhibition of nitric oxide synthase does not affect alpha 2-adrenergic-mediated cerebral vasoconstriction. Anesth Analg 78:67-72
McPherson, R W; Kirsch, J R; Moore, L E et al. (1993) N omega-nitro-L-arginine methyl ester prevents cerebral hyperemia by inhaled anesthetics in dogs. Anesth Analg 77:891-7