title: Impaired myogenic response and autoregulation of cerebral blood flow is rescued in CYP4A1 transgenic Dahl salt-sensitive rat.
abstract: We have reported that a reduction in renal production of 20-HETE contributes to development of hypertension in Dahl salt-sensitive (SS) rats. The present study examined whether 20-HETE production is also reduced in the cerebral vasculature of SS rats and whether this impairs the myogenic response and autoregulation of cerebral blood flow (CBF). The production of 20-HETE, the myogenic response of middle cerebral arteries (MCA), and autoregulation of CBF were compared in SS, SS-5(BN) rats and a newly generated CYP4A1 transgenic rat. 20-HETE production was 6-fold higher in cerebral arteries of CYP4A1 and SS-5(BN) than in SS rats. The diameter of the MCA decreased to 70 ± 3% to 65 ± 6% in CYP4A1 and SS-5(BN) rats when pressure was increased from 40 to 140 mmHg. In contrast, the myogenic response of MCA isolated from SS rats did not constrict. Administration of a 20-HETE synthesis inhibitor, HET0016, abolished the myogenic response of MCA in CYP4A1 and SS-5(BN) rats but had no effect in SS rats. Autoregulation of CBF was impaired in SS rats compared with CYP4A1 and SS-5(BN) rats. Blood-brain barrier leakage was 5-fold higher in the brain of SS rats than in SS-5(BN) and SS.CYP4A1 rats. These findings indicate that a genetic deficiency in the formation of 20-HETE contributes to an impaired myogenic response in MCA and autoregulation of CBF in SS rats and this may contribute to vascular remodeling and cerebral injury following the onset of hypertension.
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; and.
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Aron M
authors.initials: AM
authors.lastname: Geurts
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; and.
authors.forename: Sydney R
authors.initials: SR
authors.lastname: Murphy
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; and.
authors.forename: Mallikarjuna R
authors.initials: MR
authors.lastname: Pabbidi
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; and rroman@umc.edu.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Roman
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D001812:Blood-Brain Barrier / Q000378:metabolism; D002199:Capillary Permeability; D002560:Cerebrovascular Circulation; D042926:Cytochrome P-450 CYP4A / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005838:Genotype; D006706:Homeostasis; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D006973:Hypertension / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D020768:Middle Cerebral Artery / Q000201:enzymology* / Q000503:physiopathology; D010641:Phenotype; D020303:Rats, Inbred Dahl; D011917:Rats, Inbred Lew; D055647:Rats, Transgenic; D017673:Sodium Chloride, Dietary; D019895:Transposases / Q000235:genetics; D066253:Vascular Remodeling; D014661:Vasoconstriction
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D017673:Sodium Chloride, Dietary; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D042926:Cytochrome P-450 CYP4A; D019895:Transposases; C494471:sleeping beauty transposase, human
keywords: CYP4A; autoregulation of cerebral blood flow; cerebral circulation; middle cerebral artery; myogenic response