PMID- 22938512
OWN - NLM
STAT- MEDLINE
DCOM- 20130124
LR  - 20211021
IS  - 1470-8736 (Electronic)
IS  - 0143-5221 (Print)
IS  - 0143-5221 (Linking)
VI  - 124
IP  - 5
DP  - 2013 Mar
TI  - Introgression of Brown Norway CYP4A genes on to the Dahl salt-sensitive 
      background restores vascular function in SS-5(BN) consomic rats.
PG  - 333-42
LID - 10.1042/CS20120232 [doi]
AB  - The present study tested the hypothesis that the Dahl SS (salt-sensitive) rat has 
      vascular dysfunction due, in part, to the up-regulation of the CYP4A/20-HETE 
      (cytochrome P450 omega-hydroxylase 4A)/20-hydroxyeicosatetraenoic acid) system. To 
      assess the role of vascular 20-HETE, SS rats were compared with SS-5(BN) consomic 
      rats, carrying CYP4A alleles on chromosome 5 from the normotensive BN (Brown 
      Norway) introgressed on to the SS genetic background. Cerebral arteries from 
      SS-5(BN) rats had less CYP4A protein than arteries from SS rats fed either NS 
      (normal-salt, 0.4% NaCl) or HS (high-salt, 4.0% NaCl) diet. ACh 
      (acetylcholine)-induced dilation of MCAs (middle cerebral arteries) from SS and 
      SS-5(BN) rats was present in SS-5(BN) rats fed on either an NS or HS diet, but 
      absent in SS rats. In SS rats fed on either diet, ACh-induced dilation was 
      restored by acute treatment with the CYP4A inhibitor DDMS 
      (N-methyl-sulfonyl-12,12-dibromododec-11-enamide) or the 20-HETE antagonist 
      20-HEDE [20-hydroxyeicosa-6(Z),15(Z)-dienoic acid]. The restored response to ACh 
      in DDMS-treated SS rats was inhibited by L-NAME (N(G)nitro-L-arginine methyl 
      ester) and unaffected by indomethacin or MS-PPOH 
      [N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide]. Vascular relaxation 
      responses to the NO donor C(5)FeN(6)Na(2)O were intact in both SS and SS-5(BN) 
      rats and unaffected by the acute addition of DDMS, indicating that the vascular 
      dysfunction of the SS rat is due to a reduced bioavailability of NO instead of 
      failure of the VSMCs (vascular smooth muscle cells) to respond to the 
      vasodilator. Superoxide levels in cerebral arteries of SS-5(BN) rats [evaluated 
      semi-quantitatively by DHE (dihydroethidium) fluorescence] were lower than those 
      in the arteries of SS rats. These findings indicate that SS rats have an 
      up-regulation of the CYP4A/20-HETE pathway resulting in elevated ROS (reactive 
      oxygen species) and reduced NO bioavailability causing vascular dysfunction.
FAU - Lukaszewicz, Kathleen M
AU  - Lukaszewicz KM
AD  - Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
FAU - Falck, John R
AU  - Falck JR
FAU - Manthati, Vijaya L
AU  - Manthati VL
FAU - Lombard, Julian H
AU  - Lombard JH
LA  - eng
GR  - R01 HL065289/HL/NHLBI NIH HHS/United States
GR  - T32 HL007852/HL/NHLBI NIH HHS/United States
GR  - HL92026/HL/NHLBI NIH HHS/United States
GR  - HL72920/HL/NHLBI NIH HHS/United States
GR  - P01 DK038226/DK/NIDDK NIH HHS/United States
GR  - HL65289/HL/NHLBI NIH HHS/United States
GR  - GM31278/GM/NIGMS NIH HHS/United States
GR  - DK38226/DK/NIDDK NIH HHS/United States
GR  - R01 GM031278/GM/NIGMS NIH HHS/United States
GR  - R56 HL065289/HL/NHLBI NIH HHS/United States
GR  - R01 HL092026/HL/NHLBI NIH HHS/United States
GR  - R01 HL072920/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Clin Sci (Lond)
JT  - Clinical science (London, England : 1979)
JID - 7905731
RN  - 0 (Hydroxyeicosatetraenoic Acids)
RN  - 0 (Reactive Oxygen Species)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 79551-86-3 (20-hydroxy-5,8,11,14-eicosatetraenoic acid)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 1.14.13.39 (Nos3 protein, rat)
RN  - EC 1.14.15.3 (Cytochrome P-450 CYP4A)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
SB  - IM
MH  - Animals
MH  - Blood Pressure/physiology
MH  - Cerebral Arteries/physiology
MH  - Cytochrome P-450 CYP4A/*genetics/*metabolism
MH  - Endothelium, Vascular/metabolism/physiopathology
MH  - Hydroxyeicosatetraenoic Acids/metabolism
MH  - Male
MH  - Muscle, Smooth, Vascular/metabolism/physiopathology
MH  - Nitric Oxide/metabolism
MH  - Nitric Oxide Synthase Type III/metabolism
MH  - Oxidative Stress/*physiology
MH  - Rats
MH  - Rats, Inbred BN
MH  - Rats, Inbred Dahl
MH  - Reactive Oxygen Species/metabolism
MH  - Superoxide Dismutase/metabolism
MH  - Vascular Diseases/*genetics/metabolism/*physiopathology
MH  - Vasodilation/physiology
PMC - PMC3791890
MID - NIHMS516540
COIS- Conflicts of Interest/Disclosure: None
EDAT- 2012/09/04 06:00
MHDA- 2013/01/25 06:00
PMCR- 2013/10/07
CRDT- 2012/09/04 06:00
PHST- 2012/09/04 06:00 [entrez]
PHST- 2012/09/04 06:00 [pubmed]
PHST- 2013/01/25 06:00 [medline]
PHST- 2013/10/07 00:00 [pmc-release]
AID - CS20120232 [pii]
AID - 10.1042/CS20120232 [doi]
PST - ppublish
SO  - Clin Sci (Lond). 2013 Mar;124(5):333-42. doi: 10.1042/CS20120232.