Activation of the brain angiotensin system by in vivo human angiotensin-converting enzyme gene transfer in rats.
The possibility of the brain-specific expression of a component of the renin-angiotensin system was evaluated in the present study. We used the hemagglutinating virus of Japan-liposome complex to transfect human angiotensin-converting enzyme (ACE) cDNA, driven by the cytomegalovirus enhancer and beta-actin promoter, into the lateral cerebroventricle of male Sprague-Dawley rats. We evaluated the time course of hemodynamics, the tissue levels of angiotensin (Ang) II and vasopressin, and ACE activity. Intracerebroventricular transfection of the human ACE gene increased both blood pressure and heart rate. Transfected rats exhibited higher concentrations of brain Ang II and increased brain ACE activity. This activation of the brain angiotensin system was accompanied by increased vasopressin production. The increases in blood pressure and heart rate were abolished by intracerebroventricular administration of an ACE inhibitor or Ang II type 1 receptor antagonist. The expression of the transgene was widely distributed in the periventricular cell layer, the cortex, the hypothalamic nuclei, and the brain stem. Expression in the neuronal cells persisted for up to 14 days. Thus, this hemagglutinating virus of Japan-liposome method is a highly efficient system for gene delivery and is extremely useful for functional gene transfection. This novel hypertensive model may enable characterization of the functions of the renin-angiotensin system in the brain and determination of its role in the pathogenesis of hypertension.
Nakamura
S
S
Department of Geriatric Medicine, Osaka University Medical School, Suita, Osaka, Japan.
Moriguchi
A
A
Morishita
R
R
Yamada
K
K
Nishii
T
T
Tomita
N
N
Ohishi
M
M
Kaneda
Y
Y
Higaki
J
J
Ogihara
T
T
D000804:Angiotensin II / Q000097:blood / Q000378:metabolism / Q000502:physiology; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D003627:Data Interpretation, Statistical; D018014:Gene Transfer Techniques; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D008969:Molecular Sequence Data; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection / Q000379:methods; D019076:Transgenes
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D012333:RNA, Messenger; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A