GW3965, a synthetic liver X receptor (LXR) agonist, reduces angiotensin II-mediated pressor responses in Sprague-Dawley rats.
OBJECTIVE
Liver X receptors (LXRs) activate genes that regulate lipid and cholesterol metabolism. LXR agonists were shown recently to also increase murine renin gene expression in vivo. To further examine a link between lipid metabolism, the renin-angiotensin-aldosterone-system and blood pressure regulation, we investigated the effect of a LXR agonist (GW3965) on angiotensin II (Ang II)-mediated vasoreactivity and vascular angiotensin II receptor (ATR) gene expression.


METHODS
Arterial blood pressure (BP) was measured during Ang II infusions (1.5 min duration; 0.001-3 microg kg(-1)) in pentobarbital-anesthetized male Sprague-Dawley rats (n = 6-9) after oral administration of GW3965 (10 mg kg(-1), q.d.) or vehicle for 7 - 15 days. Mesenteric arteries and plasma were collected to analyze ATR gene expression and to measure plasma renin activity (PRA) and lipid profile, respectively.


RESULTS
Basal mean arterial pressure (MAP) was similar between groups. GW3965 dosing blunted the vasopressor effect of Ang II, which was significantly different with the 0.3 and 3 microg kg(-1) doses. No difference in heart rate, PRA or lipid profile was observed between groups. A time-course indicated that ATR type 1 and 2 gene expression of GW3965-treated vs. vehicle-treated rats decreased by 50%, reaching significance for ATR type 2, but not for ATR type 1, at time-points coinciding with BP measurements.


CONCLUSIONS
GW3965 decreased Ang II-mediated vasopressor responses coincident with a trend toward reduced ATR gene expression, suggesting that LXR agonists could affect vascular reactivity.
Leik
C E
CE
Cardiovascular and Metabolic Disease Research, Wyeth Research, Collegeville, PA 19426, USA.
Carson
N L
NL
Hennan
J K
JK
Basso
M D
MD
Liu
Q-Y
QY
Crandall
D L
DL
Nambi
P
P
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D008055:Lipids / Q000097:blood; D000071518:Liver X Receptors; D008297:Male; D057093:Orphan Nuclear Receptors; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000502:physiology; D012083:Renin / Q000097:blood / Q000235:genetics
D001565:Benzoates; D001596:Benzylamines; D004268:DNA-Binding Proteins; C473027:GW 3965; D008055:Lipids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011945:Receptors, Angiotensin; D018160:Receptors, Cytoplasmic and Nuclear; D000804:Angiotensin II; D012083:Renin