Angiotensin II responses in AT1A receptor-deficient mice: a role for AT1B receptors in blood pressure regulation.
Most of the classic functions of the renin-angiotensin system are mediated by type 1 (AT1) angiotensin receptors, of which two subtypes, AT1A and AT1B, have been identified. However, distinct functions for these two AT1 receptors have been difficult to separate. We examined the pressor effects of angiotensin II in Agtr1A -/- mice, which lack AT1A receptors. In enalapril-pretreated Agtr1A -/- mice, angiotensin II caused significant and dose-proportional increases in mean arterial pressure. This pressor response was not blocked by pretreatment with sympatholytic agents but was completely inhibited by the AT1-receptor antagonists, losartan and candesartan, suggesting that it is directly mediated by AT1B receptors. Chronic treatment of Agtr1A -/- mice with losartan reduced systolic blood pressure from 80 +/- 5 to 72 +/- 4 mmHg (P < 0.04), suggesting a role for AT1B receptors in chronic blood pressure regulation. These studies provide the first demonstration of in vivo pressor effects mediated by AT1B receptors and demonstrate that, when AT1A receptors are absent, the AT1B receptor contributes to the regulation of resting blood pressure.
Oliverio
M I
MI
Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, North Carolina 27705, USA.
Best
C F
CF
Kim
H S
HS
Arendshorst
W J
WJ
Smithies
O
O
Coffman
T M
TM
D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D004656:Enalapril / Q000494:pharmacology; D018738:Hexamethonium / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D019808:Losartan; D051379:Mice; D018345:Mice, Knockout; D010646:Phentolamine / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000172:deficiency* / Q000187:drug effects / Q000502:physiology*; D012083:Renin / Q000096:biosynthesis; D013565:Sympatholytics / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013565:Sympatholytics; D013777:Tetrazoles; D000804:Angiotensin II; D018738:Hexamethonium; D004656:Enalapril; D012083:Renin; D019808:Losartan; C077793:candesartan cilexetil; D010646:Phentolamine