title: Chronic production of angiotensin IV in the brain leads to hypertension that is reversible with an angiotensin II AT1 receptor antagonist.
abstract: Angiotensin IV (Ang IV) is a metabolite of the potent vasoconstrictor angiotensin II (Ang II). Because specific binding sites for this peptide have been reported in numerous tissues including the brain, it has been suggested that a specific Ang IV receptor (AT4) might exist. Bolus injection of Ang IV in brain ventricles has been implicated in learning, memory, and localized vasodilatation. However, the functions of Ang IV in a physiological context are still unknown. In this study, we generated a transgenic (TG) mouse model that chronically releases Ang IV peptide specifically in the brain. TG mice were found to be hypertensive by the tail-cuff method as compared with control littermates. Treatment with the angiotensin-converting enzyme inhibitor captopril had no effect on blood pressure, but surprisingly treatment with the Ang II AT1 receptor antagonist candesartan normalized the blood pressure despite the fact that the levels of Ang IV in the brains of TG mice were only 4-fold elevated over the normal endogenous level of Ang peptides. Calcium mobilization assays performed on cultured CHO cells chronically transfected with the AT1 receptor confirm that low-dose Ang IV can mobilize calcium via the AT1 receptor only in the presence of Ang II, consistent with an allosteric mechanism. These results suggest that chronic elevation of Ang IV in the brain can induce hypertension that can be treated with angiotensin II AT1 receptor antagonists.
authors.affiliation: Laboratories of Molecular Biochemistry of Hypertension, Clinical Research Institute of Montreal, Quebec, Canada.
authors.forename: Nadheige
authors.initials: N
authors.lastname: Lochard
authors.forename: Gaétan
authors.initials: G
authors.lastname: Thibault
authors.forename: David W
authors.initials: DW
authors.lastname: Silversides
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Reudelhuber
mesh_terms: D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000494:pharmacology; D000494:Allosteric Regulation; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D015870:Gene Expression; D005813:Genes, Synthetic; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D005914:Globins / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics*; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D021382:Protein Sorting Signals / Q000235:genetics / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D019076:Transgenes
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D005904:Glial Fibrillary Acidic Protein; D007093:Imidazoles; D021382:Protein Sorting Signals; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D011993:Recombinant Fusion Proteins; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D005914:Globins; D015059:1-Sarcosine-8-Isoleucine Angiotensin II; D012083:Renin; C081643:candesartan