title: Vascular Type 1A Angiotensin II Receptors Control BP by Regulating Renal Blood Flow and Urinary Sodium Excretion.
abstract: Inappropriate activation of the type 1A angiotensin (AT1A) receptor contributes to the pathogenesis of hypertension and its associated complications. To define the role for actions of vascular AT1A receptors in BP regulation and hypertension pathogenesis, we generated mice with cell-specific deletion of AT1A receptors in smooth muscle cells (SMKO mice) using Loxp technology and Cre transgenes with robust expression in both conductance and resistance arteries. We found that elimination of AT1A receptors from vascular smooth muscle cells (VSMCs) caused a modest (approximately 7 mmHg) yet significant reduction in baseline BP and exaggerated sodium sensitivity in mice. Additionally, the severity of angiotensin II (Ang II)-dependent hypertension was dramatically attenuated in SMKO mice, and this protection against hypertension was associated with enhanced urinary excretion of sodium. Despite the lower BP, acute vasoconstrictor responses to Ang II in the systemic vasculature were largely preserved (approximately 80% of control levels) in SMKO mice because of exaggerated activity of the sympathetic nervous system rather than residual actions of AT1B receptors. In contrast, Ang II-dependent responses in the renal circulation were almost completely eliminated in SMKO mice (approximately 5%-10% of control levels). These findings suggest that direct actions of AT1A receptors in VSMCs are essential for regulation of renal blood flow by Ang II and highlight the capacity of Ang II-dependent vascular responses in the kidney to effect natriuresis and BP control.
authors: Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, North Carolina;
authors: Matthew A
authors: MA
authors: Sparks
authors: Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, North Carolina; Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany;
authors: Johannes
authors: J
authors: Stegbauer
authors: Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, North Carolina;
authors: Daian
authors: D
authors: Chen
authors: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina; and.
authors: Jose A
authors: JA
authors: Gomez
authors: Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, North Carolina;
authors: Robert C
authors: RC
authors: Griffiths
authors: Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, North Carolina;
authors: Hooman A
authors: HA
authors: Azad
authors: Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, North Carolina;
authors: Marcela
authors: M
authors: Herrera
authors: Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, North Carolina;
authors: Susan B
authors: SB
authors: Gurley
authors: Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, North Carolina; Cardiovascular and Metabolic Disorders Research Program, Duke-National University of Singapore, Graduate Medical School, Singapore tcoffman@duke.edu.
authors: Thomas M
authors: TM
authors: Coffman
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D002395:Catecholamines / Q000652:urine; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology*; D010646:Phentolamine / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000502:physiology*; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D002395:Catecholamines; D044140:Receptor, Angiotensin, Type 1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010646:Phentolamine
keywords: angiotensin; blood pressure; renal hemodynamics; vascular