Angiotensin-II Type 1 Receptor–Mediated Hypertension in D ₄ Dopamine Receptor–Deficient Mice

Abstract

Key Words: dopamine Ⅲ receptors, angiotensin II Ⅲ mice Ⅲ hypertension Ⅲ angiotensin II Ⅲ endothelin Ⅲ vasopressins E ssential hypertension is a major risk factor for the development of cardiovascular disease. 1 It is a heterogeneous disease in which both genetics and environment influence blood pressure. 2 Dopamine affects cardiovascular regulatory mechanisms by its actions on renal hemodynamics and ion and water transport and by its regulation of hormones and humoral agents, such as aldosterone, catecholamines, endothelin, prolactin, proopiomelanocortin, renin, and vasopressin. In addition, dopamine can control blood pressure by acting on neuronal cardiovascular centers, heart, and arterial and venous vessels. Methods Generation of D 4 Dopamine-Receptor Mutant MiceThe original F 2 hybrid strain (129/SvϫC57BL/6) carrying a mutant form of the D 4 dopamine receptor was initially generated and backcrossed to C57BL/6 mice. Heterozygous (D 4 ϩ/Ϫ ) mice were mated to obtain D 4 Ϫ/Ϫ and D 4 ϩ/ϩ littermates, and the D 4 Ϫ/Ϫ mice were backcrossed with C57BL/6 mice to obtain sixth-and tenthgeneration mice in the Department of Physiology and Pharmacology, Oregon Health and Science University. 21 We used sixth-generation mice for acute studies and tenth-generation mice for chronic and immunoblotting studies. All of the animals were genotyped 21 and treated in accordance with National Institutes of Health guidelines for ethical treatment and handling of animals in research.

Intravital Förster resonance energy transfer imaging reveals elevated [Ca2+]i and enhanced sympathetic tone in femoral arteries of angiotensin II‐infused hypertensive biosensor mice

“…This suggests that local arterial AT 1 R activation seems to play a negligible role under basal conditions in control mice. Systemic application of losartan does decrease arterial BP dramatically (Xu & Brooks, 1996;Collister & Osborn, 2005;Bek et al 2006). Thus, we speculate that the effect of systemic losartan on BP is not due, directly, to the blockade of vascular AT 1 Rs in saline or normal control mice.…”

“…Chronic systemic Ang II infusion induces experimental hypertension, which involves numerous changes in the CNS (Zimmerman et al 2004;Kuroki et al 2012;Young et al 2012), immune system (Guzik et al 2007;Marvar et al 2010), cardiovascular system (Kim & Iwao, 2000;Touyz et al 2005;Ding et al 2007;Hercule et al 2007;Kirabo et al 2011;Kharade et al 2013), and the peripheral salt and water regulation organs, including the kidneys (Kim & Iwao, 2000;Bek et al 2006;Gonzalez-Villalobos et al 2009;Navar, 2010). Increased central SNA has been implicated in various hypertension models, particularly in models involving Ang II (Zimmerman et al 2004;Marvar et al 2010;Yoshimoto et al 2010;Kuroki et al 2012;Young et al 2012).…”

Chronic regulation of the renal Na+/H+exchanger NHE3 by dopamine: translational and posttranslational mechanisms

“…Maneuvers that chronically disrupt DA-dependent natriuresis such as blockade of DA generation by inhibitors of aromatic amino acid decarboxylase (14,95), pharmacological antagonism of dopamine receptors (51,55,70,84,94), and genetic deletion of DA receptors (DR 1 through DR 5 in isolation) all lead to systemic hypertension with a plethora of renal and extrarenal pathophysiological changes (1, 10,19,58,75,114,118,120). Some degree of impaired natriuresis has been described in several although not all of the single DA receptor gene deletion models (10,98).…”

Acute regulation of renal Na+/H+ exchanger NHE3 by dopamine: role of protein phosphatase 2A

“…Hypertension was found in mice with deletion of both D 1 -like receptors (D 1 and D 5 ) (1, 31) and D 2 -like receptors (D 2 , D 3 , and D 4 ) (6,11,42). A multitude of cardiovascular, neurohumoral, and renal mechanisms may contribute to the phenotypes of these mice, but both D 1 -like and D 2 -like receptor deletions have been associated with sodium retention, extracellular fluid expansion, and salt-sensitive hypertension (1,6,42,54).…”