Role of the α _2B -Adrenergic Receptor in the Development of Salt-Induced Hypertension

Abstract

Abstract-Salt sensitivity is a common trait in patients with essential hypertension and seems to have both an inherited and an acquired component (eg, is influenced by aging and renal insufficiency). Experimental evidence suggests that salt loading induces hypertension via a neurogenic mechanism mediated by the ␣ 2 -adrenergic receptors (␣ 2 -AR). To explore the ␣ 2 -AR subtype involved in this mechanism, we studied 2 groups of mice genetically engineered to be deficient in one of the 3 ␣ 2 -AR subtype genes (either ␣ 2B -AR ϩ/Ϫ or ␣ 2C -AR Ϫ/Ϫ knockout mice) compared with their wild-type counterparts. The mice (nϭ10 to 14 in each group) were submitted to subtotal nephrectomy and given 1% saline as drinking water for up to 35 days. Blood pressure (BP) was monitored by tail-cuff readings and confirmed at the end point by direct intra-arterial BP recording. The ␣ 2B -AR-deficient mice had an attenuated BP response in this protocol (baseline 101.8Ϯ2.7 versus end point 109.9Ϯ2.8 mm Hg), whereas the BP of their wild-type counterparts went from a baseline 101.9Ϯ2.3 to an end point 141.4Ϯ7.1 mm Hg. The other 2 groups had BP increases of 44.6Ϯ5.17 and 46.7Ϯ7.01 mm Hg, with no difference between the mice deficient in the ␣ 2C -AR gene subtype versus their wild-type counterparts. Body weight, renal remnant weight, and residual renal function were no different among groups. These data suggest that a full complement of ␣ 2B -AR genes is necessary to raise BP in response to dietary salt loading, whereas complete absence of the ␣ 2C -AR subtype does not preclude salt-induced BP elevation. It is unclear whether the mechanism(s) involved in this process are of central origin (inability to increase sympathetic outflow), vascular origin (inability to vasoconstrict), or renal origin (inability to retain excess salt and fluid). (Hypertension. 1999;33:14-17.)

Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression

“…Q-RT-PCR, run in triplicate and including negative controls, were performed using total RNA from the brain, kidney, aorta, and heart of mice infused with ANG II (n ϭ 6) or saline (n ϭ 6) for 6 h (6 hr); ANG II (n ϭ 6) or saline (n ϭ 6) for 7 days (7D), and ANG II (n ϭ 7) or saline (n ϭ 8) for 14 days (14D). The heart salt sample shown in B was obtained from mice subjected to subtotal nephrectomy, as previously described (23,29). After subtotal nephrectomy, experimental animals in this group were placed and maintained on 1% NaCl as drinking water for a maximal period of 35 days.…”

Functional Variant in the α 2B Adrenoceptor Gene, a Positional Candidate on Chromosome 2, Associates With Hypertension

“…The hypertensive effect mediated by the ␣ 2B -adrenergic receptor in mice has been shown to be especially important for salt-sensitive hypertension. 22,23 This is highly relevant for humans because salt sensitivity is associated with a positive family history of primary hypertension, 24 and it is also a characteristic of a large proportion of patients with primary hypertension. 25 There is also evidence that the ␣ 2B -adrenergic receptor mediates peripheral vasoconstriction in mice.…”

Haplotype-based analysis of alpha 2A, 2B, and 2C adrenergic receptor genes captures information on common functional loci at each gene

“…The presence of the del 301-303 allele leads to a small decrease in coupling efficiency resulting in reduced inhibition of adenylyl cyclase (Makaritsis et al 1999). It has been associated with a reduced basal metabolic rate in obese subjects, with an increase in body weight among nondiabetic subjects, and modulation of autonomic nervous function in nondiabetic men (Sivenius et al 2001(Sivenius et al , 2003.…”