Loss of α_2B-adrenoceptors increases magnitude of hypertension following nitric oxide synthase inhibition

Abstract

Vascular alpha(2B)-adrenoceptors (alpha(2B)-AR) may mediate vasoconstriction and contribute to the development of hypertension. Therefore, we hypothesized that blood pressure would not increase as much in mice with mutated alpha(2B)-AR as in wild-type (WT) mice following nitric oxide (NO) synthase (NOS) inhibition with N(omega)-nitro-l-arginine (l-NNA, 250 mg/l in drinking water). Mean arterial pressure (MAP) was recorded in heterozygous (HET) alpha(2B)-AR knockout mice and WT littermates using telemetry devices for 7 control and 14 l-NNA treatment days. MAP in HET mice was increased significantly on treatment days 1 and 4 to 14, whereas MAP did not change in WT mice (days 0 and 14 = 113 +/- 3 and 114 +/- 4 mmHg in WT, 108 +/- 0.3 and 135 +/- 13 mmHg in HET, P < 0.05). MAP was significantly higher in HET than in WT mice days 10 through 14 (P < 0.05). Thus blood pressure increased more rather than less in mice with decreased alpha(2B)-AR expression. We therefore examined constrictor responses to phenylephrine (PE, 10(-9) to 10(-4) M) with and without NOS inhibition to determine basal NO contributions to arterial tone. In small pressurized mesenteric arteries (inner diameter = 177 +/- 5 microm), PE constriction was decreased in untreated HET arteries compared with WT (P < 0.05). l-NNA (100 microM) augmented PE constriction more in HET arteries than in WT arteries, and responses were not different between groups in the presence of l-NNA. Acetylcholine dilated preconstricted arteries from HET mice more than arteries from WT mice. Endothelial NOS expression was increased in HET compared with WT mesenteric arteries by Western analysis. Griess assay showed increased NO(x) concentrations in HET plasma compared with those in WT plasma. These data demonstrate that diminished alpha(2B)-AR expression increases the dependence of arterial pressure and vascular tone on NO production and that vascular alpha(2B)-AR either directly or indirectly regulates vascular endothelial NOS function.

An activated renin–angiotensin system maintains normal blood pressure in aryl hydrocarbon receptor heterozygous mice but not in null mice

“…Prazosin (1 µg/g, ip) or hexamethonium (30 µg/g, ip) was injected into conscious animals to assess acute responses in blood pressure and heart rate [18], while N ω -nitro-L-arginine (LNNA) was administered in the drinking water (250 or 500 mg/L) to assess chronic changes in blood pressure [19]. To determine the effects of Ang II and ET-1 on blood pressure, mice were treated with 4 mg/kg captopril (angiotensin converting enzyme inhibitor, ACEi) in the drinking water for 3 d [15], followed by captopril in the drinking water plus 25 mg/kg PD155080 (ET A antagonist) twice per day in dough pills for 3 d [17], followed by PD155080 alone for 3 d, and finally 3 d of no treatment.…”

Impairment of coronary endothelial cell ETB receptor function after short-term inhalation exposure to whole diesel emissions

“…Vessel chambers were placed on the stage of an inverted Nikon Eclipse TS 100 microscope fitted with a video camera connected to a data acquisition computer. Inner diameter changes were recorded with edge detection software (IonOptix) as described previously (10). Arteries were treated for at least 30 min with nitric oxide synthase (NOS) inhibitor N -nitro-L-arginine (L-NNA, 100 M), ET BR antagonist BQ-788 (10 M), ETAR antagonist BQ-123 (10 M), or vehicle in the superfusate and in the lumen before constriction with increasing concentrations of ET-1 (0.1-10 nM), KCl (10 -90 mM), or thromboxane A2 mimetic U-46619 (0.1 nM-1 mM) added to the recirculating superfusate.…”

Enhanced non-eupneic breathing following hypoxic, hypercapnic or hypoxic–hypercapnic gas challenges in conscious mice

“…Studies in normal and transgenic mice have been used widely as models of sleep apnea (see Yamauchi et al, 2010). The C57BL6 mouse is a common inbred strain that is widely used in ventilatory and pulmonary function studies (Soliz et al, 2008, 2009) and to produce mice lacking genes for numerous functional proteins (Kline et al, 2002; Liu et al, 2004; Duling et al, 2006; Palmer et al, 2013b). The C57BL6 mouse was presumably chosen to be a model with “normal” physiology and indeed they display many normal traits (see Tankersley et al, 2002a; Campen et al, 2004, 2005; Tewari et al, 2013; Palmer et al, 2013a,b; Gaston et al, 2014).…”