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Loss of _2B-adrenoceptors increases magnitude of hypertension following nitric oxide synthase inhibition

Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico, Health Sciences Center, Albuquerque, New Mexico

Submitted 7 October 2005 ; accepted in final form 7 June 2006

Vascular _2B-adrenoceptors (_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 _2B-AR as in wild-type (WT) mice following nitric oxide (NO) synthase (NOS) inhibition with N-nitro-L-arginine (L-NNA, 250 mg/l in drinking water). Mean arterial pressure (MAP) was recorded in heterozygous (HET) _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 _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 µm), PE constriction was decreased in untreated HET arteries compared with WT (P < 0.05). L-NNA (100 µM) 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 _2B-AR expression increases the dependence of arterial pressure and vascular tone on NO production and that vascular _2B-AR either directly or indirectly regulates vascular endothelial NOS function.

N-nitro-L-arginine; mesenteric arteries; vasoconstriction

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