Noxiousness of Hypertension-related Norepinephrine and Upregulation of Norepinephrine Induced by High Intensity Electrical Stimulation in Healthy Volunteers

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[Purpose] The purpose of the present study was to assist the design of future experiments on pain therapeutics and to establish the reliability and understanding of animal models of neurotransmitters of sympathetic nerves. [Subjects] The subjects were fifty-five male rats and ten female volunteers. [Methods] In vitro testing of experimental animals, measuring blood pressure, muscle tension, histological changes, intracellular Ca²⁺, and enzymatic activity. We also induced hypertension-related sympathetic effects by physical therapy with high intensity electrical stimulation as evidenced by 24-hour urine analysis of norepinephrine. [Results] In isometric tension and histological analyse, norepinephrine-induced tension and collagen fibers were significantly increased in muscle strips from hypertensive rat aorta. In [Ca²⁺]_i analysis, norepinephrine-induced change of [Ca²⁺]_i in muscle strips from normotensive and hypertensive rat aorta was observed. Analysis by western blotting with anti-phosphorylated antibodies showed that the phosphorylation of ERK1/2 (extracellular signal-regulated protein kinase 1 and 2) and p38 MAPK (p38 mitogen-activated protein kinase) were significantly increased in the norepinephrine-induced state in the rats. Furthermore, high intensity electrical stimulation significantly increased pain-related concentration of norepinephrine in the healthy volunteers. [Conclusion] These results suggest that the application of norepinephrine to aorta muscle strips is associated with changed muscle tension, [Ca²⁺]_i, and phosphorylation of MAPK, and that the increased responsiveness of norepinephrine to high intensity electrical stimulation may be, in part, related to the increase of sympathetic effects.