Major risks for stroke, heart, and kidney diseases have been linked to hypertension in more than 65 million Americans. Hypertension is a multi-organ disease that involves changes in nervous and immune system function. Sympathetic nerve activity is elevated in some hypertensive humans and in some animal models of hypertension, including the DOCA-salt model. DOCA-salt hypertension in rats is associated with the impairment of a α2R function, and increased level of O2- and macrophage number in the mesenteric arterial adventitia. However, the relationships between macrophage infiltration, O2- production and α2R impairment are unknown. This dissertation tested the hypothesis that as blood pressure increases in DOCA-salt rats, macrophages infiltrate into the adventitia of mesenteric arteries. Macrophages then release O2- that disrupts α2R function, causing an increase in norepinephrine release which further increases blood pressure. A time-course study was used to determine the temporal relationship between impaired function of sympathetic nerve terminal α2R and adventitial infiltration of pro-inflammatory macrophage in the mesenteric arteries from DOCA-salt hypertensive rats. Liposomal encapsulated clodronate was used to deplete adventitial macrophages. The results of these studies revealed that pro-inflammatory macrophage infiltration and increased O2- level in the mesenteric arteries of DOCA-salt rats occurred after 10 days of initial blood pressure increase, but α2R impairment did not occur until a week after the infiltration of macrophage. Furthermore, liposomal encapsulated clodronate prevented the development of the later phases of DOCA-salt hypertension by blocking the infiltration of macrophage into the mesnteric arterial adventitia, reducing the O2- level in the mesenteric arteries, and preventing the α2R dysfunction. Focal nerve stimulation and amperometry with microelectrodes to measure norepinephrine oxidation currents at the adventitial surface of mesenteric arteries were used to elucidate the mechanism of α2R function impairment. The results suggested that there is no alteration in the amount of norepinephrine release from the readily releasable pool vesicles, and in the activity of free Gβγ function in tonic inhibition of voltage gated Ca+2 channels in DOCA-salt hypertensive MA. The α2R function impairment occurs upstream from the Gβγ protein. The balance between Gi/o and Gs is shifted to the Gs, hence the increase in sensitivity of Gs and PKA activity in DOCA-salt hypertensive mesenteric arteries.The novel aspect of this study is that it tested the hypothesis that macrophage-derived O2- disrupts α2R function, which further contributes to the increase in blood pressure in DOCA-salt rats. Hypertension is a major public health concern. Therefore, clarifying the mechanism that leads to enhanced neurogenic vasoconstriction is important for new discoveries relevant to anti-hypertensive drug development.
Read
