Effect of microglial inhibition on neuroinflammation and increased blood pressure in fructose-induced hypertensive rat model.

Neuroinflammation and increased sympathetic activity are at the forefront of the neurogenic etiology of hypertension. Microglia, the structural immune cells of the brain, plays a critical role in the inflammatory process and neuroinflammation. It is known that microglial reactivity increases with the opening of intermediate-conductance calcium-activated potassium channels (KCa3.1). Pharmacological inhibition of these channels may ameliorate neurogenic hypertension by reducing microglial reactivity and neuroinflammation. In this thesis, the effects of systemic treatment with the selective KCa3.1 blocker TRAM-34 in the fructose-induced hypertensive rat model on blood pressure (in vivo), vascular reactivity (ex vivo), microglial activity (in vitro), neuroinflammation (in vitro) and systemic inflammation (in vitro) were examined. For this purpose, hypertension was induced in rats by giving 10% fructose water. The preventive and therapeutic effect of TRAM-34 treatment on high blood pressure was evaluated with two different treatment protocols in fructose-induced hypertensive rats. Vascular reactivity studies were also performed at the end of the preventive treatment protocol. Acute high fructose administration triggered hypertension in rats and endothelial dysfunction developed in isolated mesenteric artery rings. Increased levels of microglial markers Iba-1 and CD86 as well as IL-1β, IL-6, and TNF-α in isolated NTS samples of fructose-induced hypertensive rats showed that neuroinflammation developed in this model. In addition, inflammatory cytokines and insulin levels in plasma increased. TRAM-34 treatment both prevented and treated high blood pressure. Systemic and central inflammation accompanied by hyperinsulinemia due to fructose consumption decreased with TRAM-34 treatment. In conclusion, this study obtained strong experimental evidence that pharmacological inhibition of KCa3.1 channels may be a potential target in the treatment of hypertension with neurogenic origin.