P2X3 receptor targeting in the carotid body for regulating hypertension: a translational perspective

Abstract

Although the causes of hypertension-related sympathoexcitation remain unknown, studies conducted in the laboratory of Professor Julian F. R. Paton (University of Bristol, Bristol, UK) have strongly suggested that the carotid body chemoreceptors may be responsible, at least in part, for this exacerbated sympathetic activity. In this way, the carotid body chemoreceptors may contribute both to development and maintenance of high blood pressure, emerging as a potential new target for the treatment of hypertension. Recently, Professor Julian F. R. Paton's group reported that acute antagonism of P2X3 receptors, using a new specific antagonist (AF-130) for these receptors reduced the carotid body hypersensitivity and blood pressure in Spontaneously Hypertensive Rats (SHR). The P2X3 purinergic receptors are subtypes of receptors which can be found in many tissues and organs, including the cells of the carotid bodies, where the carotid body chemoreceptors are located. It is already well described that adenosine triphosphate (ATP) is an important excitatory neurotransmitter in the chemical transduction that occurs in the carotid body chemoreceptors. Therefore, the aim of the present project is to investigate the effects of chronic pharmacological carotid body chemoreceptors inhibition in the development and maintenance of hypertension in SHR. For this, normotensive rats and SHR will be chronically treated with AF-130. During treatment, hemodynamic parameters and sympathetic renal nerve activity will be measured. After, the animals will be subjected to carotid body ablation to verify whether the treatment effects on hemodynamic parameters and sympathetic renal nerve activity are dependent on carotid body mediation. Furthermore, western blot and immunohistochemistry techniques will be applied to the carotid bodies and petrosal ganglia from normotensive rats and SHR, and also from normotensive and hypertensive patients post-mortem to examine the expression and localization of P2X3 receptors. (AU)