Abstract:
Blood pressure control remains critically unmet with increasing cases of treatment-resistance even in developed countries. However, expanding our understanding on the afferent limb of blood pressure regulation is currently offering numerous novel targets to potentially address some of these patients. The sensory nerves of the carotid body (CB) chemoreceptors have shown to generate aberrant afferent tone in a wide range of animal models of hypertension, causing exaggerated vasopressor response, disordered breathing, and elevated baseline sympathetic nerve activity. Preliminary studies have indicated upregulation of a specific purinergic receptor, P₂X₃, on carotid sinus nerve is at least partially responsible for this chronic neuroplasticity. Accordingly, the present study has developed an ovine model of two-kidney-one-clip renovascular hypertension to test whether P₂X₃ antagonism lowers renal sympathetic nerve activity (RSNA), blood pressure and improves kidney perfusion under conscious conditions. Angiotensin-II type-1 receptor (AT₁R) antagonism was also employed to investigate the relative contribution of angiotensin-II to CB hypertonicity and/or hyperreflexia. CB were activated via intracarotid potassium cyanide to chemically induce hypoxia. In hypertensive animals, no significant increases in CB-mediated vasopressor and renal blood flow responses were seen despite exaggerated RSNA response compared to normotensives. Furthermore, renal vascular conductance response was blunted in hypertension due to vascular remodelling consisting of adrenergic hyposensitivity, arterial fibrosis and/or endothelial dysfunction. In renovascular hypertension, P₂X₃ antagonism did not alleviate CB hypertonicity and/or hyperreflexia, but losartan significantly reduced the vasopressor response while this effect was not seen in normotension. Thus, AT1R has a dominant role in the chemotransduction of hypoxia from the CB in hypertension. Moreover, based on preliminary data, losartan abolished the CB-mediated RSNA response while resting RSNA was unchanged. This suggests the potential of separate reflex pathways from AT₁ positive glomus cells with the pre-sympathetic neurons in the brainstem that mediates augmented sympathoexcitation when the CB is active but not contribute to sustaining tonic afferent drive that increases resting RSNA.