Chemoreceptor Hypersensitivity, Sympathetic Excitation, and Overexpression of ASIC and TASK Channels Before the Onset of Hypertension in SHR

Abstract

Rationale increased sympathetic nerve activity has been linked to the pathogenesis of hypertension in humans and animal models. Enhanced peripheral chemoreceptor sensitivity which increases sympathetic nerve activity has been observed in established hypertension but has not been identified as a possible mechanism for initiating an increase in SNA prior to the onset of hypertension. Objective we tested this hypothesis by measuring the pH sensitivity of isolated carotid body glomus cells from young spontaneously hypertensive rats (SHR) prior to the onset of hypertension and their control normotensive Wistar Kyoto (WKY) rats. Methods and Results we found a significant increase in the depolarizing effect of low pH in SHR versus WKY glomus cells which was caused by overexpression of two acid-sensing non-voltage gated channels. One is the amiloride-sensitive acid-sensing sodium channel (ASIC3) which is activated by low pH and the other is the two-pore domain acid sensing K+ channel (TASK1) which is inhibited by low pH and blocked by quinidine. Moreover we found that the increase in sympathetic nerve activity in response to stimulation of chemoreceptors with sodium cyanide was markedly enhanced in the still normotensive young SHR compared to control WKY rats. Conclusions our results establish a novel molecular basis for increased chemotransduction that contributes to excessive sympathetic activity prior to the onset of hypertension.

Specific Respiratory Neuron Types Have Increased Excitability That Drive Presympathetic Neurones in Neurogenic Hypertension

“…14 The latter is consistent with findings of increased minute ventilation, 59 the larger carotid bodies in SH rats with smaller diameter arteries, 60 and enhanced carotid sinus nerve discharge during hypoxia. 61,62 Reflexly, carotid body stimulation increases both pre-I and post-I neuronal activities, and the chemoreflex-evoked sympathoexcitation is larger in SH than Wistar rats, 63 whereas carotid sinus nerve denervation reduced both respiratory modulation of iCSN and lumbar sympathetic nerve in SH rats 64 and arterial pressure in conscious SH rats. 14,64 In summary, prehypertensive in situ SH rats have enhanced respiratory-modulated sympathetic activity at cervical, thoracic, and lumbar levels.…”

New Approaches in the Treatment of Hypertension

“…Studies in animal models 175 and human subjects 176 have revealed enhanced carotid body (CB) sensitivity in hypertension, but the mechanisms of this abnormality are not known. CB hypersensitivity has been shown to precede the development of hypertension in SHR 175 and in patients with whitecoat hypertension.…”

“…CB hypersensitivity has been shown to precede the development of hypertension in SHR 175 and in patients with whitecoat hypertension. 176 In a small, randomized, crossover, placebo-controlled study, deactivation of CB chemoreceptors by hyperoxia (respiration with 100% oxygen) attenuated the enhanced muscle sympathetic nerve activity in untreated hypertensive men, but no change was observed in controls.…”

François Abboud

“…[1][2][3][4] But, work soon progressed to the molecular and genetic level, with Abboud's particular focus being the form and function of baroreceptor neurons. [5][6][7][8][9] As Abboud explained in a recent interview, however, research is just one third of his professional passion. He is also, in equal parts, a dedicated physician and mentor..…”