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SUMMARY Arterial baroreceptors provide a neural sensory input that reflexly regulates the autonomic drive of the circulation. Our goal was to test the hypothesis that a member of the acid sensing ion channel (ASIC) subfamily of the DEG/ENaC superfamily is an important determinant of the arterial baroreceptor reflex. We found that aortic baroreceptor neurons in the nodose ganglia and their terminals express ASIC2. Conscious ASIC2 null mice developed hypertension, had exaggerated sympathetic and depressed parasympathetic control of the circulation, and a decreased gain of the baroreflex, all indicative of an impaired baroreceptor reflex. Multiple measures of baroreceptor activity each suggests that mechanosensitivity is diminished in ASIC2- null mice. The results define ASIC2 as an important determinant of autonomic circulatory control and of baroreceptor sensitivity. The genetic disruption of ASIC2 recapitulates the pathological dysautonomia seen in heart failure and hypertension and defines a molecular defect that may be relevant to its development.

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.

Abstract-Carotid body chemoreceptors sense hypoxemia, hypercapnia, and acidosis and play an important role in cardiorespiratory regulation. The molecular mechanism of pH sensing by chemoreceptors is not clear, although it has been proposed to be mediated by a drop in intracellular pH of carotid body glomus cells, which inhibits a K ϩ current. Recently, pH-sensitive ion channels have been described in glomus cells that respond directly to extracellular acidosis. In this study, we investigated the possible molecular mechanisms of carotid body pH sensing by recording the responses of glomus cells isolated from rat carotid body to rapid changes in extracellular pH using the whole-cell patch-clamping technique. Extracellular acidosis evoked transient inward current in glomus cells that was inhibited by the acid-sensing ion channel (ASIC) blocker amiloride, absent in Na ϩ -free bathing solution, and enhanced by either Ca 2ϩ -free buffer or addition of lactate. In addition, ASIC1 and ASIC3 were shown to be expressed in rat carotid body by quantitative PCR and immunohistochemistry. In the current-clamp mode, extracellular acidosis evoked both a transient and sustained depolarizations. The initial transient component of depolarization was blocked by amiloride, whereas the sustained component was eliminated by removal of K ϩ from the pipette solution and partially blocked by the TASK (tandem-p-domain, acid-sensitive K ϩ channel) blockers anandamide and quinidine. The results provide the first evidence that ASICs may contribute to chemotransduction of low pH by carotid body chemoreceptors and that extracellular acidosis directly activates carotid body chemoreceptors through both ASIC and TASK channels. (Circ Res. 2007;101:1009-1019.)Key Words: carotid body Ⅲ ASIC Ⅲ glomus cell Ⅲ chemoreceptors Ⅲ pH sensitivity T he carotid bodies function as major peripheral chemoreceptors sensing changes in arterial blood oxygen, carbon dioxide, and pH in mammals. [1][2][3] Glomus type I cells are generally accepted as the chemosensitive elements activated by hypoxemia, hypercapnia, and acidosis. 3 The common cellular mechanism for glomus cell transduction is the release of neurotransmitters such as ATP, acetylcholine, and dopamine as a result of an increase in intracellular Ca 2ϩ caused by stimulus-induced membrane depolarization. 4 -7 This leads to synaptic activation of adjacent carotid nerve endings that elicits both hyperventilation and sympathetic activation. 1,8 The molecular identity of the P O2 , P CO2 , and pH sensors is still an important question. The depolarization induced by hypoxemia has been ascribed to a closure of K ϩ channels including large-conductance, Ca 2ϩ -activated potassium (BK) channels. 3,9 -12 The transduction of acidosis to membrane depolarization was proposed to be mediated by a drop in intracellular pH which would inhibit 1 or more types of K ϩ channels, leading to membrane depolarization. 3,13,14 The findings of extracellular pH-sensitive ion conductances, including pH-sensitive Cl Ϫ currents 15 and...