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The mechanisms that sense alterations in total body sodium content to facilitate sodium homeostasis in response to an acute sodium challenge that does not increase blood pressure have not been fully elucidated. We hypothesized that the renal sympathetic nerves are critical to mediate natriuresis via α 1 - or β-adrenoceptors signal transduction pathways to maintain sodium balance in the face of acute increases in total body sodium content that do not activate the pressure-natriuresis mechanism. To address this hypothesis, we used acute bilateral renal denervation (RDNX), an anteroventral third ventricle (AV3V) lesion and α 1 - or β-antagonism during an acute 1M NaCl sodium challenge in conscious male Sprague Dawley rats. An acute 1M NaCl infusion did not alter blood pressure and evoked profound natriuresis and sympathoinhibition. Acute bilateral RDNX attenuated the natriuretic and sympathoinhibitory responses evoked by a 1M NaCl infusion [peak natriuresis (μeq/min) sham 14.5 ± 1.3 vs. acute RDNX: 9.2 ± 1.4, p < 0.05; plasma NE (nmol/L) sham control: 44 ± 4 vs. sham 1M NaCl infusion 11 ± 2, p < 0.05; acute RDNX control: 42 ± 6 vs. acute RDNX 1M NaCl infusion 25 ± 3, p < 0.05]. In contrast, an AV3V lesion did not impact the cardiovascular, renal excretory or sympathoinhibitory responses to an acute 1M NaCl infusion. Acute i.v. α 1 -adrenoceptor antagonism with terazosin evoked a significant drop in baseline blood pressure and significantly attenuated the natriuretic response to a 1M NaCl load [peak natriuresis (μeq/min) saline 17.2 ± 1.4 vs. i.v. terazosin 7.8 ± 2.5, p < 0.05]. In contrast, acute β-adrenoceptor antagonism with i.v. propranolol infusion did not impact the cardiovascular or renal excretory responses to an acute 1M NaCl infusion. Critically, the natriuretic response to an acute 1M NaCl infusion was significantly blunted in rats receiving a s.c. infusion of the α 1 -adrenoceptor antagonist terazosin at a dose that did not lower baseline blood pressure [peak natriuresis (μeq/min) sc saline: 18 ± 1 vs. sc terazosin 7 ± 2, p < 0.05]. Additionally, a s.c. infusion of the α 1 -adrenoceptor antagonist terazosin further attenuated the natriuretic response to a 1M NaCl infusion in acutely RDNX animals. Collectively these data indicate a specific role of a blood pressure-independent renal sympathetic nerve-dependent α 1 -adrenoceptor-mediated pathway in the natriuretic and sympathoinhibitory responses evoked by acute increases in total body sodium., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Frame, Nist, Kim, Kuwabara and Wainford.)

We have previously reported that brain Gαi 2 subunit proteins are required to maintain sodium homeostasis and are endogenously upregulated in the hypothalamic paraventricular nucleus (PVN) in response to increased dietary salt intake to maintain a salt resistant phenotype in rats. However, the origin of the signal that drives the endogenous activation and up-regulation of PVN Gαi 2 subunit protein signal transduction pathways is unknown. By central oligodeoxynucleotide (ODN) administration we show that the pressor responses to central acute administration and central infusion of sodium chloride occur independently of brain Gαi 2 protein pathways. In response to an acute volume expansion, we demonstrate, via the use of selective afferent renal denervation (ADNX) and anteroventral third ventricle (AV3V) lesions, that the sensory afferent renal nerves, but not the sodium sensitive AV3V region, are mechanistically involved in Gαi 2 protein mediated natriuresis to an acute volume expansion [peak natriuresis (μeq/min) sham AV3V: 43 ± 4 vs. AV3V 45 ± 4 vs. AV3V + Gαi 2 ODN 25 ± 4, p < 0.05; sham ADNX: 43 ± 4 vs. ADNX 23 ± 6, AV3V + Gαi 2 ODN 25 ± 3, p < 0.05]. Furthermore, in response to chronically elevated dietary sodium intake, endogenous up-regulation of PVN specific Gαi 2 proteins does not involve the AV3V region and is mediated by the sensory afferent renal nerves to counter the development of the salt sensitivity of blood pressure (MAP [mmHg] 4% NaCl; Sham ADNX 124 ± 4 vs. ADNX 145 ± 4, p < 0.05; Sham AV3V 125 ± 4 vs. AV3V 121 ± 5). Additionally, the development of the salt sensitivity of blood pressure following central ODN-mediated Gαi 2 protein down-regulation occurs independently of the actions of the brain angiotensin II type 1 receptor. Collectively, our data suggest that in response to alterations in whole body sodium the peripheral sensory afferent renal nerves, but not the central AV3V sodium sensitive region, evoke the up-regulation and activation of PVN Gαi 2 protein gated pathways to maintain a salt resistant phenotype. As such, both the sensory afferent renal nerves and PVN Gαi 2 protein gated pathways, represent potential targets for the treatment of the salt sensitivity of blood pressure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Moreira, Nist, Carmichael, Kuwabara and Wainford.)