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Blockade of Brain Sodium Channels or Electroneutral Transporters Attenuates the Hypertensive Response to Central NaCl Stimulation
Author(s) -
King Jesse L,
Kinsman Brian J,
Stocker Sean D
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.868.5
Subject(s) - chemistry , epithelial sodium channel , amiloride , endocrinology , medicine , homeostasis , furosemide , sodium channel , stimulation , blockade , sodium , vasopressin , pharmacology , receptor , biochemistry , organic chemistry
Accumulating evidence suggests excess dietary salt intake elevates plasma or cerebrospinal fluid NaCl concentrations to increase sympathetic nerve activity (SNA) and arterial blood pressure (ABP) in salt‐sensitive hypertension. Both acute and chronic infusion of hypertonic NaCl into the lateral cerebral ventricle produces a sympathetically mediated increase in ABP that depends on the integrity of forebrain hypothalamic structures that contain NaCl‐sensing neurons. However, the mechanism by which these neurons detect changes in NaCl concentrations to alter ABP is not known; however, there are two possibilities. First, prior studies have suggested that the epithelial sodium channel (ENaC) mediates central pressor actions of hypertonic NaCl. Second, electroneutral transporters are expressed in hypothalamic regions involved in body fluid homeostasis including vasopressin neuroendocrine neurons. Thus, the purpose of this study was to test the hypothesis that the ENaC or electroneutral transporters mediate the hypertensive effect of central NaCl. This hypothesis was tested by pharmacological blockade of ENaC or electroneutral transporters via pretreatment with central infusion of benzamil or furosemide, respectively. At least 3 days before experiments, Male Sprague‐Dawley rats (300–450g) were anesthetized with isoflurane and instrumented with a femoral arterial catheter and intracerebroventicular (ICV) brain cannula to measure ABP and infuse drugs, respectively. On the day of the experiment, rats were pretreated with aCSF (2μL per 1 min), benzamil (5nmol) or furosemide (10 nmol) through an ICV infusion at 10 min before a second ICV infusion of 0.5M NaCl (5μL per 10 min). ICV infusion of 0.5M NaCl in aCSF‐treated rats produced a significant increase in mean ABP (Δ9±1 mmHg, n=10; P<0.01) but not heart rate (Δ−6±10 bpm, n=10). Pretreatment with the ENaC antagonist benzamil attenuated the pressor response (Δ3±1 mmHg, n=7; P<0.01) and decreased heart rate (Δ−17±5 bpm, n=7; P<0.05). Interestingly, pretreatment of the electroneutral transporter antagonist furosemide completely attenuated the pressor (Δ−1±1 mmHg, n=6, P<0.01) and tachycardic (Δ−11±7 bpm, n=6; P<0.05) response to ICV infusion of 0.5M NaCl. ICV infusion of furosemide alone did not alter baseline ABP (Δ1±1 mmHg, n=3; P<0.05) or heart rate (Δ12±7 bpm, n=3; P<0.05). These findings suggest that ENaC and electroneutral transporters play a critical role in sympathetic activation and pressor effect during central NaCl stimulation. Support or Funding Information AHA Established Investigator Award (SDS), NIH R01 HL113270, AHA Predoctoral Fellowship (BJK), and NIH F30 HL131269 (BJK)