Murray DB, McMillan R, Brower GL, Janicki JS. ETA selective receptor antagonism prevents ventricular remodeling in volume-overloaded rats. Am J Physiol Heart Circ Physiol 297: H109 -H116, 2009. First published May 8, 2009 doi:10.1152/ajpheart.00968.2008.-The objective of this study was to investigate the ability of selective endothelin receptor subtype A (ET A) endothelin receptor antagonism (ETA) to prevent the acute myocardial remodeling process secondary to volume overload. Left ventricular tissue from sham-operated (Sham) and untreated (Fist), and TBC-3214 (Fist ϩ ETA, 25 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 )-treated fistula animals was analyzed for mast cell density, matrix metalloproteinase (MMP) activity, and extracellular collagen volume fraction (CVF) 1 and 5 days following the initiation of volume overload. Compared with Fist, ETA treatment prevented the increase in left ventricular mast cell density at 1 day and 5 days. Additionally, at 1 day postfistula, a substantial decrease in MMP-2 activity below Sham levels was observed following endothelin receptor antagonism (1.7 Ϯ 0.7 vs. 0.3 Ϯ 0.3 vs. 0.9 Ϯ 0.2 arbitrary activity units, Fist vs. Fist ϩ ETA vs. Sham, P Յ 0.05). This same effect was also seen at 5 days postfistula (1.9 Ϯ 0.3 vs. 0.5 Ϯ 0.1 arbitrary activity units, Fist vs. Fist ϩ ETA, P Յ 0.05). The marked decrease in myocardial CVF seen in Fist hearts (0.7 Ϯ 0.1 vs. 1.6 Ϯ 0.1% myocardial area, Fist vs. Sham, P Յ 0.05) was prevented by ETA (1.7 Ϯ 0.1% Fist ϩ ETA, P Ͻ 0.05 vs. Fist). This preservation of the collagen matrix was also present on day 5 in the TBC-treated group vs. the Fist group (1.0 Ϯ 0.1 vs. 1.4 Ϯ 0.1%, Fist vs. Fist ϩ ETA, P Յ 0.01). Furthermore, an 8-wk preventative treatment with ETA significantly attenuated the increase in left ventricular end systolic and diastolic volumes compared with untreated fistula hearts. In conclusion, the novel findings of this study indicate that the activation of cardiac mast cells and subsequent MMP activation/collagen degradation during the acute stages of volume overload are prevented by blockade of the ET A receptor subtype. Furthermore, by preventing these events, ET-1 antagonism was efficacious in attenuating ventricular dilatation and limiting the development of structural and functional deficits.endothelin-1; mast cell; matrix metalloproteinase; TBC-3214 ENDOTHELIN (ET)-1 is a potent neurohormone produced throughout the cardiovascular system, and the observation that plasma ET-1 is elevated in patients with heart failure is suggestive of a role in the pathophysiology of heart failure (16,19,34,40,47). The cardiovascular effects of ET-1 (a 21-amino-acid peptide) are dictated by binding to one of two G protein-linked receptor subtypes [endothelin receptor subtypes A (ET A ) or B (ET B )] (23). In the heart and vasculature, binding and activation of ET A is known to mediate powerful vasoconstrictor and pressor affects, in addition to chronotropic and ionotropic effects (12,25). The ET B receptor subtype is responsible for systemic clearance of circulating ...

High dietary sodium intake increases sympathetic and blood pressure (BP) reactivity in rodents, but it is not known if dietary sodium similarly affects reactivity in non‐hypertensive humans. Importantly, exaggerated sympathetic and BP responses are predictive of future hypertension risk. PURPOSE We hypothesized that high dietary sodium would increase sympathetic and BP reactivity in male and female adults. The cold pressor test (CPT) was used to assess reactivity. METHODS Twenty‐seven healthy, non‐hypertensive adults (16M/11F; age: 26±7yrs; BMI: 24.7±1 kg/m2; mean±SD) participated in a controlled feeding study that consisted of 10 days of low (LS: 1.0 g/day), recommended (MS: 2.3 g/day), or high (HS: 7.0 g/day) sodium diets, in random order with at least a one‐month washout between diets. Twenty‐four hour urine samples were collected and sodium excretion was calculated to ensure compliance on the respective diets. Muscle sympathetic nerve activity (MSNA) was directly assessed using peroneal microneurography and beat‐to‐beat BP was assessed using photoplethysmography at rest and throughout the CPT. The CPT was completed by having participants immerse their dominant hand in an ice slurry (3° to 5°C) for 2 minutes. Data were analyzed using two‐way repeated measures ANOVAs. RESULTS As expected, twenty‐four hour sodium excretion increased with increasing amounts of dietary salt (LS: 42±40, MS: 84±36, HS: 253±111 mmol/24 hours, main effect of diet, p<0.0001), with no apparent sex differences (p = 0.98). The CPT robustly increased MSNA, but there was no effect of diet (Δ MSNA burst frequency LS: 13±6, MS: 16±6, HS: 15±5 bursts/min, p = 0.23). Similarly, the CPT acutely increased systolic BP, but there was no effect of diet (Δ systolic BP LS: 18±11, MS: 20±12, HS: 18±11 mmHg, p = 0.44). CONCLUSION These data suggest that 10 days of high dietary salt intake does not affect MSNA or BP responses to the CPT in young, healthy, non‐hypertensive adults. Support or Funding Information Supported by NIH Grant 1R01HL128388

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Rodent studies have identified specialized sodium chloride (NaCl)‐sensing neurons in the circumventricular organs (CVOs), which mediate NaCl‐induced changes in sympathetic nerve activity, arginine vasopressin (AVP), thirst, and blood pressure (BP). In humans, acute hypernatremia has been shown to increase sympathetic nerve activity, AVP, thirst and BP. However, few human studies have investigated the network of NaCl sensing regions of the brain using functional magnetic resonance imaging (fMRI). Objective To determine how the functional connectivity of sodium sensing regions of the brain change during an acute hypernatremic perturbation. Methods Resting‐state fMRI was performed on 9 healthy young adults (29±4 yrs, 5M) at baseline and during a 30 min 3% NaCl intravenous infusion at a rate of 0.15 ml/kg/min. Venous blood samples and perceived thirst (Likert scale, cm) were obtained before and immediately following the infusion. Serum electrolytes, plasma osmolality, hematocrit, and hemoglobin were assessed. Beat‐to‐beat blood pressure was measured continuously. Seed‐based voxel‐wise functional connectivity analysis was performed in AFNI using spherical seeds placed bilaterally in the subfornical organ (SFO), the organum vasculosum lamina terminalis (OVLT) as well as cortical sensory regions such as the insula. Functional connectivity was compared at baseline vs. early infusion (min 0‐15) and baseline vs. late infusion (min 16‐30) at p < 0.01, corrected for multiple comparisons with 3dClustSim. Results Thirst (∆1.9±2.0 cm), serum sodium (∆3.2±2.1 mmol/L), and plasma osmolality (∆6.9±4.7 mOsm/kg H2O) all increased from baseline to post‐infusion (p<0.05). Head motion was minimal and did not change throughout the stages of the infusion (mean motion = 0.11±0.10 mm, p>0.80). Hypertonic saline infusion increased local functional connectivity between the SFO and OVLT (Z score baseline=0.07±0.01, Z score late phase=0.17+0.01, p<0.01). A similar increase in functional connectivity was seen between the insula and somatosensory cortex. Conclusion Acute hypernatremia increases local functional connectivity within the CVOs and between cortical sensory regions of the brain.