Acute hypernatremia increases functional connectivity of NaCl sensing regions in the human brain: An fMRI pilot study.

Rodent studies demonstrated specialized sodium chloride (NaCl) sensing neurons in the circumventricular organs, which mediate changes in sympathetic nerve activity, arginine vasopressin, thirst, and blood pressure. However, the neural pathways involved in NaCl sensing in the human brain are incompletely understood. The purpose of this pilot study was to determine if acute hypernatremia alters the functional connectivity of NaCl-sensing regions of the brain in healthy young adults. Resting-state fMRI scans were acquired in 13 participants at baseline and during a 30 min hypertonic saline infusion (HSI). We used a seed-based approach to analyze the data, focusing on the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) as regions of interest (ROIs). Blood chemistry and perceived thirst were assessed pre- and post-infusion. As expected, serum sodium increased from pre- to post-infusion in the HSI group. The primary finding of this pilot study was that the functional connectivity between the SFO and a cluster within the OVLT increased from baseline to the late-phase of the HSI. Bidirectional connectivity changes were found with cortical regions, with some regions showing increased connectivity with sodium-sensing regions while others showed decreased connectivity. Furthermore, the functional connectivity between the SFO and the posterior cingulate cortex (a control ROI) did not change from baseline to the late-phase of the HSI. This finding indicates a distinct response within the NaCl sensing network in the human brain specifically related to acute hypernatremia that will need to be replicated in large-scale studies.

Inverse salt sensitivity in normotensive adults: role of demographic factors.

BACKGROUND: Salt sensitivity and inverse salt sensitivity [ISS; a reduction in blood pressure (BP) on a high sodium diet] are each associated with increased incidence of hypertension. The purpose of this analysis was to determine the prevalence of ISS in normotensive adults and whether ISS is associated with any demographic characteristic(s). METHODS: Healthy normotensive, nonobese adults [ n  = 84; 43 women; age = 37 ±â€Š13 years; baseline mean arterial pressure (MAP) = 89 ±â€Š8 mmHg] participated in a controlled feeding study, consuming 7-day low-sodium (20 mmol sodium/day) and high-sodium (300 mmol sodium/day) diets. Twenty-four-hour ambulatory BP was assessed on the last day of each diet. ISS was defined as a reduction in 24-h MAP more than 5 mmHg, salt sensitivity as an increase in MAP more than 5 mmHg and salt resistance as a change in MAP between -5 and 5 mmHg from low sodium to high sodium. RESULTS: Using this cutoff, 10.7% were ISS, 76.2% salt resistant, and 13.1% salt sensitive. Prevalence of ISS was similar between sexes and age groups ( P  > 0.05). However, ISS was more prevalent in those with normal BMI (15.8% ISS) compared with those with overweight BMI (0% ISS; P  < 0.01). Interestingly, classification of participants using a salt sensitivity index (ΔMAP/Δ urinary sodium excretion) categorized 21.4% as ISS, 48.8% salt resistant, and 29.8% salt sensitive. CONCLUSION: Overall, we found that the prevalence of ISS was 10.7% (5 mmHg cutoff) or 21.4% (salt sensitivity index), and that ISS was associated with lower BMI. These results highlight the importance of future work to understand the mechanisms of ISS and to standardize salt sensitivity assessment.

Approved Glycopeptide Antibacterial Drugs: Mechanism of Action and Resistance.

The glycopeptide antimicrobials are a group of natural product and semisynthetic glycosylated peptides that show antibacterial activity against Gram-positive organisms through inhibition of cell-wall synthesis. This is achieved primarily through binding to the d-alanyl-d-alanine terminus of the lipid II bacterial cell-wall precursor, preventing cross-linking of the peptidoglycan layer. Vancomycin is the foundational member of the class, showing both clinical longevity and a still preferential role in the therapy of methicillin-resistant Staphylococcus aureus and of susceptible Enterococcus spp. Newer lipoglycopeptide derivatives (telavancin, dalbavancin, and oritavancin) were designed in a targeted fashion to increase antibacterial activity, in some cases through secondary mechanisms of action. Resistance to the glycopeptides emerged in delayed fashion and occurs via a spectrum of chromosome- and plasmid-associated elements that lead to structural alteration of the bacterial cell-wall precursor substrates.

ETA selective receptor antagonism prevents ventricular remodeling in volume-overloaded rats.

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 + ETA, 25 mg.kg(-1).day(-1))-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 +/- 0.7 vs. 0.3 +/- 0.3 vs. 0.9 +/- 0.2 arbitrary activity units, Fist vs. Fist + ETA vs. Sham, P < or = 0.05). This same effect was also seen at 5 days postfistula (1.9 +/- 0.3 vs. 0.5 +/- 0.1 arbitrary activity units, Fist vs. Fist + ETA, P < or = 0.05). The marked decrease in myocardial CVF seen in Fist hearts (0.7 +/- 0.1 vs. 1.6 +/- 0.1% myocardial area, Fist vs. Sham, P < or = 0.05) was prevented by ETA (1.7 +/- 0.1% Fist + ETA, P < 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 +/- 0.1 vs. 1.4 +/- 0.1%, Fist vs. Fist + ETA, P < or = 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.