Masking by hypokalemia—primary aldosteronism with undetectable aldosterone

Primary aldosteronism is the most common cause of secondary hypertension; however, the dynamic regulation of aldosterone by potassium is less well studied and current diagnostic recommendations are imprecise. We describe a young man who presented with resistant hypertension and severe hypokalemia. The workup initially revealed undetectable aldosterone despite acute potassium repletion. Chronic potassium supplementation eventually uncovered hyperaldosteronism. In situ genetic studies revealed a gain-of-function KCNJ5 mutation within an aldosterone-producing adenoma that was clinically responsive to changes in extracellular potassium. We highlight a unique presentation of Conn’s syndrome and discuss the implications for the molecular mechanisms of potassium regulation of aldosterone.

Extra-gastric expression of the proton pump H+/K+-ATPase in the gills and kidney of the teleost Oreochromis niloticus

ABSTRACTPotassium regulation is essential for the proper functioning of excitable tissues in vertebrates. The H+/K+-ATPase (HKA), which is composed of the HKα1 (gene: atp4a) and HKβ (gene: atp4b) subunits, has an established role in potassium and acid–base regulation in mammals and is well known for its role in gastric acidification. However, the role of HKA in extra-gastric organs such as the gill and kidney is less clear, especially in fishes. In the present study in Nile tilapia, Oreochromis niloticus, uptake of the K+ surrogate flux marker rubidium (Rb+) was demonstrated in vivo; however, this uptake was not inhibited with omeprazole, a potent inhibitor of the gastric HKA. This contrasts with gill and kidney ex vivo preparations, where tissue Rb+ uptake was significantly inhibited by omeprazole and SCH28080, another gastric HKA inhibitor. The cellular localization of this pump in both the gill and kidney was demonstrated using immunohistochemical techniques with custom-made antibodies specific for Atp4a and Atp4b. Antibodies against the two subunits showed the same apical ionocyte distribution pattern in the gill and collecting tubules/ducts in the kidney. Atp4a antibody specificity was confirmed by western blotting. RT-PCT was used to confirm the expression of both subunits in the gill and kidney. Taken together, these results indicate for the first time K+ (Rb+) uptake in O. niloticus and that HKA is implicated, as shown through the ex vivo uptake inhibition by omeprazole and SCH28080, verifying a role for HKA in K+ absorption in the gill's ionocytes and collecting tubule/duct segments of the kidney.

Serotonin, norepinephrine and acetylcholine differentially affect astrocytic potassium clearance to modulate somatosensory signaling in male mice

Changes in extracellular potassium ([K+]e) modulate neuronal networks via changes in membrane potential, voltage-gated channel activity and alteration of transmission at the synapse. Given the limited extracellular space in the CNS, potassium clearance is crucial. As activity-induced potassium transients are rapidly managed by astrocytic Kir4.1 and astrocyte-specific Na+/K+-ATPase (NKA), any neurotransmitter/neuromodulator that can regulate their function may have indirect influence on network activity. Neuromodulators differentially affect cortical/thalamic networks to align sensory processing with differing behavioral states. Given serotonin (5HT), norepinephrine (NE), and acetylcholine (ACh) differentially affect spike frequency adaptation and signal fidelity (“signal-to-noise”) in somatosensory cortex, we hypothesize that [K+]e may be differentially regulated by the different neuromodulators to exert their individual effects on network function. This study aimed to compare effects of individually applied 5HT, NE, and ACh on regulating [K+]e in connection to effects on cortical evoked response amplitude and adaptation in male mice. Using extracellular field and K+ ion-selective recordings of somatosensory stimulation, we found that differential effects of 5HT, NE, and ACh on [K+]e regulation mirrored differential effects on amplitude and adaptation. 5HT effects on transient K+ recovery, adaptation and field post-synaptic potential amplitude were disrupted by barium (200 µM), whereas NE and ACh effects were disrupted by ouabain (1 µM) or iodoacetate (100 µM). Considering the impact [K+]e can have on many network functions; it seems highly efficient that neuromodulators regulate [K+]e to exert their many effects. This study provides functional significance for astrocyte-mediated buffering of [K+]e in neuromodulator-mediated shaping of cortical network activity.Significance statementWe demonstrate that the neuromodulators serotonin, norepinephrine, and acetylcholine all have distinct effects on astrocyte-mediated extracellular potassium regulation and that these differential actions are associated with the different effects of the neuromodulators on cortical networks. By affecting astrocytic potassium regulation, long-range neuromodulatory networks can rapidly and efficiently affect broad areas of the brain. Given that neuromodulatory networks are at the core of our behavioral state and determine how we interact with our environment, these studies highlight the importance of basic astrocyte function in general cognition and psychiatric disorders.