scholarly journals Long-Term Pharmacological Inhibition of the Activity of All NOS Isoforms Rather Than Genetic Knock-Out of Endothelial NOS Leads to Impaired Spatial Learning and Memory in C57BL/6 Mice

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1905
Author(s):  
Jhana O. Hendrickx ◽  
Sofie De Moudt ◽  
Elke Calus ◽  
Peter Paul De Deyn ◽  
Debby Van Dam ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Arterial Stiffness ◽  
Cognitive Decline ◽  
Learning And Memory ◽  
Selective Inhibition ◽  
Underlying Mechanism ◽  
Spatial Learning And Memory ◽  
Potential Contribution ◽  
Knock Out ◽  
Dependent Learning

Increasing epidemiological and experimental evidence points to a link between arterial stiffness and rapid cognitive decline. However, the underlying mechanism linking the two diseases is still unknown. The importance of nitric oxide synthases in both diseases is well-defined. In this study, we introduced arterial stiffness in both genetic (eNOS−/−, endothelial nitric oxide synthase knockout) and pharmacological (N(G)-nitro-L-arginine methyl ester (L-NAME) treatment) NO dysfunction models to study their association with cognitive decline. Our findings demonstrate that the non-selective inhibition of NOS activity with L-NAME induces cardiac dysfunction, arterial stiffness, and a decline in hippocampal-dependent learning and memory. This outcome demonstrates the importance of neuronal NOS (nNOS) in both cardiovascular and neurological pathophysiology and its potential contribution in the convergence between arterial stiffness and cognitive decline.

scholarly journals Mitochondrial clearance of Ca2+ controls insulin secretion

2019 ◽  
Author(s):  
N Vishnu ◽  
A Hamilton ◽  
A Bagge ◽  
A Wernersson ◽  
E Cowan ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Insulin Secretion ◽  
Selective Inhibition ◽  
Underlying Mechanism ◽  
Β Cells ◽  
Intact Cells ◽  
Membrane Hyperpolarization ◽  
Knock Out

SUMMARYTransport of Ca2+ from the cytosol to the mitochondrial matrix of insulin-secreting pancreatic β-cells facilitates nutrient-mediated insulin secretion. However, the underlying mechanism is unclear. The establishment of the molecular identity of the mitochondrial Ca2+ uniporter (MCU) and associated proteins has allowed mitochondrial Ca2+ transport to be modified in intact cells. We examined the consequences of deficiency of the accessory protein, MICU2, in rat and human insulin-secreting cell lines as well as in mouse islets. Glucose-induced mitochondrial Ca2+ elevation and inner membrane hyperpolarization were reduced, together with cytosolic ATP/ADP-ratios and insulin secretion. Insulin secretion in Micu2 knock out mice was attenuated in vitro as well as in vivo. While KCl-evoked sub-plasmalemmal Ca2+ increases were more pronounced, the global cytosolic Ca2+ response was, surprisingly, diminished in MICU2-deficient cells. These findings were supported by selective inhibition of mitochondrial Ca2+ uptake by mitochondrial depolarization. It is concluded that mitochondrial Ca2+ transport plays an additional and hitherto unrecognized role in stimulated β-cells by regulating net Ca2+ entry across the plasma membrane. This is likely accounted for by clearing of sub-plasmalemmal Ca2+ levels by mitochondria located near the plasma membrane.

Effects of phencyclidine on spatial learning and memory: Nitric oxide-dependent mechanisms

2006 ◽  
Vol 171 (1) ◽  
pp. 147-153 ◽  
Author(s):  
Caroline Wass ◽  
Trevor Archer ◽  
Erik Pålsson ◽  
Kim Fejgin ◽  
Daniel Klamer ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Spatial Learning And Memory
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