Background
We have demonstrated that the antihypertensive effect of the angiotensin‐converting enzyme inhibitor, captopril (
CAP
), is associated with beneficial effects on gut pathology. Coupled with the evidence that
CAP
exerts prolonged reduction in blood pressure (
BP
) after discontinuation of treatment, we investigate whether persistent beneficial actions of
CAP
are linked to alterations of gut microbiota and improvement of hypertension‐induced gut pathology.
Methods and Results
Spontaneously hypertensive rats (
SHR
) and Wistar Kyoto rats were treated with
CAP
(250 mg/kg/day) for 4 weeks followed by withdrawal for 16 weeks. Gut microbiota, gut pathology,
BP,
and brain neuronal activity were assessed.
CAP
resulted in a ≈60 mm Hg decrease in systolic
BP
after 3 weeks of treatment in
SHR
, and the decrease remained significant at least 5 weeks after
CAP
withdrawal. In contrast,
CAP
caused modest decrease in systolic
BP
in Wistar Kyoto. 16S
rRNA
gene‐sequencing–based gut microbial analyses in
SHR
showed sustained alteration of gut microbiota and increase in
Allobaculum
after
CAP
withdrawal. Phylogenetic investigation of communities by reconstruction of unobserved states analysis revealed significant increase in bacterial sporulation upon
CAP
treatment in
SHR
. These were associated with persistent improvement in gut pathology and permeability. Furthermore, manganese‐enhanced magnetic resonance imaging showed significantly decreased neuronal activity in the posterior pituitary of
SHR
4 weeks after withdrawal.
Conclusions
Decreased
BP
, altered gut microbiota, improved gut pathology and permeability, and dampened posterior pituitary neuronal activity were maintained after
CAP
withdrawal in the
SHR
. They suggest that
CAP
influences the brain‐gut axis to maintain the sustained antihypertensive effect of
CAP
after withdrawal.
Stimuli presented at short temporal delays before functional magnetic resonance imaging (fMRI) can have a robust impact on the organization of synchronous activity in resting state networks. This presents an opportunity to investigate how sensory, affective and cognitive stimuli alter functional connectivity in rodent models. In the present study we assessed the effect on functional connectivity of a familiar contextual stimulus presented 10 min prior to sedation for imaging. A subset of animals were co-presented with an unfamiliar social stimulus in the same environment to further investigate the effect of familiarity on network topology. Rats were imaged at 11.1 T and graph theory analysis was applied to matrices generated from seed-based functional connectivity data sets with 144 brain regions (nodes) and 10,152 pairwise correlations (after excluding 144 diagonal edges). Our results show substantial changes in network topology in response to the familiar (context). Presentation of the familiar context, both in the absence and presence of the social stimulus, strongly reduced network strength, global efficiency, and altered the location of the highest eigenvector centrality nodes from cortex to the hypothalamus. We did not observe changes in modular organization, nodal cartographic assignments, assortative mixing, rich club organization, and network resilience. We propose that experiential factors, perhaps involving associative or episodic memory, can exert a dramatic effect on functional network strength and efficiency when presented at a short temporal delay before imaging.
Manganese exposure produces Parkinson's-like neurologic symptoms, suggesting a selective dysregulation of dopamine transmission. It is unknown, however, how manganese accumulates in dopaminergic brain regions or how it regulates the activity of dopamine neurons. Our in vivo studies in male C57BLJ mice suggest that manganese accumulates in dopamine neurons of the VTA and substantia nigra via nifedipine-sensitive Ca 21 channels. Manganese produces a Ca 21 channel-mediated current, which increases neurotransmitter release and rhythmic firing activity of dopamine neurons. These increases are prevented by blockade of Ca 21 channels and depend on downstream recruitment of Ca 21 -activated potassium channels to the plasma membrane. These findings demonstrate the mechanism of manganese-induced dysfunction of dopamine neurons, and reveal a potential therapeutic target to attenuate manganese-induced impairment of dopamine transmission.
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