scholarly journals Functional coupling between NMDA receptors and SK channels in rat hypothalamic magnocellular neurons: altered mechanisms during heart failure

2019 ◽  
Author(s):  
HC Ferreira-Neto ◽  
JE Stern
Keyword(s):  
Heart Failure ◽  
Nmda Receptors ◽  
Neuronal Activity ◽  
Functional Coupling ◽  
Pathophysiological Mechanism ◽  
Sk Channels ◽  
Excitatory Effect ◽  
Neurosecretory Neurons ◽  
Nmdar Activation ◽  
Patch Clamp Electrophysiology

ABSTRACTGlutamatergic NMDA receptors (NMDAR) and small conductance Ca2+-activated K+ channels (SK) are critical synaptic and intrinsic mechanisms that regulate the activity of hypothalamic magnocellular neurosecretory neurons (MNNs) under physiological and pathological states, including lactation and heart failure (HF). Still, whether NMDARs and SK channels in MNNs are functionally coupled, and whether changes in this coupling contribute to exacerbated neuronal activity during HF is at present unknown. In the present study, we addressed these questions using patch-clamp electrophysiology and confocal Ca2+ imaging in a rat model of ischaemic HF. We found that in MNNs of sham rats, blockade of SK channels with apamin (200 nM) significantly increased the magnitude of an NMDAR-evoked current (INMDA). We also observed that blockade of SK channels potentiated NMDAR-evoked firing, and abolished spike frequency adaptation in MNNs from sham, but not HF rats. Importantly, a larger INMDA-ΔCa2+response was observed under basal conditions in HF compared to sham rats. Finally, we found that dialyzing recorded cells with the Ca2+ chelator BAPTA (10 mM) increased the magnitude of INMDA in MNNs from both sham and HF rats, and occluded the effects of apamin in the former. Together, our studies demonstrate that in MNNs, NMDARs and SK channels are functionally coupled, forming a local negative feedback loop that restrains the excitatory effect evoked by NMDAR activation. Moreover, our studies also support a blunted NMDAR-SK channel coupling in MNNs of HF rats, standing thus as a pathophysiological mechanism contributing to exacerbated hypothalamic neuronal activity during this prevalent neurogenic cardiovascular disease.

scholarly journals Enhanced NMDA receptor-mediated intracellular calcium signaling in magnocellular neurosecretory neurons in heart failure rats

2013 ◽  
Vol 305 (4) ◽  
pp. R414-R422 ◽  
Author(s):  
Javier E. Stern ◽  
Evgeniy S. Potapenko
Keyword(s):  
Heart Failure ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Neuronal Activity ◽  
Receptor Activation ◽  
Membrane Depolarization ◽  
Neurosecretory Cells ◽  
Firing Activity ◽  
Nmda Current ◽  
Intracellular Ca

An enhanced glutamate excitatory function within the hypothalamic supraoptic and paraventricluar nuclei is known to contribute to increased neurosecretory and presympathetic neuronal activity, and hence, neurohumoral activation, during heart failure (HF). Still, the precise mechanisms underlying enhanced glutamate-driven neuronal activity in HF remain to be elucidated. Here, we performed simultaneous electrophysiology and fast confocal Ca2+ imaging to determine whether altered N-methyl-d-aspartate (NMDA) receptor-mediated changes in intracellular Ca2+ levels (NMDA-ΔCa2+) occurred in hypothalamic magnocellular neurosecretory cells (MNCs) in HF rats. We found that activation of NMDA receptors resulted in a larger ΔCa2+ in MNCs from HF when compared with sham rats. The enhanced NMDA-ΔCa2+ was neither dependent on the magnitude of the NMDA-mediated current (voltage clamp) nor on the degree of membrane depolarization or firing activity evoked by NMDA (current clamp). Differently from NMDA receptor activation, firing activity evoked by direct membrane depolarization resulted in similar changes in intracellular Ca2+ in sham and HF rats. Taken together, our results support a relatively selective alteration of intracellular Ca2+ homeostasis and signaling following activation of NMDA receptors in MNCs during HF. The downstream functional consequences of such altered ΔCa2+ signaling during HF are discussed.

scholarly journals Ethanol and the Developing Brain: Inhibition of Neuronal Activity and Neuroapoptosis

2017 ◽  
Vol 24 (2) ◽  
pp. 130-141 ◽  
Author(s):  
Nailya Lotfullina ◽  
Roustem Khazipov
Keyword(s):  
Nmda Receptors ◽  
Neuronal Activity ◽  
Activity Patterns ◽  
Gamma Oscillations ◽  
Cortical Activity ◽  
Neuronal Firing ◽  
Developing Brain ◽  
Pathophysiological Mechanism ◽  
Intracortical Circuits ◽  
Early Activity

Ethanol induces massive neuroapoptosis in the developing brain. One of the main hypotheses that has been put forward to explain the deleterious actions of ethanol in the immature brain involves an inhibition of neuronal activity. Here, we review recent evidence for this hypothesis obtained in the somatosensory cortex and hippocampus of neonatal rodents. In both structures, ethanol strongly inhibits brain activity. At the doses inducing massive neuroapoptosis, ethanol completely suppresses the early activity patterns of spindle-bursts and gamma oscillations in the neocortex and the early sharp-waves in the hippocampus. The inhibitory effects of ethanol decrease with age and in adult animals, ethanol only mildly depresses neuronal firing and induces delta-wave activity. Suppression of cortical activity in neonatal animals likely involves inhibition of the myoclonic twitches, an important physiological trigger for the early activity bursts, and inhibition of the thalamocortical and intracortical circuits through a potentiation of GABAergic transmission and an inhibition of N-methyl-d-aspartate (NMDA) receptors, that is in keeping with the neuroapoptotic effects of other agents acting on GABA and NMDA receptors. These findings provide support for the hypothesis that the ethanol-induced inhibition of cortical activity is an important pathophysiological mechanism underlying massive neuroapoptosis induced by ethanol in the developing brain.

scholarly journals A Functional Coupling Between Carbon Monoxide and Nitric Oxide Contributes to Increased Vasopressin Neuronal Activity in Heart Failure rats

Endocrinology ◽  
2016 ◽  
Vol 157 (5) ◽  
pp. 2052-2066 ◽  
Author(s):  
Wagner L. Reis ◽  
Vinicia C. Biancardi ◽  
Yiqiang Zhou ◽  
Javier E. Stern
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Carbon Monoxide ◽  
Neuronal Activity ◽  
Functional Coupling

Humoral Immunity in Heart Failure

2019 ◽  
Vol 19 (1) ◽  
pp. 14-18 ◽  
Author(s):  
Amrita Sarkar ◽  
Khadija Rafiq
Keyword(s):  
Heart Failure ◽  
Humoral Immunity ◽  
Treatment Strategies ◽  
Pathophysiological Mechanism ◽  
Peripheral Vascular ◽  
Cardiac Inflammation ◽  
Humoral Immune ◽  
Humoral Immune System ◽  
New Treatment ◽  
Immunity Function

Cardiovascular Disease (CVD) is a class of diseases that involve disorders of heart and blood vessels, including hypertension, coronary heart disease, cerebrovascular disease, peripheral vascular disease, which finally lead to Heart Failure (HF). There are several treatments available all over the world, but still, CVD and heart failure became the number one problem causing death every year worldwide. Both experimental and clinical studies have shown a role for inflammation in the pathogenesis of heart failure. This seems related to an imbalance between pro-inflammatory and anti-inflammatory cytokines. Cardiac inflammation is a major pathophysiological mechanism operating in the failing heart, regardless of HF aetiology. Disturbances of the cellular and humoral immune system are frequently observed in heart failure. This review describes how B-cells play a specific role in the heart failure states. There is an urgent need to identify novel therapeutic targets and develop advanced therapeutic strategies to combat the syndrome of HF. Understanding and describing the elements of the humoral immunity function are essential and may suggest potential new treatment strategies.

Sustained paradoxical vasodilation during orthostasis in heart failure: a factor in the edema pathogenesis?

1994 ◽  
Vol 267 (2) ◽  
pp. H443-H448 ◽  
Author(s):  
H. Wroblewski
Keyword(s):  
Heart Failure ◽  
Blood Flow ◽  
Dilated Cardiomyopathy ◽  
Regional Blood Flow ◽  
Functional Class ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Pathophysiological Mechanism ◽  
Class Iii ◽  
Control Subjects ◽  
Subcutaneous Blood Flow

Baroreceptor-induced peripheral reflex vasoconstriction during upright posture is an important edema-prevention mechanism in humans. Congestive heart failure (CHF) has been associated with blunted baroreceptor control of regional blood flow during short-term head-up tilt. The effect of prolonged unloading of baroreceptors on subcutaneous blood flow of the calf was investigated in 12 healthy subjects and in 13 patients with severe idiopathic dilated cardiomyopathy (New York Heart Association functional class III or IV). The subjects were studied both supine and sitting for 3-h periods. When sitting, subcutaneous vascular resistance decreased -26 +/- 19% in CHF patients and increased 90 +/- 69% in control subjects (P < 0.0001). The corresponding subcutaneous blood flow increased 43 +/- 29% in patients with CHF compared with the decrease of -42 +/- 17% in control subjects (P < 0.0001). I conclude that patients with CHF secondary to idiopathic dilated cardiomyopathy have an abnormal baroreceptor-mediated peripheral vasodilation during orthostatic stress that is sustained for hours. This extended paradoxical vasodilation may participate as an additional pathophysiological mechanism contributing to lower extremity edema in patients with CHF.

scholarly journals Ignoring a basic pathophysiological mechanism of heart failure progression will not make it go away

2021 ◽  
Author(s):  
A. Martin Gerdes ◽  
Michael A. Portman ◽  
Giorgio Iervasi ◽  
Alessandro Pingitore ◽  
David KC Cooper ◽  
...  
Keyword(s):  
Heart Failure ◽  
Clinical Trials ◽  
Thyroid Hormone ◽  
Cardiac Patients ◽  
Steady Increase ◽  
Pathophysiological Mechanism ◽  
General Belief ◽  
Heart Patients ◽  
Heart Failure Progression

A link between heart failure (HF) and low thyroid hormone (TH) function has been known for over a century. Nonetheless, there is a general belief that TH treatment of HF patients may not be worth the risk. This is largely based on two clinical trials where heart patients were treated with excessive doses of TH analogs, not actual THs. Further complicating the issue is the fact that normalization of THs in non-cardiac patients can often be challenging. This issue is not going away as noted by a steady increase in TH-HF citations in recent years. In this article, we discuss what we know and how we may move the field forward.

Sign in / Sign up

Export Citation Format

Share Document