This article examines the pathophysiology of lesions caused by focal cerebral ischemia. Ischemia due to middle cerebral artery occlusion encompasses a densely ischemic focus and a less densely ischemic penumbral zone. Cells in the focus are usually doomed unless reperfusion is quickly instituted. In contrast, although the penumbra contains cells "at risk," these may remain viable for at least 4 to 8 hours. Cells in the penumbra may be salvaged by reperfusion or by drugs that prevent an extension of the infarction into the penumbral zone. Factors responsible for such an extension probably include acidosis, edema, K+/Ca++ transients, and inhibition of protein synthesis. Central to any discussion of the pathophysiology of ischemic lesions is energy depletion. This is because failure to maintain cellular adenosine triphosphate (ATP) levels leads to degradation of macromolecules of key importance to membrane and cytoskeletal integrity, to loss of ion homeostasis, involving cellular accumulation of Ca++, Na+, and Cl-, with osmotically obligated water, and to production of metabolic acids with a resulting decrease in intra- and extracellular pH. In all probability, loss of cellular calcium homeostasis plays an important role in the pathogenesis of ischemic cell damage. The resulting rise in the free cytosolic intracellular calcium concentration (Ca++) depends on both the loss of calcium pump function (due to ATP depletion), and the rise in membrane permeability to calcium. In ischemia, calcium influx occurs via multiple pathways. Some of the most important routes depend on activation of receptors by glutamate and associated excitatory amino acids released from depolarized presynaptic endings. However, ischemia also interfers with the intracellular sequestration and binding of calcium, thereby contributing to the rise in intracellular Ca++. A second key event in the ischemic tissue is activation of anaerobic glucolysis. The main reason for this activation is inhibition of mitochondrial metabolism by lack of oxygen; however, other factors probably contribute. For example, there is a complex interplay between loss of cellular calcium homeostasis and acidosis. On the one hand, a rise in intracellular Ca++ is apt to cause mitochondrial accumulation of calcium. This must interfere with ATP production and enhance anaerobic glucolysis. On the other hand, acidosis must interfere with calcium binding, thereby contributing to the rise in intracellular Ca++.

Pathophysiology and treatment of focal cerebral ischemia: Part I: Pathophysiology

The cation conductance activated upon hyperpolarization of the membrane beyond the resting value appears to represent an ubiquitous type of membrane channel. Our understanding of the respective membrane current, termed Ih, in neurons has matured from that of a "queer" current toward that of a highly regulated mechanism that is particularly important in determining integrative behavior near rest and providing the pacemaker depolarization during rhythmic-oscillatory activity.

QUEER CURRENT AND PACEMAKER: The Hyperpolarization- Activated Cation Current in Neurons

✓ The mechanisms that give rise to ischemic brain damage have not been definitively determined, but considerable evidence exists that three major factors are involved: increases in the intercellular cytosolic calcium concentration (Ca++i), acidosis, and production of free radicals. A nonphysiological rise in Ca++i due to a disturbed pump/leak relationship for calcium is believed to cause cell damage by overactivation of lipases and proteases and possibly also of endonucleases, and by alterations of protein phosphorylation, which secondarily affects protein synthesis and genome expression. The severity of this disturbance depends on the density of ischemia. In complete or near-complete ischemia of the cardiac arrest type, pump activity has ceased and the calcium leak is enhanced by the massive release of excitatory amino acids. As a result, multiple calcium channels are opened. This is probably the scenario in the focus of an ischemic lesion due to middle cerebral artery occlusion. Such ischemic tissues ca...

Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment.

tance, impaired drug clearance, and mild coagulopathy. Targeted interventions are required to effectively manage these side effects. Hypothermia does not decrease myocardial contractility or induce hypotension if hypovolemia is corrected, and preliminary evidence suggests that it can be safely used in patients with cardiac shock. Cardiac output will decrease due to hypothermiainduced bradycardia, but given that metabolic rate also decreases the balance between supply and demand, is usually maintained or improved. In contrast to deep hypothermia (<30°C), moderate hypothermia does not induce arrhythmias; indeed, the evidence suggests that arrhythmias can be prevented and/or more easily treated under hypothermic conditions. Conclusions: Therapeutic hypothermia is a highly promising treatment, but the potential side effects need to be properly managed particularly if prolonged treatment periods are required. Understanding the underlying mechanisms, awareness of physiological changes associated with cooling, and prevention of potential side effects are all key factors for its effective clinical usage. (Crit Care Med 2009; 37[Suppl.]:S186 –S202)

https://emcrit.org/wp-content/hypoarts/polderman%20mechs%20of%20hypothermia.pdf

Mechanisms of action, physiological effects, and complications of hypothermia.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels comprise a small subfamily of proteins within the superfamily of pore-loop cation channels. In mammals, the HCN channel family com...

Hyperpolarization-activated cation channels: from genes to function.

Around 1970, Fleckenstein postulated that cardiac muscle damage following ischemia or excessive stimulation with catecholamines was due to calcium entry and mitochondrial calcium overload (e .g . , REF. 1). Somewhat later, a similar hypothesis was advanced to explain cell necrosis in dystrophic skeletal muscle.2 It soon emerged that lethal calcium influx could occur, not only via voltage-sensitive calcium channels (VSCCs), but also via those operated by agonists (AOCCS).~ Subsequently, Schanne et al.4 suggested that liver cell damage due to a variety of toxins was mediated by calcium influx (see also REF. 5). These various hypotheses of calcium-related cell necrosis thus have in common the assumption that cell calcium homeostasis is upset by enhanced influx inlo the cell, the routes of entry varying with the condition. Brain damage usually occurs in one of two forms: selective neuronal vulnerability, affecting groups of neurons with a characteristic distribution within the brain, and infarction or pan-necrosis, affecting not only neurons but also glial cells and vascular elements. When it was originally thought that selective neuronal vulnerability in ischemia, hypoglycemia, and status epilepticus is a calcium-related phenomenon, it was tacitly assumed that calcium entered through VSCCs in the apical dendrites of vulnerable (burst-firing) neurons.6 It was soon reported that, following a transient ischemic insult, both net calcium accumulation and neuronal necrosis may be considerably delayed (see REF. 7). Since calcium accumulation seemed to precede light microscopical evidence of cell necrosis, the hypothesis was advanced that increased calcium cycling across damaged membranes causes gradual mitochondrial overload and, after varying delays, cell necrosis.8 However, although this may be one of the mechanisms involved, the gen'eral consensus is that some of the most important consequences of a disordered calcium homeostasis are activation of lipases, proteases, and endonucleases (see REFS. 6,9-12 and, for corresponding data on liver tissue, 13,14). Although doubts have been raised that calcium is an obligatory mediator of anoxic (or toxic) cell death, 1 5 , 1 6 recent results strongly indicate that necrosis of neurons, exposed to anoxia or excitotoxins, is calcium-mediated.'7-'9 In fact, it now seems likely that anoxic neuronal damage, at least in part, represents an excitotoxic lesion caused by enhanced

Calcium, Excitotoxins, and Neuronal Death in the Braina

1. A polarization-induced membrane current, IQ, was investigated in the slowly adapting lobster stretch receptor neurone using conventional electrophysiological techniques including intracellular ion measurements. 2. The current was readily blocked by Cs+ in a voltage-dependent manner, but proved to be unaffected by tetrodotoxin, tetraethylammonium and 4-aminopyridine. 3. From an analysis of the ionic basis of IQ, it appeared that the current is carried by both Na+ and K+ through a membrane channel whose permeability for K+ is about six times larger than that for Na+ in a normal ionic environment. In the presence of reduced external Na+ concentration the Q-channel increases its permeability for both Na+ and K+, but more so for Na+ than for K+. 4. Kinetically, IQ was found to be characterized by a steep sigmoidal relationship between membrane voltage and steady-state current activation, and by a bell-shaped relationship between membrane voltage and the time constant of the exponential phase of current activation or deactivation. A significant feature of the latter relationship is a tendency to level off at finite time-constant values in both strongly hyperpolarizing and strongly depolarizing voltage regions. 5. From the experiments a mathematical IQ model was inferred. This model was based on constant-field and channel-gating kinetics involving a voltage-dependent reaction step in series with a voltage-independent reaction step. The model was found to successfully reproduce IQ behaviour in the living preparation. 6. Functionally, the activation of IQ was found to play a role in setting the cell's resting polarization and membrane excitability. This function was inferred from experiments on unimpaled cells in which it was possible to demonstrate some overlap between the voltage ranges of IQ activation and impulse initiation. In addition, in impaled cells the activation of IQ was found to cause some shortening of post-tetanic membrane hyperpolarization and to accelerate, thereby, the post-tetanic restoration of membrane excitability to control levels.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1987.sp016476

Current activation by membrane hyperpolarization in the slowly adapting lobster stretch receptor neurone.

1. The gated membrane currents (a tetrodotoxin-sensitive Na+ current and a tetraethylammonium- and 4-aminopyridine-sensitive K+ current) of the rapidly adapting stretch receptor neurone of lobster were investigated with respect to their kinetic properties using electrophysiological, pharmacological, and mathematical techniques. 2. The currents were found to be controlled by slow inactivations as well as by fast Hodgkin-Huxley (1952) gating processes. They could be described by kinetic expressions which differed from those inferred for the slowly adapting receptor (Gestrelius & Grampp, 1983a; Gestrelius, Grampp & Sjolin, 1983) only with respect to some of the parameter values. 3. With these expressions, and additional equations for the cell's pump and leak current components (Edman, Gestrelius & Grampp, 1986), a mathematical receptor model was formulated which accurately predicts the impulse activity of the living preparation in different functional circumstances and which, therefore, was adopted as an appropriate theory of firing regulation. 4. From a model analysis it appeared (a) that the 'rapid' adaptation of the receptor's impulse activity is mainly an effect of slow Na+ current inactivation starting a regenerative process of accommodation which, basically, is due to a small ratio of subthreshold Na+ to K+ currents; (b) that, because of the transmembrane Na+ influx being limited by accommodation, impulse firing is only little affected by a Na+-dependent pump current activation; and (c) that the phenomenon of increased firing frequency initially during prolonged stimulation ('negative adaptation') is an effect of the slow K+ current inactivation being faster than the slow Na+ current inactivation at comparable degrees of membrane polarization. 5. From further model studies it also appeared that, during depolarizations between successive action potentials evoked by constant stimulation, the membrane behaves like a high-resistance constant-current generator feeding into a short-circuiting capacitor. In consequence, the cell's stimulus sensitivity (change in firing frequency with stimulation strength) is, at functionally relevant stimulation intensities, mainly determined by the membrane capacitance and by the amplitude of the interspike membrane depolarization while, at higher stimulation intensities and firing frequencies, it becomes more and more a function of the spike duration itself.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1987.sp016475

Analysis of gated membrane currents and mechanisms of firing control in the rapidly adapting lobster stretch receptor neurone.

The hypothesis that neuroepithelial endocrine (NEE) cells control spontaneous tone in isolated guinea pig tracheal preparations was examined. Epithelium-denuded preparations were unable to develop ...

https://www.physiology.org/doi/pdf/10.1152/jappl.1999.86.3.789

Evidence that neuroepithelial endocrine cells control the spontaneous tone in guinea pig tracheal preparations.

1. The ion currents in the slowly and rapidly adapting stretch receptor neurone of lobster were investigated with respect to their nature and stationary kinetics in sub- and near-threshold voltage regions using electrophysiological and pharmacological techniques. 2. In both neurones the following currents were identified: (a) a tetrodotoxin-sensitive Na current, (b) a tetraethylammonium and 4-aminopyridine-sensitive K current, (c) a Co (or Mn)-sensitive Ca-dependent K current, (d) an ouabain-sensitive pump current and (e) a remaining leak current carried mainly by Na, K and Cl. 3. In suprathreshold voltage regions the balance between the individual membrane currents leads to the formation of a stationary negative conductance (negative slope in the voltage dependence of the ionic current) in the slowly, but not in the rapidly adapting cell. 4. These observations are compatible with the fact that during prolonged suprathreshold stimulation a stationary low frequency impulse during is possible in the slowly adapting cell, whereas in the rapidly adapting cell it is not.

Subthreshold and near-threshold membrane currents in lobster stretch receptor neurones.

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