Control respiratory

When the mitochondria are allowed to produce ATP, for example by adding ADP and Pj to an incubation, the potential and current parameters of the proton circuit both change in the direction which indicates an increase in the proton conductance of the membrane due to proton re-entry through the ATP synthase. Thus, falls and this lowers the thermodynamic back pressure upon the respiratory chain, which therefore respires more rapidly. 

There is a controversy as to whether a drop in A/tH+ created by net ATP synthesis and by the addition of proton translocator create equal respiratory stimulations this will be discussed in a later section. However, brown fat mitochondria investigated in our laboratory [36,37] show the same relationships between respiratory stimulation and A/tH+ decrease with a proton translocator and the 32000 uncoupling protein 

Reversed electron transfer and the proton circuit driven by A TP hydrolysis 

The three proton pumps of the mitochondrial respiratory chain normally function in parallel with respect to the proton circuit. It is however possible to manipulate the conditions such that the proton electrochemical potential generated by two of the pumps can be used to reverse the third proton pump (but not cytochrome oxidase). 

One way in which this may be achieved is shown in Fig. 2.4. The proton electrochemical potential generated by the downhill flow of electron from Complex III to oxygen can be used to drive Complex I in reverse, protons entering the matrix through this complex and driving electrons uphill from the ubiquinone pool to the NADH/NAD pool, with a redox potential some 300 mV more negative. 

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Propofol (Diprivan) is used for induction and maintenance of anesthesia. It also may be used for sedation during diagnostic procedures and procedures that use a local anestiietic. This drug also is used for continuous sedation of intubated or respiratory-controlled patients in intensive care units. 

Luft, R., Ikkos, D., Palmieri, G., Emster, L., Aftelius, B. (1962). A case of severe hypermetabolism of non-thyroid origin with a defect in the maintenance of mitochondrial respiratory control A correlated clinical, biochemical and morphological study. J. Clin. Invest. 41, 1776-1804. 

The Chemiosmotic Theory Can Account for Respiratory Control and the Action of Uncoupiers... 

In most tissues, where the primary role of the citric acid cycle is in energy-yielding metabohsm, respiratory control via the respiratory chain and oxidative phosphorylation regulates citric acid cycle activity (Chapter 14). Thus, activity is immediately dependent on the supply of NAD, which in turn, because of the tight couphng between oxidation and phosphorylation, is dependent on the availabihty of ADP and hence, ulti-... 

In the periphery, there are no obvious biological effects from w-conotoxin when injected into an adult rodent. However, when injected into a neonatal rodent, a slow depression in respiration takes place suggesting that inhibition of some o -conotoxin binding site in the periphery may result in a dysfunction in respiratory control (J. M. McIntosh, unpublished results). 

The endogenous opioids are another family of peptides involved in different physiological processes including pain regulation, respiratory control, stress responses, appetite, thermoregulation, and humoral and cellular immune function (Bodnar RJ., 2008). Opioids act through their receptors, which are also members of the GPCR family, and are expressed in the central and peripheral nervous system as well as on cells of the immune system (Henriksen and Willoch 2008 Hauser... 

The well-known fact that in irreversibly damaged cells, respiratory control is lost and is accompanied by oxidation of cytochromes a and as, as well as NADH (Taegtmeyer et al., 1985), was originally thoug it to be due to substrate deficiency (Chance and Williams, 1955) but may be due to an enzymatic defect resulting in an inability to metabolize NADH-linked substrates (Pelican etal., 1987). It seems likely therefore that return of function is dependent on preservation of mitochondrial membrane integrity, and the structure and activities of respiratory chain (R.C) complexes I-IV (Chance and Williams, 1955). 

Polarographic studies of a mitochondrial fraction from Hymenolepis diminuta showed that of four substrates tested, DL-glycerol-3-phosphate was the most rapidly oxidized, but the highest respiratory control ratio (1.7) was obtained with dl-isocitric acid. With isocitrate as substrate oxyclozanide at 1.61 nM stimulated O uptake and relieved oligomycin inhibition of adinosine diphosphate-stimulated respiration, but at concentrations above 2 pM progressively inhibited O uptake. Rafoxanide, niclosamide, 3,4,5-tribromo-salicylanilide, nitroxynil, resorantel, di-chlorophen, and 2,4-dinitrophenol exhibited effects similar to those of oxyclozanide on the respiration in cestode mitochondria. The relative potencies were compared and the possible mode of action discussed [38]. 

A different and simpler approach to the measurement of P/O ratios came from the introduction of an oxygen electrode suitable for biochemical studies. Chance and Williams (1955) established conditions under which mitochondrial respiration, in the presence of excess substrate, was totally dependent on the amount of ADP available, i.e., the mitochondria were exhibiting respiratory control. From the change in potential when a known amount of ADP was admitted into the electrode vessel, the oxygen uptake and thus the P/O ratio could be determined, completely confirming the earlier results. 

The rates of oxidative phosphorylation and the citric acid cycle are closely coordinated, and are dependent mainly on the availability of and ADR If is limited, the rate of oxidative phosphorylation decreases, and the concentrations of NADH and FADH increase. The accumulation of NADH, in turn, inhibits the citric acid cycle. The coordinated regulation of these pathways is known as respiratory control. ... 

Coenzyme availability can also often have a limiting effect (5). If the coenzyme is regenerated by a second, independent metabolic pathway, the speed of the second pathway can limit that of the first one. For example, glycolysis and the tricarboxylic acid cycle are mainly regulated by the availability of NAD" (see p. 146). Since NAD is regenerated by the respiratory chain, the latter indirectly controls the breakdown of glucose and fatty acids (respiratory control, see p. 144). 

The simple regulatory mechanism which ensures that ATP synthesis is automatically coordinated with ATP consumption is known as respiratory control. It is based on the fact that the different parts of the oxidative phosphorylation process are coupled via shared coenzymes and other factors (left). 

Salkovskis P, Jones D, Clark D (1986) Respiratory control in the treatment of panic attacks replication and extension with concurrent measurement of behaviour and pC02. Br J Psychiatry 148 526-532... 

Electrical Stimulation Devices. Bioelectrodes that transmit electrical signals into the body are generally known as electrical stimulation devices, examples of which include cardiac pacemakers, transcutaneous electronic nerve stimulators (TENs) for pain suppression, and neural prostheses such as auditory stimulation systems for the deaf and phrenic nerve stimulators for artificial respiratory control. In these, and other similar devices, electrodes transmit current to appropriate areas of the body for direct control of, or indirect influence over, target cells. 

However, in individuals with increased intracranial pressure, asthma, chronic obstructive pulmonary disease, or cor pulmonale, this decrease in respiratory function may not be tolerated. Opioid-induced respiratory depression remains one of the most difficult clinical challenges in the treatment of severe pain. Research is ongoing to understand and develop analgesic agents and adjuncts that avoid this effect. Research to overcome this problem is focused on 5 receptor pharmacology and serotonin signaling pathways in the brainstem respiratory control centers. 

The toxic effect is known as histotoxic hypoxia. Cyanide also directly stimulates chemoreceptors, causing hyperpnea. Lack of ATP will affect all cells, but heart muscle and brain are particularly susceptible. Therefore, cardiac arrythmias and other changes often occur, resulting in circulatory failure and delayed tissue ischemic anoxia. Death is usually due to respiratory arrest resulting from damage to the CNS, as the nerve cells of the respiratory control center are particularly sensitive to hypoxia. The susceptibility of the brain to pathological damage may reflect the lower concentration of cytochrome oxidase in white matter. 

These effects on the mitochondria will lead to a reduction of respiratory control in the renal cells, and their functions, such as solute reabsorption, will be compromised. 

Salicylic acid, the major metabolite of aspirin, uncouples the electron transport chain in the mitochondria. This results in (a) increased use of oxygen and production of carbon dioxide, (b) lack of ATP, and (c) excess energy no longer utilized in ATP production. The result is increased respiration and raised temperature. The alterations in respiration lead to alkalosis followed by acidosis. The lack of ATP and loss of respiratory control will cause increased metabolic activity and hypoglycemia after an initial mobilization of glucose from glycogen. 

One reason for Roche s success with Dalmane was that it did not share two undesirable features of the barbiturates, the then reigning class of sedatives REM suppression and suicidal potency. The barbiturates are CNS depressants that can induce unconsciousness, but because they have a very low margin of safety they can also shut down the respiratory control system of the brain stem. That is how they kill, and that is why they are still popular in Oregon and other places where individuals are free to elect a definitive end to unbearably unpleasant conscious awareness. Physician-assisted suicide is sometimes accomplished by turning off breathing, by pulling the plug internally as it were. 

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