Mechanisms respiratory control

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). 

The effect of benzene on the respiration of isolated heart mitochondria was studied by Stolze and Nohl (1994). Respiratory control and ATP/oxygen values decreased in the presence of benzene at 100 pM. A concomitant increase in superoxide radical formation was observed. This suggests a mechanism for benzene-mediated damage to cardiovascular tissue and other tissues as well. 

The regulation of the rate of oxidative phosphorylation by the ADP level is called respiratory control or acceptor control. The level of ADP likewise affects the rate of the citric acid cycle because of its need for NAD+ and FAD. The physiological significance of this regulatory mechanism is evident. The ADP level increases when ATP is consumed, and so oxidative phosphorylation is coupled to the utilization of ATP. Electrons do not flow from fuel molecules to O ... 

G5. Gilbert, D., Demonstration of a respiratory control mechanism in human skin in vitro. J. Invest. Dermatol. 42, 45-49 (1964). 

Continued mitochondrial oxidation of NADH and the reduction of O2 are dependent on sufficient ADP being present. This phenomenon, termed respiratory control, is an Important mechanism for coordinating oxidation and ATP synthesis in mitochondria. 

This review is not an exhaustive survey, but rather focuses on principal advances and existing limitations. For additional insight there are several reviews on the physiological aspects of respiratory control (I, 2, 3, 4, 5) and respiratory control models (6, 7, 8). A brief review of the important physiological observations related to mechanisms of control, the stimuli, and the receptors is included. This information is the physiological background for the discussions of respiratory control models. 

Mechanisms of Respiratory Control. To meet the metabolic demands of the body and to maintain the acid-base balance, ventilation is regulated by various stimuli acting at several locations in the body. Although the mechanism by which each stimulus acts in amplifying or diminishing ventilation is not well known, these stimuli clearly inhibit and excite the central respiratory centers in the medulla, either directly or indirectly. The electrical impulses generated in these centers are responsible for the motor activities which produce the ventilatory response. 

Although the assumption of such a control mechanism involving reference values for the controlled variables is intuitively attractive, the existence of such reference values is still questioned (26). However, in most respiratory control models to date such a servomechanistic regulation is generally used only recently have other performance criteria been suggested (26). 

JNK activation may be a mechanism that is associated with the initiation of mitochondrial permeability transition (MPT) (Hanawa et al. 2008 Latchoumycan-dane et al. 2006, 2007). As discussed above, both JNK activation (Matsumaru et al. 2003) and MPT (Lemasters 1998) are known to occur as a result of increased oxidative stress. MPT leads to additional oxidative stress with loss of mitochondrial membrane potential and loss of the ability of the hepatocyte to synthesize ATP. Latchoumycandane et al. (2006, 2007) found that leflunomide protected mice from mitochondrial permeabilization. Direct evidence for a role of JNK activation in acetaminophen-induced MPT was recently reported by Hanawa et al. (2008). A time course of events indicated GSH depletion by 1-2 h, JNK activation in liver homogenate by 2-4- h, JNK translocation to mitochondria by 4 h, and increased toxicity (serum ALT by 6 h). The JNK inhibitor did not alter GSH depletion but blocked JNK activation in homogenate, JNK translocation to mitochondria, and toxicity. Mitochondria from liver of acetaminophen-treated mice showed decreased State III respiration and decreased respiratory control ratios, whereas mice treated with acetaminophen plus JNK inhibitor were partially protected from these losses. Addition of activated JNKl or JNK2 to mitochondria from acetaminophen-treated mice plus JNK inhibitor showed a decrease in State 111 respiration and decreased respiratory control ratio. Addition of the MPT inhibitor cyclosporine A prevented these decreases. It was hypothesized that activated JNK is an important mediator of acetaminophen-induced MPT (Hanawa et al. 2008). 

Like any closed-loop system, the behavior of the respiratory control system is defined by the continual interaction of the controller and the peripheral processes being controlled. The latter include the respiratory mechanical system and the pulmonary gas exchange process. These peripheral processes have been extensively studied, and their quantitative relationships have been described in detail in previous reviews. Less well understood is the behavior of the respiratory controller and the way in which it processes afferent inputs. A confounding factor is that the controller may manifest itself in many different ways, depending on the modeling and experimental approaches being taken. Traditionally, the respiratory control system has been modeled as a closed-loop feedback/feedforward regulator whereby homeostasis of arterial blood gas and pH is maintained. Alternatively, the respiratory controller may be viewed as a... 

Does the substance affect the mechanisms of respiratory control (central or peripheral) leading to hypoventilation (respiratory depression) or hyperventilation (respiratory stimulation) ... 

The respiratory mechanism for controlling blood pH begins in the brain with respiratory center neurons that are sensitive to blood CO2 levels and pH. A significant increase in the CO2 of arterial blood, or a decrease below about 7.38 of arterial blood pH, causes the breathing to increase both in rate and depth, resulting in hyperventilation. This increased ventilation eliminates more carbon dioxide, reduces carbonic acid and hydrogen-ion concentrations, and increases the blood pH back toward the normal level (see > Figure 15.11). 

Carbon dioxide is normally present in the atmosphere at about 0.035 percent by volume. It is also a normal end-product of human and animal metabolism. The exhaled breath contains up to 5.6 percent carbon dioxide. The greatest physiological effect of carbon dioxide is to stimulate the respiratory center, thereby controlling the volume and rate of respiration. It is able to cause dilation and constriction of blood vessels and is a vital constituent of the acid-base mechanism that controls the pH of the blood. 

The molecular mechanism by which the passage of electrons along the respiratory chain is coupled to the phosphorylation of ATP has been the object of an immense amount of investigation since the phenomenon of respiratory control was first observed. At various times a... 

Smith JC, Funk GD, Johnson SM, Feldman JL. Cellular mechanisms generating respiratory rhythm insights fiom in vitro and computational studies. In Trouth CO, Minis R, Kiwull-Schone H, Schlaeike M, eds. Ventral Brainstem Mechanisms and Control of Respiration and Blood Pressure. New Witk Marcel Dekker, 1995 463—496. 

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