PMC:6194691 / 163749-171057 JSONTXT

{"project":"MyTest","denotations":[{"id":"30340614-27799072-30706539","span":{"begin":6298,"end":6299},"obj":"27799072"},{"id":"30340614-21068832-30706540","span":{"begin":6855,"end":6858},"obj":"21068832"},{"id":"30340614-24670647-30706541","span":{"begin":6860,"end":6863},"obj":"24670647"},{"id":"30340614-27799072-30706542","span":{"begin":6899,"end":6900},"obj":"27799072"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"General principles of concentration maintenance: balancing input and output. CO2 as an example\nThe concentration of a substance can only be maintained at a constant level if its rate of elimination, Relim, is equal to its rate of input, Rin,11 Relim=Rin.\nIf input exceeds elimination the concentration will increase; if it is less the concentration will decrease. In the face of a given rate of input, be it by influx from outside or local production within the brain, a steady-state can only be achieved if the elimination rate can increase far enough to balance the input (see input Rin2 in Fig. 22a). A steady-state is not possible if elimination is unable to match input (see input at level 2) and under these conditions the concentration will continually increase. Thus it is the relative rates of input and elimination, rather than the rate of input itself that is of primary importance.\nFig. 22 The relation between the rate of elimination of a substance and its concentration. The solid curve in a and line in b show the rate of elimination as a proportion of its possible maximum versus concentration. Possible rates of input are shown as the dashed lines. In a if the rate of input is Rin,1 which is less than the maximum possible rate of elimination, Relim,max, the concentration can be maintained at css. If the rate of input is Rin,2, which exceeds Relim,max, no steady-state is possible and the concentration continually increases. At low concentrations as shown in detail in b the rate of elimination is usually proportional to concentration\nThe rate of elimination of a substance from the brain parenchyma is determined by its concentration and the ability of the efflux mechanisms to remove the substance. This ability is usually described as the clearance. For a substance eliminated by a single type of transport, the clearance is determined by the number of transporters, the affinity-constant for the substrate and the transporter and the maximum turnover rate. Clearance can be calculated from measurable quantities as12 CL=Relim/c.where Relim is the rate of elimination and c is the concentration of the substance. At sufficiently low concentrations the relation between elimination rate and concentration is linear and the clearance is a constant (see Fig. 22b). At higher concentrations (see Fig. 22a) the relation is no longer linear and the clearance decreases as concentration increases.\nThe larger the clearance, the higher the rate of elimination possible at any given concentration (see Fig. 23a) and therefore the lower the concentration needed to achieve an elimination rate equal to a particular rate of input, Rin, (see Fig. 23b), i.e.13 c=Rin/CL.\nFig. 23 The relationship between the rates of input and elimination, substrate concentration in ISF and clearance. At steady-state the rate of elimination must equal the rate of input. The horizontal dashed lines show rates of input (R1, R2, R3 and Rin). The clearance, CL, is the slope of the line for the plot of rate of elimination versus concentration. Lines for three values of clearance (CL1, CL2 and CL3) are shown. a To achieve the steady-state concentration, cisf, clearance must be higher to balance the higher rate of input i.e. the rate of input required is proportional to clearance. b For a given rate of input, the steady-state concentration is inversely proportional to CL (compare the three steady state concentrations c1 c2 and c3 achievable for the three clearance values CL1, CL2 and CL3). c For a given clearance the steady-state concentration is proportional to the rate of input. Changes in input need not produce changes in concentration if the clearance can be changed, e.g. for the increase from R1 to R3 shown in a the concentration would be constant if the clearance could be increased from CL1 to CL3\nWhen the clearance is constant, changes in input (R1, R2, R3 in Fig. 23c) lead to proportional changes in steady-state concentration. Such changes in ISF concentration may be fine if the ISF concentration is not critical. Constant clearance avoids the disasters that could occur if the elimination rate could not increase with ISF concentration because then increased rate of input would produce progressively increasing concentration within the parenchyma.\nIf close control of ISF concentration is required there must either be some means to reduce or prevent changes in input or the clearance must alter. When input is from plasma one way in which changes in input can be made less sensitive to plasma concentration is for the input mechanism to be operating not too far from its maximum rate, i.e. for the substrate concentration in plasma to be well above the Km for the input mechanism. However, the same limitation may apply to efflux as to influx, with the resulting changes in ISF concentration difficult to predict (e.g. for glucose, see Fig. 14 and Appendix D).\nIf input is determined by production within the parenchyma, closer control in the face of variable input than would be seen for constant clearance must be achieved by altering the mechanisms of elimination to change the clearance. In order for the system to be modified some sort of signal is required ‘to inform’ the elimination system that the input and/or the concentration has changed.\nIn principle this can be done by feedback control in which increased concentration somehow modifies the mechanism of elimination to increase the clearance, e.g. by recruiting more transporters. To some extent this occurs with CO2. Increased pCO2 is associated with lower pH and stimulation of cerebral blood flow, which washes away the excess CO2 (see Sect. 5.2), i.e. increased pCO2 increases the clearance for CO2. However, feedback control still requires that there be a change in the concentration to stimulate and maintain the process (see Fig. 24).\nFig. 24 Diagram illustrating possible schemes for neurovascular coupling, i.e. regulation of blood flow changes associated with nerve activity. Two forms of control are shown, a simple feedback based on the signal to be regulated, e.g. pCO2, and b feedback plus feed-forward. The feed-forward element, signal2, in b, possibly from astrocytes, allows blood flow to increase with smaller changes in the primary quantity to be regulated, signal1\n(Figure reproduced from [4])\nCloser control is possible with feed-forward regulation, in which the change in input itself or something closely linked to the input stimulates the change in clearance whether or not the concentration changes. In principle the control could be perfect if somehow a change in input rate could produce proportional change in clearance as indicated in Fig. 23a. It is now clear that increased brain activity, which increases production of CO2, increases blood-flow even without increases in CO2 concentration. This process, called neurovascular coupling [515, 516], is considered in more detail in [4] which can be consulted for further references.\nWhen substrate elimination is limited by transport across the blood–brain barrier rather than by blood-flow, the clearance can be increased by inserting more transporters, by increasing the activity of each transporter, i.e. an increase in the turnover rate or, if the transport isn’t saturated by increasing the affinity of the transporter for the substrate."}

{"project":"2_test","denotations":[{"id":"30340614-27799072-30706539","span":{"begin":6298,"end":6299},"obj":"27799072"},{"id":"30340614-21068832-30706540","span":{"begin":6855,"end":6858},"obj":"21068832"},{"id":"30340614-24670647-30706541","span":{"begin":6860,"end":6863},"obj":"24670647"},{"id":"30340614-27799072-30706542","span":{"begin":6899,"end":6900},"obj":"27799072"}],"text":"General principles of concentration maintenance: balancing input and output. CO2 as an example\nThe concentration of a substance can only be maintained at a constant level if its rate of elimination, Relim, is equal to its rate of input, Rin,11 Relim=Rin.\nIf input exceeds elimination the concentration will increase; if it is less the concentration will decrease. In the face of a given rate of input, be it by influx from outside or local production within the brain, a steady-state can only be achieved if the elimination rate can increase far enough to balance the input (see input Rin2 in Fig. 22a). A steady-state is not possible if elimination is unable to match input (see input at level 2) and under these conditions the concentration will continually increase. Thus it is the relative rates of input and elimination, rather than the rate of input itself that is of primary importance.\nFig. 22 The relation between the rate of elimination of a substance and its concentration. The solid curve in a and line in b show the rate of elimination as a proportion of its possible maximum versus concentration. Possible rates of input are shown as the dashed lines. In a if the rate of input is Rin,1 which is less than the maximum possible rate of elimination, Relim,max, the concentration can be maintained at css. If the rate of input is Rin,2, which exceeds Relim,max, no steady-state is possible and the concentration continually increases. At low concentrations as shown in detail in b the rate of elimination is usually proportional to concentration\nThe rate of elimination of a substance from the brain parenchyma is determined by its concentration and the ability of the efflux mechanisms to remove the substance. This ability is usually described as the clearance. For a substance eliminated by a single type of transport, the clearance is determined by the number of transporters, the affinity-constant for the substrate and the transporter and the maximum turnover rate. Clearance can be calculated from measurable quantities as12 CL=Relim/c.where Relim is the rate of elimination and c is the concentration of the substance. At sufficiently low concentrations the relation between elimination rate and concentration is linear and the clearance is a constant (see Fig. 22b). At higher concentrations (see Fig. 22a) the relation is no longer linear and the clearance decreases as concentration increases.\nThe larger the clearance, the higher the rate of elimination possible at any given concentration (see Fig. 23a) and therefore the lower the concentration needed to achieve an elimination rate equal to a particular rate of input, Rin, (see Fig. 23b), i.e.13 c=Rin/CL.\nFig. 23 The relationship between the rates of input and elimination, substrate concentration in ISF and clearance. At steady-state the rate of elimination must equal the rate of input. The horizontal dashed lines show rates of input (R1, R2, R3 and Rin). The clearance, CL, is the slope of the line for the plot of rate of elimination versus concentration. Lines for three values of clearance (CL1, CL2 and CL3) are shown. a To achieve the steady-state concentration, cisf, clearance must be higher to balance the higher rate of input i.e. the rate of input required is proportional to clearance. b For a given rate of input, the steady-state concentration is inversely proportional to CL (compare the three steady state concentrations c1 c2 and c3 achievable for the three clearance values CL1, CL2 and CL3). c For a given clearance the steady-state concentration is proportional to the rate of input. Changes in input need not produce changes in concentration if the clearance can be changed, e.g. for the increase from R1 to R3 shown in a the concentration would be constant if the clearance could be increased from CL1 to CL3\nWhen the clearance is constant, changes in input (R1, R2, R3 in Fig. 23c) lead to proportional changes in steady-state concentration. Such changes in ISF concentration may be fine if the ISF concentration is not critical. Constant clearance avoids the disasters that could occur if the elimination rate could not increase with ISF concentration because then increased rate of input would produce progressively increasing concentration within the parenchyma.\nIf close control of ISF concentration is required there must either be some means to reduce or prevent changes in input or the clearance must alter. When input is from plasma one way in which changes in input can be made less sensitive to plasma concentration is for the input mechanism to be operating not too far from its maximum rate, i.e. for the substrate concentration in plasma to be well above the Km for the input mechanism. However, the same limitation may apply to efflux as to influx, with the resulting changes in ISF concentration difficult to predict (e.g. for glucose, see Fig. 14 and Appendix D).\nIf input is determined by production within the parenchyma, closer control in the face of variable input than would be seen for constant clearance must be achieved by altering the mechanisms of elimination to change the clearance. In order for the system to be modified some sort of signal is required ‘to inform’ the elimination system that the input and/or the concentration has changed.\nIn principle this can be done by feedback control in which increased concentration somehow modifies the mechanism of elimination to increase the clearance, e.g. by recruiting more transporters. To some extent this occurs with CO2. Increased pCO2 is associated with lower pH and stimulation of cerebral blood flow, which washes away the excess CO2 (see Sect. 5.2), i.e. increased pCO2 increases the clearance for CO2. However, feedback control still requires that there be a change in the concentration to stimulate and maintain the process (see Fig. 24).\nFig. 24 Diagram illustrating possible schemes for neurovascular coupling, i.e. regulation of blood flow changes associated with nerve activity. Two forms of control are shown, a simple feedback based on the signal to be regulated, e.g. pCO2, and b feedback plus feed-forward. The feed-forward element, signal2, in b, possibly from astrocytes, allows blood flow to increase with smaller changes in the primary quantity to be regulated, signal1\n(Figure reproduced from [4])\nCloser control is possible with feed-forward regulation, in which the change in input itself or something closely linked to the input stimulates the change in clearance whether or not the concentration changes. In principle the control could be perfect if somehow a change in input rate could produce proportional change in clearance as indicated in Fig. 23a. It is now clear that increased brain activity, which increases production of CO2, increases blood-flow even without increases in CO2 concentration. This process, called neurovascular coupling [515, 516], is considered in more detail in [4] which can be consulted for further references.\nWhen substrate elimination is limited by transport across the blood–brain barrier rather than by blood-flow, the clearance can be increased by inserting more transporters, by increasing the activity of each transporter, i.e. an increase in the turnover rate or, if the transport isn’t saturated by increasing the affinity of the transporter for the substrate."}