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Actions of dinitrophenol and some other metabolic inhibitors on cortical neurones
Abstract:
1. In cats under methoxyflurane, DNP and other metabolic inhibitors were tested on cortical neurones by iontophoresis from micropipettes.2. DNP, dinitro-o-cresol, iodoacetate, pentachlorophenol and oligomycin (uncouplers or inhibitors of oxidative phosphorylation), as well as moderate anoxia, blocked selectively and reversibly spontaneous firing and discharges evoked by ACh; responses evoked by glutamate were facilitated by moderate doses of DNP and blocked only by large amounts.3. Azide, cyanide, ouabain and strophanthidine had a mainly excitatory effect; the cardiac glycosides tended to depress more strongly responses to glutamate.4. Intracellular observations showed that DNP causes a sharp fall in electrical excitability, associated with a hyperpolarization and fall in membrane resistance.5. The hyperpolarizing action of DNP had a mean reversal level (E(DNP)) nearly 30 mV more negative than the resting potential; E(DNP) was identical with the mean reversal level for the depolarizing action of ACh, measured on the same cells.6. DNP had its usual hyperpolarizing effect on neurones whose IPSPs had been made positive by raising the internal [Cl]; the mean E(IPSP) was over 30 mV more positive than E(DNP).7. It is concluded that DNP lowers excitability by raising the membrane conductance to K(+) (g(K)) and that it blocks ACh responses selectively because ACh has a precisely opposite action on these neurones.8. In the Discussion, it is suggested that the rise in g(K) is mediated by an increase in internal free Ca(2+), caused by a slowing of mitochondrial activity, and that a similar mechanism may play a significant role in general anaesthesia.
Insights
2,4-dinitrophenol (DNP) and metabolic inhibitors affect cortical neuron excitability. DNP hyperpolarizes neurons by increasing potassium conductance, selectively blocking acetylcholine responses, potentially explaining anesthetic effects.
Area of Science:
- Neuropharmacology
- Cellular Neuroscience
- Metabolic Inhibition
Background:
- Metabolic inhibitors and uncouplers of oxidative phosphorylation are known to affect cellular function.
- The precise mechanisms by which these compounds influence neuronal excitability, particularly in the central nervous system, require further elucidation.
- Understanding these effects is crucial for comprehending neuronal function and the action of certain anesthetics.
Purpose of the Study:
- To investigate the effects of 2,4-dinitrophenol (DNP) and other metabolic inhibitors on the electrical activity of feline cortical neurons.
- To determine the specific ionic mechanisms underlying the observed changes in neuronal excitability.
- To explore the potential role of these mechanisms in general anesthesia.
Main Methods:
- Iontophoretic application of DNP and other metabolic inhibitors (dinitro-o-cresol, iodoacetate, pentachlorophenol, oligomycin, azide, cyanide, ouabain, strophanthidine) to feline cortical neurons.
- Recording of spontaneous and evoked neuronal firing.
- Intracellular recordings to measure membrane potential, resistance, and reversal potentials.
Main Results:
- DNP and other oxidative phosphorylation inhibitors, along with moderate anoxia, reversibly blocked spontaneous and acetylcholine (ACh)-evoked neuronal firing.
- Glutamate-evoked responses were initially facilitated by DNP but blocked by higher concentrations.
- DNP induced hyperpolarization and decreased membrane resistance, with a reversal potential (E(DNP)) significantly more negative than the resting potential and identical to the ACh reversal potential.
Conclusions:
- DNP reduces neuronal excitability by increasing membrane conductance to potassium ions (g(K)).
- The selective blockade of ACh responses by DNP is attributed to its opposing action on these neurons.
- A proposed mechanism involves DNP-induced increase in intracellular calcium, stemming from slowed mitochondrial activity, potentially contributing to general anesthesia.