Regulation of pH and HCO3 in brain and CSF of the developing mammalian central nervous system.

Acute (2-h) metabolic acidosis or alkalosis was induced in immature rats to ascertain the ability of their incompletely-developed CNS to regulate pH when challenged with perturbations in blood [H] and [HCO3]. Brain and cisternal CSF pH were determined from steady-state distribution of [14C]dimethadione, a weak organic acid. By 1 week post partum, there was a remarkable stability of pH in the cerebral cortex of animals subjected to arterial pH extremes of 7.1 and 7.5. However, CSF pH in 1-week-old animals rendered alkalotic remained 0.07-0.08 units above control due to lack of a compensatory increase in pCO2, and to a blood-CSF barrier apparently more permeable to HCO3. As arterial HCO3, i.e. [HCO3]art, was varied from about 10 to 30 mmol/l, the infants maintained [HCO3]csf only half as effectively as adults, i.e. delta [HCO3]art was 0.4 and 0.2 at 1 and greater than 4 weeks, respectively. Throughout postnatal ontogenesis, [HCO3]csf was more resistant to alteration by metabolic acidosis than by alkalosis. Overall, the results indicate that immature rats challenged with systemic acid-base loads are less capable than adults in regulating CSF pH, but they are able to maintain brain pH.

The ketogenic diet: mechanism of anticonvulsant action.

Although the ketogenic diet has been used in the therapy for epilepsy for more than 50 years, there are few studies concerned with the effects of this diet on the central nervous system. Recent attempts to unravel the biochemical effects of the ketogenic diet on the brain seem to be a fruitful approach to understanding how the ketogenic diet causes anticonvulsant effects. Another exciting approach is the development of animal models in which various effects of the diet can be correlated with changes in seizure protection. It would be useful to determine whether the diet produces any neurophysiological effects that could account for some, or all, of its antiseizure properties. Finally, the efficacy of the diet is impressive. It is likely that the ketogenic diet will never be of major therapeutic importance because of the expense and commitment required of the patient and the family. Nevertheless, it appears obvious that continued study of a therapy which seems to work so well will give us some valuable clues as to the mechanism of seizures and their control. Further investigations into the mechanism of action of the ketogenic diet should be encouraged.

Oxazolidinediones.

Even though the oxazolidinediones have been the subject of many clinical and laboratory studies, no all-inclusive mechanism of action can be formulated from the data reported to date. Studies of neurotransmitter and membrane effects appear to be fruitful areas for future investigations. Also, the search must continue for adequate laboratory models of absence seizures. It is to be expected that our knowledge of the mechanisms of the anticonvulsant effects of the oxazolidinediones will increase as our experiments improve and as our understanding of the pathophysiology of absence seizures expands. However, we still have a long way to go.

Effects of penicillin pretreatment on renal tubular para-aminohippurate transport in the immature rat.

The effect of pretreatment with penicillin on para-aminohippurate (PAH) transport by the kidney of the immature rat was evaluated in vivo. After 3 days of penicillin administration, renal clearances of inulin (CIN), PAH (CPAH), and the renal tubular transport maximum (Tm) for PAH were measured in rats as young as 17 days of age. The CPAH in 19- to 21-day-old rats pretreated with procaine penicillin was 54% greater than that of their littermate controls. Similarly, CPAH of rats that received sodium penicillin was 31% greater than control. CIN was not increased after penicillin pretreatment. Pretreatment of rats older than 24 days did not change CIN or CPAH. The Tm for PAH of 17-day-old rats pretreated with sodium penicillin was 51% greater than that of control rats. It was concluded that pretreatment with penicillin enhances the renal secretion of organic anions by the immature rat.

Effects of CO2 on transmembrane potentials of rat liver and muscle in vivo.

1. The effects of increasing the inspired CO(2) concentration on the transmembrane resting potential (RP), intracellular electrolytes, and cell pH of rat liver and muscle were studied.2. Elevation of CO(2) produced a rapid reversible fall in hepatic RP. This effect is mediated by a decrease in plasma pH and is in part due to hypoxia.3. The decrease in hepatic RP could not be accounted for by shifts in electrolytes, and an effect on membrane permeability is suggested.4. The hepatic RP was also found to be decreased by hypoxia and increased by hyperoxia.5. Muscle RP showed no immediate change in response to CO(2) but after 60 min there was significant depolarization. This effect could be accounted for on the basis of electrolyte shifts between cells and plasma, by use of the Goldman equation.6. Cell pH data showed that liver is buffered approximately threefold more than skeletal muscle.7. While intracellular pH fell in response to CO(2) the H(+) gradient remained constant in muscle and increased in liver.

Effects of ouabain and diphenylhydantoin on transmembrane potentials, intracellular electrolytes, and cell pH of rat muscle and liver in vivo.

1. The effects of ouabain and diphenylhydantoin (DPH) to inhibit and stimulate, respectively, the Na(+)-K(+) pump were used to correlate transmembrane resting potentials (RP), ionic gradients, and cell pH (DMO method) in rat muscle and liver in vivo.2. Ouabain effects included a rise in K(+) and fall in Na(+) concentration in plasma, a rise in intracellular Na(+) and Cl(-) and a fall in K(+) concentration and pH(i) in muscle, and a rise in intracellular K(+) concentration in liver.3. Measured muscle RP was decreased from -90 to -65 mV by ouabain with the RP predictable from the Goldman equation for Na(+) and K(+) with P(Na)/P(K) = 0.01.4. Measured hepatic RP was increased from -44 to -48 mV by ouabain, whereas the Goldman equation predicts the potential should decrease. A change in permeability of some ion or activation of an electrogenic pump component is necessary to explain this result.5. DPH produced no significant effect on muscle electrolytes or RP and failed to reverse the effect of ouabain at the time measured and in the doses used.6. DPH produced a slight rise in hepatic cell K(+) and a rise from -42 to -47 mV in hepatic RP. This hyperpolarization also cannot be explained without invoking a permeability change or activation of an electrogenic pump. In all cases intracellular Cl(-) in both muscle and liver changed in the direction expected from the change in the RP. Muscle Cl(-) appears passively distributed if a constant amount of extra or bound Cl(-) is first subtracted from each group. Hepatic intracellular Cl(-) is always less than expected on the basis of passive distribution, although errors in determination do not allow elimination of the possibility that Cl(-) distribution is determined only by the RP.8. Cell pH and RP data were used to calculate H(+) gradients. DPH had no effect on cell pH and only slightly increased the H(+) gradient in liver. Ouabain produced a slight fall in muscle cell pH but reduced the H(+) gradient by half. In liver only the H(+) gradient was increased slightly. The data support the concept of a loose coupling between active H(+) and Na(+)-K(+) transport.

Effects of nephrectomy and KC1 on transmembrane potentials, intracellular electrolytes, and cell pH of rat muscle and liver in vivo.

1. The ability of 24 hr nephrectomy and KCl to raise plasma K(+) concentration was used to correlate transmembrane resting potential (RP), ionic gradients, and cell pH (DMO method) in rat muscle and liver in vitro.2. Effects of 24 hr nephrectomy on electrolytes included a rise in plasma K(+) and fall in Na(+), with a rise in intracellular K(+) and fall in intracellular Na(+) in both liver and muscle. Intracellular Cl(-) concentration rose in muscle and decreased in liver.3. Measured muscle RP was decreased from -91 to -77 mV by 24 hr nephrectomy, with the RP predictable from the Goldman equation for Na(+) and K(+) with P(Na)/P(K) = 0.01 and Cl(-) behaving as if passively distributed.4. Measured hepatic RP was increased from -43 to -48 mV by 24 hr nephrectomy, with a change in ionic permeability or activation of an electrogenic pump necessary to explain the results.5. Plasma acid-base changes consisted of metabolic acidosis with partial respiratory compensation. Cell pH rose slightly in both liver and muscle; the H(+) gradient remained constant in muscle but increased slightly in liver.6. KCl was injected into intact rats while the RPs were continuously measured in muscle or liver. Muscle RP was found to decrease and hepatic RP to increase along a similar time course.7. Infusion of KCl into the portal vein led to an increase in the hepatic RP for values of hepatic venous K(+) of 15-25 mM, whereas infusion sufficient to increase the hepatic venous K(+) concentration to 30-40 mM produced no change or a slight decrease in hepatic RP.8. The rat muscle RP can be adequately described by the Goldman equation for Na(+) and K(+), whereas the hepatic RP may well have both diffusion and electrogenic components which respond differently to an increase in plasma K(+) concentration.