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Biomedical subjects

R C Thomas

Publications and source records attributed to R C Thomas.

At least 109 records · Page 6Linked to original sources
PubMed1975

Metabolism of minoxidil, a new hypotensive agent I: absorption, distribution, and excretion following administration to rats, dogs, and monkeys.

Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide), a potent new hypotensive agent, was 14C-labeled in the 2-position of the pyrimidine ring in 17 percent yield from Ba14CO3. This material was used to study the absorption, distribution, and excretion of the drug in rats, dogs, and monkeys. Following oral administration of a single dose, the drug was rapidly and well absorbed and rapidly eliminated by each species as judged by plasma levels and urinary excretion of unchanged drug and total drug-related materials. Chronic oral administration of the drug at a high level (10 mg/kg) for 30 days slightly increased the rate of clearance of minoxidil and minoxidil-related material from circulation. Water diuresis, resulting from water loading of dogs, caused an even greater increase in the rates of disappearance of the drug and drug-related material. Whole-body autoradiography studies in rats showed that minoxidil was rapidly distributed following its oral and intravenous administration. It was subsequently concentrated, primarily in the excretory system. Minoxidil-related material was detected in aorta walls, but not in the CNS, following both routes of drug administration.

Animals↗
PubMed1975

Metabolism of minoxidil, a new hypotensive agent II: biotransformation following oral administration to rats, dogs, and monkeys.

The biotransformation of minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) was studied in the rat, dog, and monkey and compared to reported results in the human. Chromatographic profiles of urinary metabolites show that each species excreted substantially the same metabolites but in quite different relative amounts. The monkey and the human exhibited similar metabolite profiles, whereas the dog and rat were quantitatively different from each other and from the monkey and human. The major excretory product for the monkey and human was a glucuronide conjugate of minoxidil. Substantially smaller amounts of unchanged minoxidil, 2,4-diamino-6-(4'-hydroxypiperidino)pyrimidine 3-oxide, and more polar metabolites also were excreted by these two species. The major excretory product in the rat was unchanged minoxidil. Almost as much (combined) of the two acidic metabolites, 2,4-diamino-6-(4'-carboxy-n-butylamino)pyrimidine and its 3-oxide, also were produced. Smaller amounts of the glucuronide of minoxidil, 2,4-diamino-6-(4'-hydroxypiperidino)pyrimidine 3-oxide, its 3'-hydroxy isomer, and 2,4-diamino-6-piperidinopyrimidine also were excreted by the rat. The major metabolite of minoxidil excreted by the dog was the 4'-hydroxy metabolite. Smaller amounts of unchanged minoxidil and polar metabolites and much smaller amounts of the glucuronide of minoxidil, the 3'-hydroxy metabolite, and 2,4-diamino-6-piperidinopyrimidine also were excreted by the dog. Evidence was obtained for a glucuronide conjugate of the 4'-hydroxy metabolite in this species. The major circulatory material in dog plasma was the 4'-hydroxy metabolite, whereas it was the glucuronide of minoxidil in monkey plasma.

Animals↗
PubMed1975

Micro-electrode measurement of the internal pH of crab muscle fibres.

The internal pH of crab muscle fibres was measured using recessed-tip pH-sensitive micro-electrodes. Immediately following electrode penetration the mean internal pH was 7-21 +/- 0-02 (S.E. of mean) and the mean membrane potential was -64-9 +/- 0-6 mV (S.E. of mean). If H+ ions were passively distributed across the fibre membrane the internal pH would have been 6-39. 2. The internal pH tended to rise before stabilizing at a mean value of 7-27 +/- 0-02 (S.E. of mean). The difference between immediate and stabilized values is highly significant and suggests acid injury on electrode penetration. 3. Changing the membrane potential or external pH had only small, slow effects on internal pH. 4. External CO2 caused a large and rapid decrease in internal pH. With low concentrations of CO2, the effect was dependent on the initial pH as predicted by the Law of Mass Action. During a long exposure to 2-65% CO2 at pH 7-5, the internal pH returned slowly to its previous value, suggesting active transport of H+ (or OH- or HCO3-) ions across the fibre membrane. 5. The internal buffering power calculated from the response to 2-65% CO2 was 47-3 +/- 2-8 slykes (m-equiv H+/pH unit per l.) (S.E. of mean).

Animals↗
PubMed1974

Intracellular pH of snail neurones measured with a new pH-sensitive glass mirco-electrode.

1. The construction and properties of a new design of pH-sensitive micro-electrode are described. The electrodes are very durable, and have a recessed configuration so that only the extreme tip, which can be as small as 1 mum in diameter, needs to enter the cell.2. The average intracellular pH in thirty-two snail neurones was 7.4. This was not in accord with a passive distribution of H(+) ions across the cell membrane.3. Changing membrane potential or external pH had only slow effects on internal pH.4. Removing external K had no effect, and removing external Na had only slow and variable effects on intracellular pH.5. Anoxia, azide and DNP all caused a slow fall in internal pH.6. External CO(2) caused large and rapid decreases in internal pH, which external bicarbonate appeared to offset slowly. Injected bicarbonate increased internal pH.7. The size of the pH changes caused by CO(2) suggested a minimum intracellular buffering power of 25 m-equiv H(+)/unit pH per l., equivalent to that of 150 mM Tris maleate, pH 7.4.8. External ammonia caused a large and rapid increase in internal pH, while the injection of ammonium ions had the opposite effect.

Ammonia↗
PubMed1974

Intracellular chloride activity and the effects of acetylcholine in snail neurones.

1. Cl(-)-sensitive micro-electrodes were used to measure intracellular Cl(-) in snail neurones. The electrodes consisted of a sharpened and chlorided silver wire mounted inside a glass micropipette.2. The electrodes appeared to record changes in internal Cl(-) accurately but in H cells the chloride equilibrium potential (E(Cl)) as measured by the Cl(-)-sensitive electrode was always less negative than E(ACh).3. In some H cells ACh caused a measurable increase in internal Cl(-) when the cell was at its resting potential. In voltage-clamped cells there was a close correlation between the change in internal Cl(-) and the extra clamp current caused by a brief application of ACh. This confirmed that ACh increases the cell's membrane permeability only to Cl(-) ions, and that E(ACh) was equal to E(Cl).4. There was good agreement between the measured change in internal Cl(-) and that calculated from the cell size and clamp charge only when it was assumed that a constant voltage offset was added to the potential of the Cl(-)-sensitive electrode while it was inside the nerve cell.5. Cl(-)-sensitive electrodes with AgCl as the sensitive material appear to be unsuitable for intracellular measurement of Cl(-), although they might be suitable for following changes in E(Cl).6. In certain D cells ACh also caused an increase in internal Cl(-) although it decreased the membrane potential. In the presence of hexamethonium, ACh caused a hyperpolarization and a smaller increase in internal chloride.7. It is concluded that the intracellular Cl(-) in both H and D cells is about 8.3 mM, giving an E(Cl) of about -58 mV.

Acetylcholine↗
PubMed1972

Intracellular sodium activity and the sodium pump in snail neurones.

1. Recessed-tip Na(+)-sensitive micro-electrodes were used to measure [Na(+)](i) continuously in snail neurones for experiments lasting up to several hours. The average resting [Na(+)](i) in twenty-two cells was 3.6 mM.2. Inhibition of the Na pump by ouabain caused [Na(+)](i) to increase at an average rate of 0.54 m-mole/min. This corresponds to a passive influx of Na quantitatively similar to that observed in squid axons.3. Changing external K over the range 1-8 mM had little effect on [Na(+)](i), but K-free or 0.25 mM-K Ringer caused a rise in [Na(+)](i).4. Increasing membrane potential by up to 90 mV caused an increased influx of Na, but did not inhibit the pump.5. Reducing external Na caused a decrease in [Na(+)](i) but did not affect the pump rate at a given [Na(+)](i). The pump rate at low [Na(+)](i) was proportional to [Na(+)](i) minus a threshold value of about 1 mM.6. The Na pump appeared still to be electrogenic at subnormal rates of activity.7. It is concluded that, given sufficient external K, the rate of the Na pump depends principally on [Na(+)](i). Changes in external Na or membrane potential appear to affect the pump only indirectly, by changing the Na influx and thus [Na(+)](i).

Action Potentials↗