Biomedical subjects

F E Baker

Publications and source records attributed to F E Baker.

9 recordsLinked to original sources

PubMed1995

Metabolic acidosis is a potent stimulus for cellular inorganic phosphate generation in uraemia.

1. During metabolic acidosis, significant fluxes of inorganic phosphate (Pi) may occur from cellular to extracellular fluid. In this study Pi was measured in erythrocytes of uraemic patients before and after haemodialysis and was related to their plasma pH (acidosis), plasma Pi (hyperphosphataemia) and cellular organic phosphate concentrations. 2. Before dialysis, the ratio of cellular to extracellular Pi concentration correlated inversely with plasma pH, increasing 2.5-fold as pH fell from 7.4 to 7.2. 3. An increase in cellular Pi similar to that seen in the patients was observed within 90 min of adding acid to normal erythrocytes in vitro. 4. The total Pi content of the cell suspension increased 25% on decreasing plasma pH from 7.4 to 7.2, largely as a result of generation of Pi from 2,3-bisphosphoglycerate in the cells. This was accompanied by net efflux of Pi into plasma. 5. In addition, the increase in the steady-state cellular Pi concentration on adding a constant extracellular Pi load was 50% greater at pH 7.2 than at 7.4, implying that alterations in the regulation of the transmembrane Pi gradient also contribute to the rise in cellular Pi observed at low pH. 6. At normal plasma Pi concentration (1 mM), glycolytic flux (lactate production) was inhibited by 20% when pH was lowered from 7.4 to 7.2. However, this inhibition was blocked when cellular Pi was increased by adding Pi to the plasma in vitro. 7. Metabolic acidosis is therefore a potent stimulus for Pi generation in erythrocytes, and this Pi may serve to stimulate glycolysis which is normally inhibited by low pH.

Acidosis↗

PubMed1990

Prenatal nicotine exposure impairs beta-adrenergic function: persistent chronotropic subsensitivity despite recovery from deficits in receptor binding.

Gestational exposure to nicotine has been shown to interfere with biochemical markers of development of central and peripheral noradrenergic activity. The current study examines the development and function of cardiac beta-adrenergic receptors in the offspring of pregnant rats given nicotine infusions of 6 mg/kg/day from gestational days 4 through 20, administered by subcutaneously implanted osmotic minipumps. Prenatal nicotine exposure delayed the development of beta-adrenergic receptor binding capabilities, as assessed with [125I]pindolol in membrane preparations from heart and kidney. The deficits in receptor binding were associated with marked subsensitivity of chronotropic responses to administration of a beta-adrenergic agonist, isoproterenol. Although the effects on receptor binding resolved after weaning, functional deficiencies in responsiveness to isoproterenol or to preganglionic electrical stimulation of sympathetic nerves to the heart persisted into adulthood. These results indicate that prenatal exposure to nicotine produces long-term alterations in adrenergic responsiveness of sympathetic target tissues.

Aging↗

PubMed1989

Prenatal exposure to nicotine impairs nervous system development at a dose which does not affect viability or growth.

Prenatal exposure to high doses of nicotine (greater than 6 mg/kg/day) via maternal infusions has been shown to impair nervous system development and to decrease viability and growth. In the current study, we have examined the effects of infusing pregnant rats with 2 mg/kg of nicotine per day from gestational days 4 through 20. At this lower dose, there was neither interference with maternal weight gain nor any increase in resorption rate. Intrauterine and postnatal growth was maintained at normal or supranormal rates in the exposed offspring. Nevertheless, sufficient nicotine penetrated the fetal brain to cause persistent alterations in [3H]nicotine binding sites, abnormalities of cellular development [assessed by measurements of ornithine decarboxylase (ODC) activity and deoxyribonucleic acid (DNA)], and impairment of development of peripheral noradrenergic projections (assessed by kidney norepinephrine levels); in each case, the neural alterations were virtually equivalent to those obtained previously at the higher, growth-suppressant dosage. These findings indicate that growth impairment alone is insufficient to predict the adverse effects of nicotine on development.

Analysis of Variance↗

PubMed1989

Role of sympathetic neurons in development of beta-adrenergic control of ornithine decarboxylase activity in peripheral tissues: effects of neonatal 6-hydroxydopamine treatment.

Sympathetic neurons are thought to regulate the development of their postsynaptic targets. In the current study, we examined the effects of sympathectomy with 6-hydroxydopamine in neonatal rats on the ontogeny of beta-receptor binding sites and their linkage to both cyclic AMP production and ornithine decarboxylase activity. Cardiac norepinephrine levels and turnover were used to confirm the completeness and permanence of the lesion. The ability of isoproterenol, a beta-adrenergic agonist, to stimulate ornithine decarboxylase (a growth-related enzyme) in heart, lung and kidney, was reduced by neonatal sympathectomy; the effect persisted into young adulthood. The effect represented a selective uncoupling of enzyme activity from receptor activation, as receptor binding capabilities were unaffected and the linkage of beta-receptors to cyclic AMP was enhanced. Comparison of the effects of peripheral sympathectomy with those of central lesions (intracisternal 6-hydroxydopamine) confirmed the importance of sympathetic nerve terminals in determining the coupling of the receptors to ornithine decarboxylase. These data suggest that sympathetic neurons program their target organs to specific trophic responses during development.

Animals↗

PubMed1989

Effects of prenatal nicotine exposure on development of central and peripheral cholinergic neurotransmitter systems. Evidence for cholinergic trophic influences in developing brain.

The development of cholinergic systems in brain regions was evaluated biochemically in developing control rats and rats whose mothers received nicotine via continuous minipump infusion during gestational days 4 to 20. The cerebral cortex displayed a unique maturational pattern of choline acetyltransferase (ChAT) activity and high-affinity synaptosomal [3H]choline uptake capabilities, characterized by increases in the concentration of these components and a postnatal spike of neuronal activity as assessed with the uptake/ChAT ratio; the peak of activity coincided with the time at which neurogenesis declines and synaptogenesis rises. Evaluation of the same markers in midbrain + brainstem indicated rises in uptake which were relatively unselective, primarily reflecting tissue growth and no postnatal peak of uptake/ChAT; cerebellum likewise showed primarily tissue growth-related changes in ChAT rather than increases in its specific concentration. Prenatal exposure to nicotine had a marked adverse effect on developmental patterns of ChAT, uptake and uptake/ChAT only in cerebral cortex, the region previously shown to exhibit major abnormalities caused by this drug and other treatments with cholinomimetic effects. ChAT was unaffected in peripheral projections to the adrenal. Nicotine may thus selectively disrupt central nervous system development by stimulating nicotinic receptors which are present in fetal brain, prematurely eliciting the events ordinarily triggered postnatally by cholinergic projections.

Animals↗

PubMed1988

Role of sympathetic neurons in biochemical and functional development of the kidney: neonatal sympathectomy with 6-hydroxydopamine.

Renal sympathetic function develops over the first 3 weeks of postnatal life in the rat. In the current study, the effects of neonatal sympathectomy with 6-hydroxydopamine were examined on renal biochemical and functional development. The completeness and persistence of sympathetic nerve loss were confirmed by direct measurement of norepinephrine levels and turnover. Evidence was obtained for adverse effects on cellular maturation, as shown by perturbations in the ornithine decarboxylase/polyamine system, which is controlled partially by beta adrenergic input and which regulates macromolecule synthesis in developing cells. A later phase of 6-hydroxydopamine-induced alterations in renal development was seen during the period in which synaptogenesis is prominent and sympathetic tone is high (end of the 2nd postnatal week to end of the 3rd week): the denervated kidneys displayed supersensitivity of beta adrenergically mediated cyclic AMP responses without changes in receptor binding. The alterations in biochemical indices of cellular maturation were accompanied by abnormalities of renal function. 6-Hydroxydopamine caused an increase in the fractional excretion of sodium and deficits in physiological responsiveness of the kidney to a vasopressin analog. Later on, alterations in glomerular filtration rate and basal urinary osmolality also were prominent. These results indicate that neonatal sympathectomy has an adverse effect on the biochemical and functional development of the kidney.

Animals↗

PubMed1988

Trophic control of lung development by sympathetic neurons: effects of neonatal sympathectomy with 6-hydroxydopamine.

The onset of peripheral sympathetic neuronal function is thought to provide trophic regulatory signals for development of adrenergic target tissues. In the current study, we examined the effects on lung development of neonatal sympathectomy with 6-hydroxydopamine. The completeness of the lesion and effectiveness in reducing sympathetic input to the tissue were confirmed by direct measurement of norepinephrine levels and turnover. Despite the denervation, no evidence of beta-receptor up-regulation was found; in fact, receptor binding sites tended to be reduced throughout development. The cyclic AMP response to isoproterenol challenge was initially suppressed in the lesioned animals, but became supersensitive even in the face of reduced receptor binding capabilities. Evidence was also obtained for ontogenetic abnormalities in the ornithine decarboxylase/polyamine system, which is partially controlled by beta-adrenergic input and which regulates macromolecule synthesis in replicating and differentiating cells. Eventually, the alterations were reflected in aberrant developmental patterns of DNA, RNA and protein in the lung. These results indicate that sympathetic neurons influence the biochemical development of the lung and may serve to program permanently the relationships among receptor sites, receptor coupling to cellular function, and control of cell maturation.

Animals↗

PubMed1985

The effect of bezafibrate on hyperlipidaemia in experimental nephrotic syndrome in rats.

The effects of bezafibrate on hyperlipidaemia in experimental nephrotic syndrome in rats has been investigated. The treated group received bezafibrate 10 mg kg-1 p.o. daily. No significant differences in total serum cholesterol occurred, but a significant reduction in serum triglyceride (P less than 0.005) and elevation in HDL cholesterol (P less than 0.005) occurred. These findings may have implications for therapeutic intervention in severe hyperlipidaemia of the nephrotic syndrome in man.

Animals↗

PubMedDate not supplied

Prenatal terbutaline exposure in the rat: selective effects on development of noradrenergic projections to cerebellum.

Terbutaline, used in the treatment of premature labor and asthma, crosses the placenta and can stimulate beta 2-adrenergic receptors in the fetus. This study examines the effects of prenatal exposure to terbutaline (10 mg/kg SC on gestational days 17, 18 and 19) on the development of noradrenergic projections in brain regions of the fetal and neonatal rat, using synaptosomal uptake of [3H]norepinephrine as a marker for synaptogenesis. Although terbutaline exposure did not compromise body or brain region growth, uptake was adversely affected selectively in the cerebellum, a region which also displays close coupling of fetal beta 2-receptors to control of cell development near term. These results thus provide biochemical evidence that terbutaline may be a neurobehavioral teratogen.

Animals↗