Biomedical subjects

C J Doll

Publications and source records attributed to C J Doll.

6 recordsLinked to original sources

PubMed1996

Unifying theory of hypoxia tolerance: molecular/metabolic defense and rescue mechanisms for surviving oxygen lack.

We develop a unifying theory of hypoxia tolerance based on information from two cell level models (brain cortical cells and isolated hepatocytes) from the highly anoxia tolerant aquatic turtle and from other more hypoxia sensitive systems. We propose that the response of hypoxia tolerant systems to oxygen lack occurs in two phases (defense and rescue). The first lines of defense against hypoxia include a balanced suppression of ATP-demand and ATP-supply pathways; this regulation stabilizes (adenylates) at new steady-state levels even while ATP turnover rates greatly decline. The ATP demands of ion pumping are down-regulated by generalized "channel" arrest in hepatocytes and by "spike" arrest in neurons. Hypoxic ATP demands of protein synthesis are down-regulated probably by translational arrest. In hypoxia sensitive cells this translational arrest seems irreversible, but hypoxia-tolerant systems activate "rescue" mechanisms if the period of oxygen lack is extended by preferentially regulating the expression of several proteins. In these cells, a cascade of processes underpinning hypoxia rescue and defense begins with an oxygen sensor (a heme protein) and a signal-transduction pathway, which leads to significant gene-based metabolic reprogramming-the rescue process-with maintained down-regulation of energy-demand and energy-supply pathways in metabolism throughout the hypoxic period. This recent work begins to clarify how normoxic maintenance ATP turnover rates can be drastically (10-fold) down-regulated to a new hypometabolic steady state, which is prerequisite for surviving prolonged hypoxia or anoxia. The implications of these developments are extensive in biology and medicine.

Adenosine Monophosphate↗

PubMed1993

Reduced ionic conductance in turtle brain.

Whole cell recording techniques were employed to measure whole cell (Gw) and specific membrane (Gm) conductance in turtle and rat pyramidal neurons in slices. Results indicate that rat neurons are 4.2 times more conductive compared with turtle neurons at 25 degrees C, which is accentuated by temperature, so that rat neurons at 37 degrees C are 22 times more conductive than turtle neurons at 15 degrees C. A conductance Q10 of 1.9 was measured for both turtle (15-25 degrees C) and rat (25-35 degrees C) pyramidal neurons. Conductance measurements of turtle pyramidal neurons over 6-9 h of anoxia indicate no statistical difference between Gm or Gw from normoxic control measures. These results indirectly support the concept of low ATP-dependent ion pump activity in the turtle brain as one mechanism for reduced energy expenditure in the normoxic state.

Animals↗

PubMed1991

Effects of anoxia and metabolic arrest on turtle and rat cortical neurons.

The responses of turtle and rat cortical pyramidal neurons to various pharmacological treatments were measured using intracellular recordings. Turtle neurons survived both anoxia and pharmacological anoxia for 180 min with no noticeable effect. Rat pyramidal neurons responded with a loss in membrane resistance, followed by a transient hyperpolarization, and a subsequent depolarization to a zero membrane potential (41.3 +/- 6.5 min, anoxia; 25.8 +/- 12.6 min, pharmacological anoxia). Metabolic arrest caused a rapid loss in membrane resistance, transient hyperpolarization, and a rapid depolarization in both turtle (4.6 +/- 1.1 min) and rat (3.1 +/- 0.5 min) neurons. Iodoacetate alone had a similar effect on the rat as metabolic arrest (6.5 +/- 0.8 min), but the turtle exhibited more prolonged survival (53.5 +/- 4.6 min). Ouabain caused a rapid depolarization in the rat cortical neuron (8.6 +/- 1.1 min), but no initial loss in membrane resistance or a hyperpolarization. These results demonstrate that the turtle neuron, which survives anoxia, is no better at surviving total metabolic inhibition than the rat neuron. In addition, anoxia takes 13 times longer to depolarize a rat cortical neuron than metabolic arrest, and neither of these treatments is totally mimicked by ouabain alone.

Action Potentials↗

PubMed1991

Channel arrest: implications from membrane resistance in turtle neurons.

A widespread defense strategy used by hypoxia-tolerant animals is metabolic depression. One possible mechanism for metabolic depression is "channel arrest." This hypothesis predicts that ion leakage through plasma membrane leakage channels is reduced during an anoxic episode. The decreased ion flux would result in the conservation of energy through the reduction of ATP-demanding ion pumping. We tested this hypothesis with the anoxia-tolerant turtle (Chrysemys picta) as a model system. With intracellular recording used in cortical slices, whole cell input resistance and specific membrane resistivity were monitored under control and anoxic conditions. There were no significant changes in resistance, indicating that the channel arrest defense mechanism was not utilized for energy conservation during short-term anoxia (less than or equal to 120 min).

Animals↗

PubMed1990

A pharmacological model of ischemia in the hippocampal slice.

The effects of various metabolic inhibitors on the time course of changes in membrane potential was studied using intracellular recordings from CA1 hippocampal neurons in vitro. Concurrent application of cyanide and iodoacetic acid, agents which block oxidative phosphorylation and glycolysis respectively, result in more rapid loss of membrane function than blockade of either pathway alone. This pharmacological regimen mimics the anoxia and the hypoglycemia encountered during ischemia in vivo, both in terms of the metabolic derangement as well as the time course of changes in membrane function. Thus, this treatment appears to represent a well-controlled pharmacological model of ischemia in vitro.

Animals↗

PubMed1989

Turtles and rats: a biochemical comparison of anoxia-tolerant and anoxia-sensitive brains.

When temperature differences are taken into account, turtle brains use glucose at one-sixth the rate reported in rat brains. Na+-K+-ATPase activities are 2- to 2.5-fold higher in rat than in turtle brains. Maximal activities of hexokinase and lactate dehydrogenase are similar, whereas citrate synthase activities are two- to threefold higher in rat than turtle brains at the respective biological temperatures. Voltage-dependent Ca2+ channel densities, when compared between the two species, showed no consistent pattern. These data, along with the threefold differences in density of voltage-dependent Na+ channels reported by Lutz et al., are consistent with the idea that lower rates of channel and pump-mediated Na+ and K+ fluxes result in lower rates of aerobic energy metabolism in turtle brains compared with rat brains.

Adaptation, Physiological↗