The locus coeruleus (LC) lies in the dorsal pons and supplies noradrenergic (NA) input to many regions of the brain, including respiratory control areas. The LC may provide tonic input for basal respiratory drive and is involved in central chemosensitivity since focal acidosis of the region stimulates ventilation and ablation reduces CO 2 -induced increased ventilation. The output of LC is modulated by both serotonergic and glutamatergic inputs. A large percentage of LC neurons are intrinsically activated by hypercapnia. This percentage and the magnitude of their response are highest in young neonates and decrease dramatically after postnatal day P10. The cellular bases for intrinsic chemosensitivity of LC neurons are comprised of multiple factors, primary among them being reduced extracellular and intracellular pH, which inhibit inwardly rectifying and voltage-gated K + channels, and activate L-type Ca 2+ channels. Activation of K Ca channels in LC neurons may limit their ultimate response to hypercapnia. Finally, the LC mediates central chemosensitivity and contains pH-sensitive neurons in amphibians, suggesting that the LC has a long-standing phylogenetic role in respiratory control.

Chemosensitive (CS) neurons are found in discrete brainstem regions, but whether the CS response of these neurons is due to intrinsic chemosensitivity of individual neurons or is mediated by changes in chemical and/or electrical synaptic input is largely unknown. We studied the effect of synaptic blockade (11.4 mM Mg2+/0.2mM Ca2+) solution (SNB) and a gap junction uncoupling agent carbenoxolone (CAR--100 microM) on the response of neurons from two CS brainstem regions, the NTS and the LC. In NTS neurons, SNB decreased spontaneous firing rate (FR). We calculated the magnitude of the FR response to hypercapnic acidosis (HA; 15% CO2) using the Chemosensitivity Index (CI). The percentage of NTS neurons activated and CI were the same in the absence and presence of SNB. Blocking gap junctions with CAR did not significantly alter spontaneous FR. CAR did not alter the CI in NTS neurons and resulted in a small decrease in the percentage of activated neurons, which was most evident in NTS neurons from rats younger than postnatal day 10. In LC neurons, SNB resulted in an increase in spontaneous FR. As with NTS neurons, SNB did not alter the percentage of activated neurons or the CI in LC neurons. CAR resulted in a small increase in spontaneous FR in LC neurons. In contrast, CAR had a marked effect on the response of LC neurons to HA: a reduced percentage of CS LC neurons and decreased CI. In summary, both NTS and LC neurons appear to contain intrinsically CS neurons. CS neurons from the two regions receive different tonic input in slices (excitatory for NTS and inhibitory for LC); however, blocking chemical synaptic input does not affect the CS response in either region. In NTS neurons, gap junction coupling plays a small role in the CS response, but gap junctions play a major role in the chemosensitivity of many LC neurons.

Substantial ATP supply by glycolysis is thought to reflect cellular anoxia in vertebrate muscle. An alternative hypothesis is that the lactate generated during contraction reflects sustained glycolytic ATP supply under well-oxygenated conditions. We distinguished these hypotheses by comparing intracellular glycolysis during anoxia to lactate efflux from muscle during sustained, aerobic contractions. We examined the tailshaker muscle of the rattlesnake because of its uniform cell properties, exclusive blood circulation, and ability to sustain rattling for prolonged periods. Here we show that glycolysis is independent of the O 2 level and supplies one-third of the high ATP demands of sustained tailshaking. Fatigue is avoided by rapid H ؉ and lactate efflux resulting from blood flow rates that are among the highest reported for vertebrate muscle. These results reject the hypothesis that glycolysis necessarily reflects cellular anoxia. Instead, they demonstrate that glycolysis can provide a high and sustainable supply of ATP along with oxidative phosphorylation without muscle fatigue.31 P magnetic resonance spectroscopy ͉ high-energy phosphates ͉ rattlesnake L actate generation by tissues is often taken as a sign of tissue hypoxia (1). This thinking has led to the anaerobic threshold hypothesis, which links lactate generation in exercising muscle to an intracellular O 2 limitation to respiration of pyruvate (2). However, many tissues seem to generate lactate under aerobic conditions (so-called aerobic glycolysis) in a process linking glycolytic ATP supply to ion transport (3-5). For example, lactate generation by muscles exercising at rates well below their aerobic maximum (6) supports this alternative explanation. Muscle PO 2 seems to be well above limits to mitochondrial respiration in these muscles as indicated by indirect measures of tissue oxygenation involving myoglobin saturation (6, 7). This finding questions an O 2 limit to respiration as the basis for lactate generation in exercising muscle. However, these indirect measures do not have the spatial resolution to determine intracellular PO 2 to rule out local tissue anoxia (8).A definitive test of whether an O 2 limitation is responsible for lactate generation during sustained contractions is possible by using a direct comparison of glycolysis during anoxic and sustained aerobic contractions. New magnetic resonance (MR) techniques for partitioning intracellular ATP supply in vivo permitted this comparison in human muscles and were used to show that glycolytic flux is independent of O 2 state (9). The similarities of flux under anoxia and aerobic conditions in that study indicated that glycolysis is not mutually exclusive with oxidative phosphorylation. This glycolytic flux should generate a high lactate efflux into the blood during aerobic contractions and serves as a test for MR results. The rattlesnake tailshaker muscles are well suited for a direct comparison of intracellular glycolysis to lactate efflux. First, the uniform muscle fiber properties (10, 11...