We review recent cross-disciplinary experimental and theoretical investigations on metabolism of the amino acid neurotransmitters glutamic acid and gamma-aminobutyric acid (GABA) in the brain during hypoxia and hypercapnia and their possible role in central control of breathing. The roles of classical modifiers of central chemical drive to breathing (H+ and cholinergic mechanisms) are summarized. A brief perspective on the current widespread interest in GABA and glutamate in central control is given. The basic biochemistry of these amino acids and their roles in ammonia and bicarbonate metabolism are discussed. This review further addresses recent work on central respiratory effects of inhibitory GABA and excitatory glutamate. Current understanding of the sites and mechanisms of action of these amino acids on or near the ventral surface of the medulla is reviewed. We focus particularly on tracer kinetic investigations of glutamatergic and GABAergic mechanisms in hypoxia and hypercapnia and their possible role in the ventilatory response to hypoxia. We conclude with some speculative remarks on the critical importance of these investigations and suggest specific directions of research in central mechanisms of respiratory control.

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Recent data suggest that the increase in ventilation during hypoxia may be related to the release of the excitatory amino acid neurotransmitter glutamate centrally. To further investigate this, we studied the effects of MK-801, a selective noncompetitive N-methyl-D-aspartate receptor antagonist, on the hypoxic ventilatory response in lightly anesthetized spontaneously breathing intact dogs. The cardiopulmonary effects of sequential ventriculocisternal perfusion (VCP) at the rate of 1 ml/min with mock cerebrospinal fluid (CSF, control) and MK-801 (2 mM) were compared during normoxia and 8 min of hypoxic challenge with 12% O2. Minute ventilation (VE), tidal volume (VT), and respiratory frequency (f) were recorded continuously, and hemodynamic parameters [heart rate (HR), blood pressure (MAP), cardiac output (CO), pulmonary arterial pressure, and pulmonary capillary wedge pressure] were measured periodically. Each dog served as its own baseline control before and after each period of sequential VCP under the two different O2 conditions. During 15 min of normoxia, there were no significant changes in the cardiopulmonary parameters with mock CSF VCP, whereas with MK-801 VCP for 15 min, VE decreased by approximately 27%, both by reductions in VT and f (17 and 9.5%, respectively). HR, MAP, and CO were unchanged. During 8 min of hypoxia with mock CSF VCP, VE increased by 171% associated with increased VT and f (25 and 125%, respectively). HR, MAP, and CO were likewise augmented. In contrast, the hypoxic response during MK-801 VCP was characterized by an increased VE of 84%, mainly by a rise in f by 83%, whereas the VT response was abolished. The cardiovascular excitation was also inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)

Our understanding of cell structure and function derives from applications of a variety of physical and life science disciplines, methods and models to an important physiological process, namely, the exchange and transport of ions and molecules across biological membranes. We know that ion transport through membranes arises from a diversity of interrelated and interactive physical and chemical phenomena over a wide range of spatial and temporal scales. Among these phenomena common to all cellular structure and function include metabolism, kinetics of molecules, chemically mediated alteration of cell membrane electrical potential, membrane ion conductance, electrical signal propagation, and modulation by chemo- and mechanoreceptive mechanisms. This review focuses on the unique information contained in fluctuations in electrical properties associated with cell membrane ion transport.

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Times of peak gadolinium concentration ([Gd]) after intravenous (IV) and left ventricular (LV) bolus injection of gadopentetate dimeglumine were determined in renal cortex and medulla in normal rabbits and in rabbits after saline load (overhydration) or hemorrhage (dehydration). Magnetic resonance images were obtained with echo-planar inversion-recovery sequences, and signal intensity-versus-time curves in cortical and medullary regions of interest were converted to [Gd]-versus-time curves. Cortical perfusion measured with microspheres demonstrated that the three physiologic states were significantly different. There were three separate [Gd] peaks in both the cortex and medulla as the bolus moved from one anatomic compartment to the next. The first cortical peak occurred sooner after LV than after IV bolus injection (P < .05) and later in dehydrated than in normal and overhydrated rabbits (P < .05). The first medullary peak always followed the first cortical peak by about 6-10 seconds and mirrored the cortical patterns. The second and third cortical peaks were consistent with proximal and distal tubular transit. These peaks similarly showed faster response to LV than IV injection and were delayed by hemorrhage. The authors conclude that quantitative physiologic information can be obtained with dynamic contrast-enhanced MR imaging of the kidney.

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The ratio of carbon dioxide (CO2) to bicarbonate (HCO-3) is important in acid-base homeostasis and to the central chemical drive to ventilation. The entry of HCO-3 from blood into the central nervous system (CNS) has been controversial, and the entry of CO2, assumed to be rapid, has not been separated from HCO-3 entry. Therefore the rates of movement of CO2 and of HCO-3 from blood to CNS were evaluated. The first-pass brain uptake of 11C-labeled CO2-HCO-3 was studied under conditions with and without carbonic anhydrase inhibition (CAI), with the isotope injected either as CO2 (acid injectate) or as HCO-3 (alkaline injectate) into the aortic arch of anesthetized dogs. The uptake of 11C under conditions without CAI was about 80% and remained the same whether the isotope was injected as CO2 or as HCO-3. The uptake of 11C under conditions of cerebroventricular administration of acetazolamide was 61.5 +/- 2.0% after injection as CO2 and 56.7 +/- 8.3% after injection as HCO-3. The uptake of 11C under conditions of systemic CAI was 50.3 +/- 3.0% after injection as CO2 and 19.3 +/- 1.1% after injection as HCO-3. The uptakes were comparable for the combination of cerebroventricular and intravenous acetazolamide. From the values for 11C uptake with systemic CAI and the uncatalyzed reaction rates for interconversion of CO2 and HCO-3, the first-pass brain uptake was calculated to be 87.7 +/- 7.8% for CO2 and 16.3 +/- 1.8% for HCO-3. Thus there is a very rapid diffusion of CO2 from blood to brain and a significant movement of HCO-3 from blood to brain.