Brain-derived neurotrophic factor (BDNF) governs both the selective survival of neurons during development and the experience-based regulation of synaptic strength throughout life. BDNF produced a concentration-dependent increase in the respiratory control index (RCI, a measure of the efficiency of respiratory coupling, ATP synthesis and organelle integrity) of rat brain mitochondria. This effect was mediated via a MAP kinase pathway and highly specific for oxidation of glutamate plus malate (complex I) by brain mitochondria. The oxidation by brain mitochondria of the complex II substrate succinate was unaffected by BDNF. The failure of BDNF to modify respiratory activity associated with mitochondrial preparations isolated from rat liver indicates that the actions of the neurotrophin are tissue specific. BDNF also increased the RCI values associated with Ca2+ -induced respiration to a similar extent. This is the first demonstration that BDNF, in addition to modifying neuronal plasticity, can modify brain metabolism and the efficiency of oxygen utilization. The finding that neurotrophins can alter mitochondrial oxidative efficiency has important implications for neurodegenerative and psychiatric diseases.

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1. The mechanical and pharmacological properties of small pulmonary arteries (100-300 microns normalized lumen diameter) were directly compared with those of the left main pulmonary artery (1-2 mm) from the rat. The active and passive length-tension characteristics and responses to a variety of agonists and antagonists were dependent on arterial diameter. 2. Maximum contractile function was obtained in both groups of vessels when stretched so as to give an equivalent transmural pressure of 30 mmHg. This is substantially lower than that found for systemic vessels, and reflects the normal low pulmonary arterial pressure. 3. Noradrenaline was a powerful vasoconstrictor in large but not small pulmonary arteries (P less than 0.001). In contrast, bradykinin produced a significantly greater response in the small arteries (P less than 0.001). In comparison with large pulmonary arteries, small arteries were more sensitive to noradrenaline (P less than 0.05) and 5-hydroxytryptamine (P less than 0.001), less sensitive to endothelin-1 (P less than 0.001) and had the same sensitivity to prostaglandin F2 alpha. 4. The mechanism that maintains the low arterial tone of the pulmonary circulation is unknown, but it may involve the release of relaxing factors from the endothelium. In this preparation, basal resting tone could not be demonstrated in either large or small arteries. 5. Acetylcholine-induced relaxation of pre-contracted pulmonary arteries was reduced or absent in the small artery, despite histological evidence of an intact endothelium. In large arteries pre-contracted with prostaglandin F2 alpha, acetylcholine (100 mumol/l) caused 88.2% relaxation compared with 25.2% in the small artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracerebral injection of ibotenate into mouse pups induced grey matter lesions and white matter cysts; co-administration of brain-derived neurotrophic factor (BDNF) produced a dose-dependent reduction in these lesions. In contrast, glial cell line-derived neurotrophic factor (GDNF) had no significant effect, whereas nerve growth factor (NGF) or interleukin-1β (IL-1β) resulted in dose-dependent exacerbation. The neuroprotective effects of BDNF were abolished by co-administration of anti-BDNF antibody or MEK inhibitors, or ABT-737, a BH3 mimetic and Bcl-2 antagonist. The actions of BDNF, GDNF and NGF were measured in a parallel in vitro study on the oxidative metabolism of mouse brain mitochondria. BDNF produced a concentration-dependent increase in the respiratory control index (RCI, a measure of respiratory coupling efficiency, ATP synthesis, and organelle integrity) when co-incubated with synaptosomes containing signal transduction pathways; but GDNF failed to modify RCI, and NGF had only weak effects. BDNF had no effect on pure mitochondria, and enhanced oxidation only when complex I substrates were used. The effect of BDNF was inhibited by anti-BDNF antibody, MEK inhibitors or ABT-737, and also by IL-1β, indicating that the mitochondrial effects are mediated via the same MEK-Bcl-2 pathway as the neuroprotection. The complex I inhibitor rotenone, a compound implicated in the aetiology of Parkinson's disease, inhibited both the in vitro mitochondrial and in vivo neuroprotective effects of BDNF. The ability of BDNF to modify brain metabolism and the efficiency of oxygen utilization via a MEK-Bcl-2 pathway may be an important component of the neuroprotective action observed with this neurotrophin.

S U M M A R Y 1. The rebreathing and steady-state methods for assessing the response to inhaled carbon dioxide were compared in six normal subjects under control conditions and during metabolic acidosis and alkalosis.2. The slopes of the CO, response lines obtained with the two methods under control conditions were not significantly different.3. Metabolic acidosis and alkalosis produced a significant change in the intercept of the response line when this was assessed with the steady-state technique. The slope of the response lines did not change significantly in alkalosis but there was probably a small increase during acidosis. 4. Using the rebreathing technique there was no significant change in intercept in acidosis and alkalosis, but the slope varied significantly from control values. 5. It is concluded that the two methods of assessing the respiratory response to inhaled CO, are comparable under normal acid-base conditions. This similarity does not hold in metabolic changes of the acid-base state.