Circulating n-3 fatty acids and linoleic acid as indicators of dietary fatty acid intake in post-myocardial infarction patients.

BACKGROUND AND AIMS: Population-based studies often use plasma fatty acids (FAs) as objective indicators of FA intake, especially for n-3 FA and linoleic acid (LA). The relation between dietary and circulating FA in cardiometabolic patients is largely unknown. We examined whether dietary n-3 FA and LA were reflected in plasma lipid pools in post-myocardial infarction (MI) patients. METHODS AND RESULTS: Patients in Alpha Omega Cohort filled out a 203-item food-frequency questionnaire from which eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and LA intake were calculated. Circulating individual FA (% total FA) were assessed in cholesteryl esters (CE; n = 4066), phospholipids (PL; n = 838), and additionally in total plasma for DHA and LA (n = 739). Spearman correlation coefficients (rs) were calculated for dietary vs. circulating FA. Circulating FA were also compared across dietary FA quintiles, overall and in subgroups by sex, obesity, diabetes, statin use, and high alcohol intake. Patients were on average 69 years old and 79% was male. Moderate correlations between dietary and circulating levels were observed for EPA (rs∼0.4 in CE and PL) and DHA (rs ∼0.5 in CE and PL, ∼0.4 in total plasma), but not for ALA (rs ∼0.0). Weak correlations were observed for LA (rs 0.1 to 0.2). Plasma LA was significantly lower in statin users and in patients with a high alcohol intake. CONCLUSIONS: In post-MI patients, dietary EPA and DHA were well reflected in circulating levels. This was not the case for LA, which may partly be influenced by alcohol use and statins.

The 2015 Dutch food-based dietary guidelines.

The objective of this study was to derive food-based dietary guidelines for the Dutch population. The dietary guidelines are based on 29 systematic reviews of English language meta-analyses in PubMed summarizing randomized controlled trials and prospective cohort studies on nutrients, foods and food patterns and the risk of 10 major chronic diseases: coronary heart disease, stroke, heart failure, diabetes, breast cancer, colorectal cancer, lung cancer, chronic obstructive pulmonary disease, dementia and depression. The committee also selected three causal risk factors for cardiovascular diseases or diabetes: systolic blood pressure, low-density lipoprotein cholesterol and body weight. Findings were categorized as strong or weak evidence, inconsistent effects, too little evidence or effect unlikely for experimental and observational data separately. Next, the committee selected only findings with a strong level of evidence for deriving the guidelines. Convincing evidence was based on strong evidence from the experimental data either or not in combination with strong evidence from prospective cohort studies. Plausible evidence was based on strong evidence from prospective cohort studies only. A general guideline to eat a more plant food-based dietary pattern and limit consumption of animal-based food and 15 specific guidelines have been formulated. There are 10 new guidelines on legumes, nuts, meat, dairy produce, cereal products, fats and oils, tea, coffee and sugar-containing beverages. Three guidelines on vegetables, fruits, fish and alcoholic beverages have been sharpened, and the 2006 guideline on salt stayed the same. A separate guideline has been formulated on nutrient supplements. Completely food-based dietary guidelines can be derived in a systematic and transparent way.

N-6 and n-3 fatty acid cholesteryl esters in relation to incident stroke in a Dutch adult population: a nested case-control study.

BACKGROUND AND AIMS: There are few prospective studies on fatty acid status in relation to incident stroke, with inconsistent results. We assessed the associations of plasma n-6 and n-3 PUFA in cholesteryl esters with the risk of total stroke and stroke subtypes in Dutch adults. METHODS AND RESULTS: We conducted a nested case-control study using data from a population-based cohort study in adults aged 20-65 years. Blood sampling and data collection took place during 1993-1997 and subjects were followed for 8-13 years. We identified 179 incident cases of stroke and 179 randomly selected controls, matched on age, gender, and enrollment date. Odds ratios (OR) with 95% confidence intervals (95%CI) were calculated per standard deviation (SD) increase of PUFA in cholesteryl esters using multivariable conditional logistic regression. Cases comprised 93 ischemic, 50 hemorrhagic, and 36 unspecified strokes. The n-6 PUFA linoleic acid and arachidonic acid contributed ~55% and ~6.5% respectively to total plasma fatty acids, whereas the n-3 PUFA alpha-linolenic acid contributed ~0.5% and eicosapentaenoic acid plus docosahexaenoic acid (EPA-DHA) ~1.3%. After adjustment for confounders, n-6 and n-3 PUFA were not associated with incident total stroke or stroke subtypes. The OR (95% CI) for total stroke was 0.95 (0.74-1.23) per SD increase in linoleic acid and 1.02 (0.80-1.30) per SD increase in arachidonic acid. ORs (95% CI) for total stroke were 0.94 (0.72-1.21) for alpha-linolenic acid and 1.16 (0.94-1.45) for EPA-DHA. CONCLUSION: In the present study, plasma n-6 or n-3 fatty acids were not related to incident stroke or stroke subtypes.

No effects of n-3 fatty acid supplementation on serum total testosterone levels in older men: the Alpha Omega Trial.

The intake of the n-3 fatty acids alpha-linolenic acid (ALA), acid (EPA) and docosahexaenoic acid (DHA) has been related to testosterone levels in epidemiological analyses. The aim of this study was to assess whether the n-3 fatty acids affects testosterone levels in post-myocardial infarction (MI) patients, who are at risk of testosterone deficiency. In a double-blind, placebo-controlled trial of low-dose supplementation of n-3 fatty acids, we included 1850 male post-MI patients aged 60-80 years who participated in the Alpha Omega Trial. Patients were randomly allocated to margarines that provided 400 mg/day of EPA-DHA (n = 453), 2 mg/day of ALA (n = 467), EPA-DHA plus ALA (n = 458), or placebo (n = 472). Serum testosterone levels were assessed at baseline and after 41 months using whole day blood samples obtained at the subjects' home or at the hospital. Subjects were on average age of 68.4 (SD 5.3) years old and had baseline mean serum total testosterone of 14.8 (SD 5.6) nmol/L. The four randomized groups did not differ for baseline characteristics. ALA, EPA-DHA, and EPA-DHA plus ALA supplementation did not affect serum total testosterone compared to placebo. Moreover, n-3 fatty acid supplementation did not affect the risk of incident testosterone deficiency (n = 76 with total testosterone <8.0 nmol/L). We conclude that n-3 fatty acids supplementation did not affect serum total testosterone in men who had had a MI.

Levels and trends in cardiovascular risk factors and drug treatment in 4837 elderly Dutch myocardial infarction patients between 2002 and 2006.

BACKGROUND: It is important to gain insight into opportunities for secondary prevention of cardiovascular disease. Our aim was to investigate levels and trends in cardiovascular risk factors and drug treatment in Dutch post-myocardial infarction (MI) patients between 2002 and 2006 and to make comparisons with the EUROASPIRE surveys (1999-2007). METHODS: We analysed data from 4837 post-MI patients (aged 69 years, 78% men) from 32 Dutch hospitals, using baseline cross-sectional data from the Alpha Omega Trial. RESULTS: Between 2002 and 2006, significant declines were found in the prevalence of smoking (23% to 16%, p < 0.001), hypercholesterolaemia (≥5 mmol/l; 54% to 27%, p < 0.0001) and hypertension (≥140/90 mmHg; 58% to 48%, p < 0.001). The prevalence of antithrombotic drugs was high (97%). The prevalence of lipid-modifying drugs and antihypertensives was high, and increased (74% to 90%, p < 0.0001 and 82% to 93%, p < 0.001, respectively). The prevalence of obesity (27%) was high in 2002 and decreased to 24% in 2006, albeit not significantly. Diabetes prevalence was high and increased between 2002 and 2006 (18% to 22%, p = 0.02). In comparison with EUROASPIRE patients, who were on average 8-10 years younger, our study in 2006 included patients with lower levels of obesity, hypertension, hypercholesterolaemia, diabetes and lower use of antiplatelets and ß-blockers, but similar levels of lipid-modifying drugs. CONCLUSIONS: This study showed that older Dutch post-MI patients were adequately treated with drugs, and that risk factors reached lower levels than in the younger EUROASPIRE patients. However, there is room for improvement in diet and lifestyle, given the high prevalence of smoking, obesity, and diabetes.

A model study of the regulation of gastric acid secretion.

A computer simulation model is presented of the gastric phase regulation of gastric acid secretion in humans. The model is based on experimental data from the literature and includes terms representing gastric pH and gastric volume-dependent gastrin secretion, gastrin-dependent acid secretion, food storage in the stomach, and gastric emptying. We have explored the predictive value of the model in assessing the relative importance of gastric pH-dependent and gastric volume-dependent acid secretion mechanisms under various conditions. Similarly we have studied the role of gastric acid deregulation in achlorhydria, the Zollinger-Ellison syndrome, and duodenal ulcer, and the influence of the antacid drugs cimetidine and ranitidine under duodenal ulcer conditions. Model analysis of normal gastric acid regulation suggests that gastric volume-controlled acid secretion is of major importance during eating and predicts that pH-dependent gastrin secretion is of major importance in preventing excessively low pH levels between meals and during the night.

Irreversible inhibition of rat hepatic glutathione S-transferase isoenzymes by a series of structurally related quinones.

The effect of several structurally related 1,4-benzoquinones (BQ) and 1,4-naphthoquinones (NQ) on the activity of rat hepatic glutathione S-transferases (GST) was studied. For the 1,4-benzoquinones, the extent of inhibition increased with an increasing number of halogen substituents. Neither the type of halogen nor the position of chlorine-atoms was of major importance. Similarly, 2,3-dichloro-NQ demonstrated a considerably higher inhibitory activity than 5-hydroxy-NQ. 2-Methyl derivatives of NQ did not inhibit GST activity at all. The irreversible nature of the inhibition was shown both by the time-course of the inhibition as well as by the fact that removal of the inhibitor by ultrafiltration did not restore the enzymatic activity. Incubation of quinones and enzyme in the presence of the competitive inhibitor S-hexyl-glutathione, slowed the inhibition considerably, indicating an involvement of the active site. Isoenzyme 3-3 was found to be most sensitive towards the whole series of inhibitors, whereas the activity of isoenzyme 2-2 was least affected in all cases. The inhibition by quinones is probably mainly due to covalent modification of a specific cysteine residue in or near the active site. The differential sensitivities of individual isoenzymes indicates that this residue is more accessible and/or easier modified in isoenzyme 3-3 than in any of the other isoenzymes tested. The findings suggest that quinones form a class of compounds from which a selective in vivo inhibitor of the GST might be developed.

Effects of CO2 and H+ on the ventilatory response to peripheral chemoreceptor stimulation.

To determine whether the stimulatory effect of CO2 on the peripheral chemoreceptors is due to molecular CO2, H+ or both we measured steady-state ventilation (Ve) during normoxia in 9 and during hypoxia in 5 chloralose-urethane anaesthetized cats using the artificial brain stem perfusion technique. This technique allows one to manipulate independently the PaCO2, PaO2 and the pHa of the blood in the systemic circulation (peripheral) and the blood perfusing the brain stem (central). Keeping the central conditions constant the H+ and CO2 concentrations in the systemic circulation were changed by i.v. infusion of 0.3 M HCl or 0.6 M NaHCO3 and by giving the animal different CO2 mixtures to inhale. The peripheral H+ concentration ([H+]p) range covered was from 27 to 103 nmol X 1(-1); the peripheral arterial CO2 tension (PaPCO2) ranged from 2.3 kPa to 8.4 kPa. Fitting the data with the function VE = a[H+]p + bPaPCO2 + c revealed that the coefficient b was not significantly different from zero at the 0.05 level during normoxia and hypoxia. The mean value (+/- SEM) found for the coefficient a was 33.0 +/- 3.6 at normoxia and 36.0 +/- 15.4 ml X min-1 X nM-1 at hypoxia. We conclude that the steady-state ventilatory response due to the stimulation of the peripheral chemoreceptors with CO2 is mediated by H+. The effects of molecular CO2 are negligible.

Response of vertebral and carotid blood flow to isocapnic changes in end-tidal oxygen tension.

The response of the vertebral and carotid blood flow to isocapnic hypoxia was measured in 9 cats anaesthetized with chloralose-urethane using perivascular electromagnetic flow probes. The carotid flow was already significantly increased when going from hyperoxia (PETO2 55 kPa) to normoxia. For the vertebral blood flow a significant increase compared to hyperoxia was observed at a moderate level of hypoxia (PETO2 9 kPa). The time course of the response of the blood flow to isocapnic step-like changes in PETO2 was fitted with a first order model. The mean time constant (+/- SD) for steps into hypoxia for the carotid flow was 35 +/- 38 sec(8 cats) and for the vertebral flow, 44 +/- 37 sec (5 cats). The mean time constant (+/- SD) for steps out of hypoxia was significantly smaller and found to be 23 +/- 22 sec (8 cats) and 19 +/- 18 sec (4 cats), respectively. We argue that a major part of the changes in vertebral and carotid blood flow to steps into hypoxia goes to brain tissue.

Effects of halothane on the ventilatory response to hypoxia and hypercapnia in cats.

The influence of halothane 0.8-1.2% inspired on the peripheral hypoxic chemoreflex was investigated in 13 cats subjected to artificial brain stem perfusion (ABP). This technique allows for an independent control of blood gas tensions and halothane concentration between blood perfusing the brain stem (central) and the systemic circulation (peripheral). In six cats the ventilatory response to isocapnic hypoxia was assessed during overall halothane anesthesia (HO) before and during ABP. Before ABP, systemic and brain stem circulations both were rendered hypoxic. During ABP, hypoxia was induced systemically while the brain stem was maintained hyperoxic. The ventilatory response in non-ABP cats (mean 698 ml . min-1 at PaO2 6.6 kPa; 50 mmHg) was about half the response in ABP cats (mean 1,194 ml . min-1 at PaO2 6.5 kPa; 49 mmHg), indicating that in the presence of halothane, central hypoxia depressed ventilation appreciably. Compared with chloralose-urethane anesthesia (CU), halothane reduced the ventilatory response to hypoxia in both perfusion conditions but never abolished it. To assess the influence of halothane on peripheral and central mediation of the CO2 response during hypoxia, each was assessed during CU anesthesia, during HO, and with halothane applied exclusively peripherally against a background of CU (CUHP). In all drug states, the periphery was kept hypoxic and brain stem hyperoxic. Compared with CU anesthesia, HO and CUHP anesthesia reduced both peripheral (Sp) and central (Sc) CO2 sensitivity but not the Sp/Sc ratio. Similarly, the extrapolated PaCO2 at zero ventilation was not detectably different among these three states.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of brain stem hypoxaemia on the regulation of breathing.

In 22 cats, anaesthetized with chloralose-urethane, the brain stem was artificially perfused with their own blood via a gas exchanger in which the central PaO2 and PaCO2 were imposed independently from the peripheral PaO2 and PaCO2 in the systemic arterial blood. The effects of brain stem hypoxaemia on ventilation and on the ventilatory responses to central and peripheral chemoreceptor stimulation were investigated. When the central PaO2 was lowered from 375 mm Hg to 100 and 50 mm Hg, keeping all other blood gas tensions constant, ventilation decreased on the average by 0.22 L X min-1 and 0.54 L X min-1, respectively. The increase in ventilation due to peripheral hypoxaemia and the sensitivities to central and peripheral CO2 (delta VE/delta PaCO2) were independent of the central PaO2, despite the depression of ventilation. The sensitivity to central CO2 was also not influenced when central hypoxaemia was combined with peripheral hypoxaemia. The linear VE-VT relation was not affected by central hypoxaemia. Our findings suggest that the functioning of respiratory neurons in the brain stem is unaltered during moderate central hypoxaemia.

Central respiratory CO2 sensitivity at extreme hypocapnia.

In 7 cats anaesthetized with chloralose-urethane the ponto-medullary region was artificially perfused with blood having PaCO2 values (central PaCO2) in the range of 0.3-4.5 kPa. The ventilatory response to changes in central PaCO2 was measured at constant hypercapnic and hypoxic conditions in the systemic circulation. Ventilation decreased upon lowering the central PaCO2 down to values of 0.5 kPa. There was no threshold for the effect of the central PaCO2 on ventilation. The CO2 sensitivity was undiminished at extreme hypocapnia compared to eucapnia. Under extreme central hypocapnic conditions the breathing pattern became irregular. It is concluded that there is still central CO2 sensitivity related to ventilation at extreme hypocapnia. Our findings suggest that central chemosensitive structures have a neural threshold below a PaCO2 of 0.5 kPa.

Influence of peripheral O2 tension on the ventilatory response to CO2 in cats.

The effects of peripheral hypoxia on ventilation were investigated in 18 cats anaesthetized with chloralose urethane. The ponto-medullary region of the brain was artificially perfused via a cannulated vertebral artery, using an extracorporeal circuit fed from a femoral artery. In this way the carbon dioxide tension (PacCO2) and the oxygen tension in the blood supplying the brainstem could be imposed independently from the peripheral PCO2 (PapCO2) and PO2 (PapO2) in the systemic circulation. In all experiments the brainstem was kept hyperoxic. The steady-state ventilation VE could be described by (formula; see text) where Sp and Sc represent the peripheral and central sensitivity to carbon dioxide and K is a constant. Sc and K were independent of the PapO2. In general, peripheral hypoxia increased and peripheral hyperoxia decreased Sp, compared to normoxia. It is concluded that: (1) there is no interaction in the ventilatory response between peripheral O2-CO2 and central CO2 stimuli; and (2) a positive interaction in the ventilatory response between peripheral hypoxia and CO2 originates from the arterial chemoreceptors.

Sites of action of halothane on respiratory pattern and ventilatory response to CO2 in cats.

To assess the major sites of action of halothane on the control of breathing, the ventilatory response to CO2 was studied in 11 cats and partitioned into tidal volume and frequency response. In these cats artificial perfusion of the ponto-medullary region was applied. In essence, this technique allows one to deliver to the brainstem blood-gas tensions and anesthetic concentrations at predetermined levels which are independent from those in the systemic circulation; thus the central and peripheral effects of halothane and CO2 can be determined separately. In cats exposed both centrally and peripherally to halothane (1.0-1.6%) tachypnea was observed which disappeared when the blood perfusing the brainstem was purged of halothane. From these results is follows that the tachypnea is exclusively due to an action of halothane on structures in the brainstem. In these cats the extrapolated Paco2 at zero ventilation was significantly lower during general halothane anesthesia than during light chloralose-urethane anesthesia (P less than 0.05). In cats lightly anesthetized with chloralose-urethane, halothane (0.5-1.5%) was either administered centrally or peripherally. In these experiments the "overall" ventilatory CO2 sensitivity of both the peripheral and central chemorereflex pathways decreased significantly (P less than 0.01). However, the ratio between these two sensitivities remained the same (P less than 0.5). The extrapolated Paco2 at zero ventilation was not affected by halothane provided its concentration was below 1% (P less than 0.7). From these results we conclude that the depressant effect of halothane on ventilation originates centrally as well as peripherally. Furthermore, from the findings that the ratio of the CO2 sensitivities and the extrapolated Paco2 at zero ventilation remained constant, the authors argue that halothane acts on the processing part of the neural respiratory drive (integrating centers) rather than on the neural activity of the peripheral and central chemoreceptors per se. The peripheral effect is mainly on the neuromechanical link between integrating centers and respiratory movements.

Effect of temperature on the ventilatory response curve to carbon dioxide in anaesthetized cats.

Effects of body temperature on the ventilatory control system were studied in 17 anaesthetized cats. At different body temperatures (stabilized within 0.1 degrees C) CO2 response curves were measured in each cat. In with chloralose-urethan anaesthetized cats it was found that in the body temperature range of 34-40 degrees C, in which neither shivering nor panting occurred, no statistically significant trend with temperature was found in the slope (S) and the extrapolated intercept on the PaCO2-axis (B) of the linear CO2 response curve during hyperoxia as well as hypoxia. In two with pentobarbital anaesthetized cats similar results were obtained. The resting ventilation (at FICO2 = 0) did not change significantly, while the resting PaCO2 during hyperoxia showed a trend to increase with temperature just reaching the level of significance (P less than 0.05). Breathing frequency increased significantly with temperature (P less than 0.0005). When body temperature was elevated above 41 degrees C both the slope (S) and the intercept of the CO2 response curve (B) decreased. In three cats ventriculo-cisternal perfusion was performed and no apparent influence of body temperature was found on the relation between the PCSFCO2 and PETCO2 and on the VE-PCSFCO2 response curves. These findings show that body temperature has no important modifying effect on the ventilatory response to CO2 in anaesthetized cats in the temperature range of 34-40 degrees C.

Ventilatory response to carbon dioxide and apnoeic thresholds.

In 11 cats anaesthetized with chloralose-urethane, the steady state ventilation during hyperoxia was measured as a function of the central PaCO2 (PacCO2) and peripheral PaCO2 (PapCO2) using the technique of artificial ponto-medullary perfusion. The ventilatory response was described by VE = Sc . PacCO2 + Sp . PapCO2 - K where Sc and Sp represent the overall central and peripheral sensitivity to carbon dioxide. The post-hyperventilation apnoeic threshold values of PapCO2 for several fixed values of PacCO2 were also assessed. It was found that down to PaCCO2's and PapCO2's of about 3.5 kPa (26 mm Hg) the response surface for spontaneous ventilation could be used to satisfactorily predict the PapCO2 as a function of PacCO2 at apnoea. In 4 cats the ventilatory response to changes in central PCO2 was measured after carotid body denervation. These response curves were linear down to the PCO2-axis. We conclude that in anaesthetized cats during hyperoxia: (1) the above equation for the ventilation appears to be valid down to CO2 tensions of about 3.5 kPa (26 mm Hg); (2) the peripheral and central chemoreceptors exhibit neural activity down to at least 2.0 kPa (15 mm Hg); (3) in non-artificially perfused cats the CO2 response curve is linear down to ventilation zero; (4) the PaCO2 at apnoea (apnoeic 'threshold') in non-artificially perfused cats does not constitute a neural threshold for the peripheral or for the central chemoreceptors. Using these results a respiratory controller equation is proposed and some possible implications for the neural organization of the respiratory controller are discussed.

Influence of the depth of anaesthesia on the peripheral and central ventilatory CO2 sensitivity during hyperoxia.

The influence of the depth of anaesthesia on the contribution of central and peripheral chemoreceptors to the slope of the ventilatory response to CO2 during hyperoxia was studied in 12 cats anaesthetized with chloralose-urethane or pentobarbital. By artificial perfusion of the pontomedullary region of the brainstem it was possible to assess the peripheral (Sp) and central (Sc) ventilatory sensitivity to CO2, as well as to vary selectively the level of anaesthesia at the ponto-medullary region (central level) or the overall level. In each cat Sp and Sc were assessed at the initial and at one or two deeper anaesthetic levels. Going from the initial to deeper anaesthetic levels both Sp and Sc decreased. However, Sp/Sc did not change significantly, whether the overall or the central level of anaesthesia was increased. Also the B-value, i.e. the PaCO2 of the extrapolated ventilation-PaCO2 curve at zero ventilation, did not change significantly when going to deeper anaesthetic levels. It is concluded that the respiratory depression caused by the anaesthetics used is due to an influence on the respiratory integrating centres, central chemoreceptors, or both.

Relative contribution of central and peripheral chemoreceptors to the ventilatory response to CO2 during hyperoxia.

Using the technique of artificial ponto-medullary perfusion, the steady state ventilation during hyperoxia was measured in 15 anaesthetized cats as a function of the central PaCO2 (PaCO2) and peripheral PaCO2 (PapCO2). To a first approximation the ventilatory response was linearly related to both the central and peripheral arterial carbon dioxide pressures, viz. VE=SC . PacCO2 + Sp . PapCO2 - K where Sc and Sp represent the overall central and peripheral sensitivity to carbon dioxide. The mean ratio Sp/Sc was 0.48 (range 0.21 to 1.08). In carotid sinus denervated cats Sp was zero, while the values of Sc in these cats were in the range of Sc of cats with intact carotid sinus nerves. It is concluded that the peripse to CO2 under steady-state conditions. Chemodenervation experiments revealed that the carotid bodies play an essential role in this contribution.

Influence of the CSF bicarbonate concentration on the ventilatory response to CO2 in relation to the location of the central chemoreceptors.

In anaesthetized cats, in which the cerebrospinal fluid bicarbonate concentration was varied by a ventriculocisternal perfusion technique, the ventilatory response to CO2 during hyperoxia could be satisfactorily described by VE = S(PCSFCO2 -B). Both the slope S and the intercept B were positively and linearly related to the CSF bicarbonate concentration. Assuming that the PCSFCO2 is equal to the PCO2 in extracellular fluid, it can be shown that VE is a linear, but not a unique function of the [H+] at the site of the chemoreceptors; the slope of this relation varies with the bicarbonate concentration at that site, possibly due to chemical complex formation between HCO-3 and Ca2+ or Mg2+. Changes in the B-value were related to the location of the central chemoreceptors with the models of Pappenheimer and Berndt aand their coworkers. It was found that changes in the CSF bicarbonate concentration are reflected for 60 per cent at the site of the central chemoreceptors, and that this was independent of the cerebral perfusion. Using Berndt's model a distance between CSF and central chemoreceptors of approximately 100 micron was found; this calculated distance is relatively insensitive to relationship (logarithmic or not) between ventilation and H+ concentration and to changes in cerebral perfusion, owing to the approximate nature of the diffusion model.