CSF acidosis augments ventilation through cholinergic mechanisms

Ventilation is influenced by the acid-base status of the brain extracellular fluids (ECF). CO2 may affect ventilation independent of changes in H+. Whether the acidic condition directly alters neuronal firing or indirectly alters neuronal firing through changes in endogenous neurotransmitters remains unclear. In this work, ventriculocisternal perfusion (VCP) was used in anesthetized (pentobarbital sodium, 30 mg/kg) spontaneously breathing dogs to study the ventilatory effects of acetylcholine (ACh), eucapnic acidic (pH approximately 7.0) cerebrospinal fluid (CSF), and hypercapnic acidic (pH approximately 7.1) CSF in the absence and presence of atropine (ATR). Each animal served as its own control. Base line was defined during VCP with control mock CSF (pH approximately 7.4). With ATR (4.8 mM) there was an insignificant downward trend in minute ventilation (VE). ACh (6.6 mM) increased VE 53% (n = 12, P less than 0.01), eucapnic acidic CSF increased VE 41% (n = 12, P less than 0.01), and hypercapnic acidic CSF increased VE 47% (n = 6, P less than 0.01). These positive effects on ventilation were not seen in the presence of ATR. This suggests that acidic brain ECF activates ventilatory neurons through muscarinic cholinergic mechanisms. Higher concentrations of ACh increased ventilation in a concentration-dependent manner. Higher concentrations of ATR decreased ventilation progressively, resulting in apnea. The results suggest that ACh plays a significant role in the central augmentation of ventilation when the brain ECF is made acidic by either increasing CSF PCO2 or decreasing CSF bicarbonate.     

Adrenergic and cholinergic interaction in central ventilatory control

The ventrolateral medulla, which functions as integrator of cardiorespiratory control, contains cholinergic and adrenergic neurons. Exogenously administered cholinergic and adrenergic agents affect both ventilation and circulation. It is not clear whether these agents act in an independent or coordinate manner. beta-Adrenergic and alpha 2-adrenergic agents stimulate and depress the cardiorespiratory system, respectively. beta-Adrenergic and alpha 2-adrenergic agents stimulate and depress the production of adenosine 3',5'-cyclic monophosphate (cAMP), respectively. Increased intracellular cAMP may facilitate the release of acetylcholine (ACh). This work seeks to answer the following questions: 1) Are the cardiorespiratory effects of adrenergic agents secondary to possible changes in ACh release? 2) Does cAMP production have an intermediate role? By means of ventriculocisternal perfusion in anesthetized (pentobarbital sodium, 30 mg/kg) spontaneously breathing dogs, isoproterenol (ISO) increased ventilation (VE) 75% (P less than 0.05); heart rate and cardiac output were also increased (P less than 0.05). Esmolol (a beta-antagonist) blocked both the cardiovascular and ventilatory effects of ISO. Atropine (a cholinergic antagonist) blocked the ventilatory effects of ISO, but the circulatory changes persisted. Forskolin (a direct activator of adenylate cyclase) increased VE 51% (P less than 0.05), and its effect was also blocked by atropine. Clonidine decreased VE 42% (P less than 0.05); heart rate and cardiac output were also decreased.(ABSTRACT TRUNCATED AT 250 WORDS)     

31P nuclear magnetic resonance spectroscopy study of the anaerobic threshold in humans

The relationships among the lactate threshold (LT), ventilatory threshold (VT), and intracellular biochemical events in exercising muscle have not been well defined. Therefore 14 normal subjects performed incremental plantar flexion to exhaustion on 2 study days, the first for determination of LT and VT and the second for continuous 31P nuclear magnetic resonance spectroscopy of calf muscle. Exercising calf muscle pH fell precipitously at 66.4 +/- 3.4% (SE) of the maximum O2 uptake (VO2max) and was termed the intramuscular pH threshold. This did not occur at a significantly different metabolic rate from that at the LT (78.6 +/- 5.9% VO2max) or at the VT (75.0 +/- 4.1% VO2max, P = 0.15 by analysis of variance). Four subjects showed an intramuscular pH threshold and VT without a perceptible rise in forearm venous blood lactate. It is concluded that traditional markers of the "anaerobic threshold," the LT and VT, occur as intramuscular pH becomes acid for a group of normal subjects undergoing incremental exercise to exhaustion. It is speculated that neuronal pathways linking intramuscular biochemical events to the ventilatory control center may explain the intact VT in those subjects without an "intermediary" LT.     

Brain glutamate metabolism during metabolic alkalosis and acidosis.

Glutamate modifies ventilation by altering neural excitability centrally. Metabolic acid-base perturbations may also alter cerebral glutamate metabolism locally and thus affect ventilation. Therefore, the effect of metabolic acid-base perturbations on central nervous system glutamate metabolism was studied in pentobarbital-anesthetized dogs under normal acid-base conditions and during isocapnic metabolic alkalosis and acidosis. Cerebrospinal fluid transfer rates of radiotracer [13N]ammonia and of [13N]glutamine synthesized de novo via the reaction glutamate+NH3-->glutamine in brain glia were measured during normal acid-base conditions and after 90 min of acute isocapnic metabolic alkalosis and acidosis. Cerebrospinal fluid [13N]ammonia and [13N]glutamine transfer rates decreased in metabolic acidosis. Maximal glial glutamine efflux rate jm equals 85.6 +/- 9.5 (SE) mumol.l-1 x min-1 in all animals. No difference in jm was observed in metabolic alkalosis or acidosis. Mean cerebral cortical glutamate concentration was significantly lower in acidosis [7.01 +/- 0.45 (SE) mumol/g brain tissue] and tended to be larger in alkalosis, compared with 7.97 +/- 0.89 mumol/g in normal acid-base conditions. There was a similar change in cerebral cortical gamma-aminobutyric acid concentration. Within the limits of the present method and measurements, the results suggest that acute metabolic acidosis but not alkalosis reduces glial glutamine efflux, corresponding to changes in cerebral cortical glutamate metabolism. These results suggest that glutamatergic mechanisms may contribute to central respiratory control in metabolic acidosis.     

CSF bicarbonate regulation in respiratory acidosis and alkalosis.

CSF bicarbonate regulation was studied in respiratory acidosis and alkalosis of 4h duration in antsthetized dogs. PCO2, pH, HCO3, ammonia, and lactate in CSF and arterial and safittal sinus bloof were measured when equal volumes of saline or acetazolamide (8 mg) were injected into lateral cerebral ventricles. The brain CO2 dissociation curve was determined at the end of all experiments. CSF and arterial bicarbonate increased 11.8 and 5.9 meg/l, respectively, in acidosis. Acetazolamide limited the rise in CSF bicarbonate to 4.2 meg/l, and prevented the CSF bicarbonate increase associated with hyperammonemia. During alkalosis CSF bicarbonate fell 6.5 meg/l and CSF lactate increased almost 2 meg/l while arterial bicarbonate fell 5.7 meg/l and lactate remained unchanged. Thus plasma bicarbonate changes account for some of the CSF unchanged. Thus plasma bicarbonate changes account for some of the CSF bicarbonate alterations in respiratory acid-base-disturbances. In acidosis additional CSF bicarbonate is formed by the choroid plexus and glial cells on the inner and outer surfaces of the brain--a reaction catalyzed by the locally present carbonic anhydrase. In alkalosis the greater fall in CSF bicarbonate than blood is due to selective brain and CSF lactic acidosis.     

Computational Design and Analysis of a Poly-Epitope Fusion Protein: A New Vaccine Candidate for Hepatitis and Poliovirus

International Journal of Peptide Research and Therapeutics - Infections with HCV, HBV and poliovirus are still considered to be substantial global health burdens. Vaccination is one of the most...     

Survivin as a Target for Anti-cancer Phytochemicals According to the Molecular Docking Analysis

International Journal of Peptide Research and Therapeutics - Survivin is a unique member of the inhibitor of apoptosis protein family. Research has approved Survivin’s ability to interact...     

Performance,rumen fermentation,blood minerals,leukocyte and antioxidant capacity of young Holstein calves receiving high-surface ZnO instead of common ZnO

ABSTRACT

This study was conducted to assess the effect of feeding high-surface ZnO instead of common ZnO on the performance, rumen fermentation, blood minerals, leukocytes and antioxidant capacity of pre- and post-weaning calves. Thirty male suckling Holstein calves were allotted to one of three experimental groups (10 replicates) in a completely randomised design. Calves received: (1) a low Zn diet without Zn supplementation (control diet), (2) a high Zn diet containing 50 mg supplementary Zn/kg dry matter (DM) as common ZnO or (3) a high Zn diet containing 50 mg supplementary Zn/kg DM as high-surface ZnO (nano-ZnO). The control diet contained a native Zn content of 35.5, 34.7 or 33.7 mg/kg DM for the age periods of 7 to 30, 31 to 70 and 71 to 100 d, respectively. Supplementation of the diet with Zn did not change the dry matter intake (DMI) of calves during d 7 to 30 but increased the ADG in this period (p < 0.05). During age periods of 31 to 70 and 71 to 100 d, DMI and ADG of the Zn supplemented calves were higher (p < 0.05) than the control animals. The nutrient digestibility and the concentration of rumen volatile fatty acids were positively affected (p < 0.05) and the rumen ammonia-N concentration decreased (p < 0.05) by dietary Zn supplementation. Furthermore, the incidence of diarrhoea and pneumonia was lower in calves receiving the Zn supplemented diets. Irrespective of ZnO source, the blood total antioxidant capacity, leukocyte and haematocrit levels significantly increased (p < 0.05) with the ZnO supplemented diets. The post-weaning DMI, nutrient digestibility and blood haematocrit levels were higher in calves receiving high-surface ZnO, compared to those supplemented with common ZnO. With inclusion of the Zn sources in pre- and post-weaning diets, the blood Zn concentration increased (p < 0.05), but the blood Cu, Fe, Ca, P and Mg levels remained unchanged. Regardless of source, dietary supplementation of young calves with ZnO improved the performance and decreased rumen ammonia-N and the incidence of diseases. Moreover, high-surface ZnO had advantages over common ZnO in increasing the post-weaning feed intake, digestibility and blood Zn concentration.     

Utilization of the human gamma-satellite insulator for the enhancement of anti-PCSK9 monoclonal antibody expression in Chinese hamster ovary cells

Molecular Biology Reports - Monoclonal antibodies (mAbs) are widely employed as invaluable therapeutics for a vast number of human disorders. Several approaches have been introduced for the...