Biological signals最新文献

The respiratory and nonrespiratory hypotheses of O2 chemoreception in arterial chemoreceptors have been compared to provide a perspective that both mechanisms can potentially coexist. The nonrespiratory membrane mechanism operates at a relatively higher level of PO2 and that respiratory metabolic mechanisms at a lower level. The two mechanisms may overlap in the intermediate range of PO2.

In the present article we review in a concise manner the literature on the mechanisms of O2 chemoreception in the carotid body of adult mammals. In the first section we describe the basic structure of the carotid body, and define this organ as a secondary sensory receptor. In the second section is presented the most relevant literature on the O2 metabolism in the carotid body to define the parameters of O2 chemoreception, including hypoxic thresholds and P50 of the hypoxic responses. The final section is devoted to the mechanisms of detection of the hypoxic stimulus. We provide the data in favor and against each of the current three models on O2 chemoreception: the membrane model, the metabolic hypothesis with its different versions and the NAD(P)H oxidase model.

Glomus cells of the carotid body are dye and electrically coupled due to the presence of gap junctions between them. During stimulation by hypoxia, hypercapnia and acidity, about 70% of the cells uncouple to various degrees, whereas the rest either develop tighter coupling or are unaffected. Similar results have been obtained with exogenous administrations of naturally present transmitters such as dopamine and cholinergic substances. Uncoupling is associated with a decrease in junctional conductance and closing of intercellular channels. Tighter coupling is accompanied by opposite effects on these parameters. We think that cell isolation uncoupling leads to release of larger amounts of transmitters toward the carotid nerve sensory terminals. Tighter coupling would reduce the quantities of released chemicals. We may have a delicate titration process modulating the sensory discharge frequency, since a single sensory fiber divides to innervate up to 20 glomus cells. Thus, the discharge frequency of this fiber (the sensory unit) will result from the contributions of its many branches, each impinging on variously active glomus cells.

Chronic hypoxia in vivo promotes long-term changes in the carotid body (CB) response to low PO2. By exposing cultured rat CB chemoreceptors (glomus cells) to 6% O2 for 1-3 weeks, we are investigating the cellular and molecular mechanisms of hypoxic adaptation. Recent studies have uncovered a series of plastic changes in glomus cells including hypertrophy, differential regulation of Na+, Ca2+, and K+ currents, and upregulation of the 'plasticity protein', GAP-43. We have also identified cyclic AMP as a possible intracellular mediator of at least some of these effects of chronic hypoxia. Associated with the changes in ionic currents, glomus cells become electrically more excitable. However, a complete understanding of the physiological response of chronically hypoxic glomus cells to chemostimuli will require more detailed knowledge of the specific alterations in the sensing and signaling pathways, including modifications in neurotransmitter (e.g. catecholamine) functions.

Though exogenously delivered acetylcholine excites the carotid body, past evidence has been considered as unsupportive in assigning acetylcholine an excitatory role during hypoxia or hypercapnia. With ganglionic transmission used as the model, data is presented which aims at blocking the postsynaptic cholinergic receptors, at preventing the presynaptic release of acetylcholine, and at quantitating its release under stimulating conditions. The data support an excitatory role for acetylcholine during hypoxia.

Ventilation is not constant during steady-state prolonged hypoxia. This raises questions as to the role of the carotid body (CB) in sustained hypoxia. Studies in awake goats using an extracorporeal CB circuit to allow separation of systemic (CNS) and CB blood gases provided evidence that prolonged hypoxia isolated to the CB causes time-dependent increased CB sensitivity to hypoxia. These findings were confirmed in recordings of afferent CB discharge in anesthetized goats. Studies in cats have been compatible with those in goats. It is concluded that prolonged hypoxic stimulation of the CB increases its sensitivity to hypoxia and is at least partly responsible for increased ventilatory drive during prolonged hypoxia such as during altitude acclimatization.

G proteins are signal coupling molecules that play major roles in mediating the effects of transmitters as well as certain sensory signals. In the present study we examined whether oxygen chemoreception in the carotid body is coupled to G proteins. Experiments were performed on carotid bodies isolated from anesthetized cats. Presence of G proteins was examined with ADP-ribosylation of the carotid body membranes. Pertussis toxin (PTX), which inactivates G proteins in neuronal tissues, ADP-ribosylated a single band of carotid body protein with a molecular mass of 41 kDa. With cholera toxin (CTX) only a faint band of protein corresponding to approximately 45 kDa was evident. Perfusing the isolated carotid bodies with PTX (2.5 micrograms/min; 60 min) attenuated the sensory response to hypoxia by 52% of the controls. Perfusion with CTX (50 micrograms/min; for 60 min), on the other hand, increased baseline activity and potentiated the hypoxic response by 125% of controls. Heat-inactivated toxins, however, had no influence on the carotid body sensory response to hypoxia. These results suggest that G proteins are present in the chemoreceptor tissue and they seem to be coupled to the transduction and/or to the transmission of the hypoxic stimulus.

Effects of melatonin on hypothalamic neurotransmitters in male mice were studied. Exogenous melatonin administered intraperitoneally significantly increased (p < 0.05) hypothalamic concentrations of aspartic acid and gamma-aminobutyric acid by over 29 and 50% respectively. Conversely, hypothalamic beta-endorphin concentration was significantly decreased (p < 0.05) 30 min after melatonin administration with doses between 5- and 100 micrograms/kg. Similarly, melatonin, at a concentration of 100 micrograms/kg, decreased (p < 0.05) the serotonin level in mouse hypothalamus by 46%. Melatonin, however, did not affect the concentration of hypothalamic glutamic acid over a dose range of 0.5-300 micrograms melatonin/kg. Our findings suggested that actions of pineal melatonin in animals such as inhibition on serum corticosterone levels might be mediated by the potentiation of activities of hypothalamic neurons containing gamma-aminobutyric acid and aspartic acid or by the inhibition of the beta-endorphin and serotonin hypothalamic neurons. The neurons containing glutamic acid in the hypothalamus were, however, not influenced by melatonin. Our results are in line with the suggestion that melatonin actions on adrenal corticosterone release or other endocrine secretions may be mediated by way of its actions on hypothalamic neurotransmitter activities.

Since melatonin and putative melatonin receptors can be detected in a variety of peripheral tissues, direct endocrine and paracrine actions of melatonin on the physiological functions of different organ systems in response to internal and external stimuli probably exist. As an extension of our earlier work on the pharmacological characterization of 2-[125I]iodomelatonin binding sites in the duck jejunum, the regional and diurnal variations of melatonin and putative melatonin receptors of different segments of the duck gastro-intestinal tract were studied in an attempt to understand the role of melatonin in the physiology of the digestive system. Although no significant effects of diurnal variation and pinealectomy on the regional distribution of melatonin were observed, significant regional variations of melatonin levels were detected with decreasing levels as follows: colon > oesophagus, caecum > duodenum, jejunum > ileum. The densities of melatonin binding sites showed a significant variation between different intestinal regions at either mid-light or mid-dark, with the following descending order: ileum, jejunum > duodenum, colon > caecum > oesophagus. Analysis of the distribution of melatonin binding sites in the wall of the intestine revealed maximal binding in the mucosa and minimal binding in the muscular layers of the jejunum. Similar results were obtained for other intestinal regions as revealed by autoradiography. No significant changes in the affinities of melatonin binding sites were detected between different regions and tissue layers of the alimentary canal. Moreover, the densities and affinities of melatonin binding sites among different regions of the gut exhibited no significant diurnal variations. The demonstration of regional variations in melatonin levels and the density of melatonin binding sites along the gastro-intestinal tract, with a concentration of the putative melatonin receptors in the mucosal layer, suggests a possible direct action of melatonin in the regulation of fluid/electrolyte transport and nutrient absorption in the gut.

To elucidate the possible role of plasminogen activator (PA) in spermatogenesis and spermiation in mammals, we studied the hormonal regulation of PA secretion in cultured rat and mouse seminiferous tubules during defined stages of spermatogenesis. Results indicated that: (1) under basal conditions, segments of rat seminiferous tubules released primarily urokinase-type PA (uPA) at all stages of the cycle. The highest level of PA secretion occurred at stages VIIab, VIIcd and VIII. FSH, 8-bromo cyclic AMP and forskolin (FK) stimulated PA secretion, predominantly tissue-type PA (tPA). (2) In contrast, mouse seminiferous tubules secreted only tPA under basal conditions. In the presence of 50 microM MIX, seminiferous tubules at stages VII and VIII secreted higher levels of both types of PA than at the other stages. Both tPA and uPA secretion was enhanced by addition of FSH and FK to the organ culture media. (3) Segments of both rat and mouse seminiferous tubules at stages IX-XII in which the sperm residual bodies are absorbed into the Sertoli cells were also very sensitive to the addition of FSH to the organ culture. These results suggest that tPA in rat and mouse testes may play an essential role in the process of spermatogenesis and spermiation as well as in sperm residual body absorption.