C. Di Giulio

Obstructive sleep apnea and type 2 diabetes

Type 2 diabetes and obstructive sleep apnea (OSA) are diseases with high prevalence and major public health impact. There is evidence that regular snoring and OSA are independently associated with alterations in glucose metabolism. Thus, OSA might be a risk factor for the development of type 2 diabetes. Possible causes might be intermittent hypoxia and sleep fragmentation, which are typical features of OSA. OSA might also be a reason of ineffective treatment of type 2 diabetes. There is further evidence that the treatment of OSA by continuous positive airway pressure (CPAP) therapy might correct metabolic abnormalities in glucose metabolism. It is assumed that this depends on therapy compliance to CPAP. On the other hand, there are also hints in the literature that type 2 diabetes per se might induce sleep apnea, especially in patients with autonomic neuropathy. Pathophysiological considerations open up new insights into that problem. Based on the current scientific data, clinicians have to be aware of the relations between the two diseases, both from the sleep medical and the diabetological point of view. The paper summarizes the most important issues concerning the different associations of OSA and type 2 diabetes.

The role of hypoxia in erectile dysfunction mechanisms

Chronic hypoxia is related to many pathological conditions: aging, heart and respiratory failure, sleep apneas, smoke, chronic obstructive pulmonary disease (COPD), diabetes, hypertension and arteriosclerosis, all characterized by reductions of sleep-related erections (SREs) and by erectile dysfunction (ED). Sleep-related erections occur naturally during rapid eye movement (REM) sleep in sexually potent men. Hypoxia is also a physiological condition at altitude. The level of inspired oxygen decreases progressively with the increase of altitude; for this reason, this study was performed to evaluate the relationship of SREs with hypoxic environment. SREs have been recorded by an erectometer (RigiScan) on three mountain climbers (mean age: 32.5) during a 26-day stay at an altitude ranging from 2000 to 5600 m above sea level. Twenty-four records have been made at progressively increasing altitudes. A data analysis was carried out on a statistical mean of the three values of each variable and an analysis of variance (ANOVA) and Newman–Keuls test were carried out for multiple comparison among groups. At altitudes over 4450 m, we found lack of rigidity at 80–100% and 60–79%. Mean % of rigidity and rigidity time of 80–100% (tip and base) decreased progressively with altitude. No significant reductions were shown in rigidity time at 0–19% and at 20–39% (tip and base), of total number, of total and mean duration of SREs. Pathological rigidometric records at high altitude in sexually potent men at sea level clarify the primary role of hypoxia in physiopathological ED pathway.

Long-term regulation of carotid body function: acclimatization and adaptation--invited article.

Physiological responses to hypoxia either continuous (CH) or intermittent (IH) depend on the O(2)-sensing ability of the peripheral arterial chemoreceptors, especially the carotid bodies, and the ensuing reflexes play important roles in maintaining homeostasis. The purpose of this article is to summarize the effects of CH and IH on carotid body function and the underlying mechanisms. CH increases baseline carotid body activity and sensitizes the response to acute hypoxia. These effects are associated with hyperplasia of glomus cells and neovascularization. Enhanced hypoxic sensitivity is due to alterations in ion current densities as well as changes in neurotransmitter dynamics and recruitment of additional neuromodulators (endothelin-1, ET-1) in glomus cells. Morphological alterations are in part due to up-regulation of growth factors (e.g. VEGF). Hypoxia-inducible factor-1 (HIF-1), a transcriptional activator might underlie the remodeling of carotid body structure and function by CH. Chronic IH, on the other hand, is associated with recurrent apneas in adults and premature infants. Two major effects of chronic IH on the adult carotid body are sensitization of the hypoxic sensory response and long-lasting increase in baseline activity i.e., sensory long-term facilitation (LTF) which involve reactive oxygen species (ROS) and HIF-1. In neonates, chronic IH leads to sensitization of the hypoxic response but does not induce sensory LTF. Chronic IH-induced sensitization of the carotid body response to hypoxia increases the likelihood of unstable breathing perpetuating in more number of apneas, whereas sensory LTF may contribute to increased sympathetic tone and systemic hypertension associated with recurrent apneas.

Sustained hypoxia promotes hyperactive response of carotid body in the cat.

Carotid body chemosensory activities were measured before and after 0.2, 5,6 and 7 h of sustained isocapnic (PaCO(2) approximately equal to 30 Torr) hypoxia (PaO(2) approximately equal to 43 Torr) in the cats (n=7). The activity increased from 5.4 impsec(-1) at 0.2 h to about 13 impsec(-1) at 7 h. This increase in chemosensory activities were due to both an augmented sensitivity and to a long-term facilitation and not due to arterial [H(+)] changes.

Neuroglobin, a New Oxygen Binding Protein is Present in the Carotid Body and Increases after Chronic Intermittent Hypoxia

affinities and binds CO (Burmester & Hankeln, 2004).The physiological role of Ngb is not well understood, but it has been proposed that Ngb participates in several processes such as oxygen transport, oxygen storage, and NO detoxification (Burmester and Hankeln, 2004). Ngb as well as hemoglobin is a respiratory proteinthat reversibly binds gaseous ligands (NO and O

Further characterization of stimulus interaction of cat carotid chemoreceptors

The hypothesis that the maximal response to pCO2 of carotid body chemoreceptors would be the same regardless of pO2, if the receptor molecule behaves like a hemoglobin molecule, was investigated using single or a few fiber carotid body chemoreceptors in cats in vivo which were anesthetized and artificially ventilated. In one series, graded levels of CO2 inhalation in steady-state at p(a)O2 = 354 +/- 19 Torr showed a linear response from 1 to 20.1 +/- 2.3 imp/s for p(a)CO2 increase from 32 to 178 +/- 18 Torr, and at p(a)O2 of 48 +/- 3.8 Torr, from 3.8 to 18.6 +/- 1.7 imp/s for p(a)CO2 increase from 21 to 109 +/- 11 Torr, levelling off thereafter. In another series of multi-fiber preparation, close intra-arterial injection of blood plus saline containing pCO2 of about 270 Torr gave peak responses of 44 +/- 9, 42 +/- 6 and 42 +/- 7 imp/s at p(a)O2 of 40 +/- 4, 82 +/- 6 and 388 +/- 18 Torr, respectively. Thus, the chemosensory responses to p(a)CO2 reached the same level of maximal activity regardless of p(a)O2. Taken together, the maximal responses in both steady-state and transient-state to p(a)CO2 appeared to be the same at hypoxic and hyperoxic p(a)O2. This stimulus-response relationship of the receptor molecule is analogous to O2-CO2 interaction with hemoglobin molecule with a Bohr effect, reaching a saturation point at a finite pO2.

Neuroglobin in Aging Carotid Bodies

Neuroglobin (Ngb) is a member of the vertebrate globin family expressed particularly in the brain and in the retina. Ngb is concentrated in the mitochondria-containing areas of neurons, and its distribution is correlated with oxygen consumption rates. Previously we have shown that Ngb is expressed in carotid body (CB) tissues. Considering that hypoxia and aging may be linked through a series of adaptive and protective mechanisms (e.g. reduction in mitochondrial numbers), we investigate the role of Ngb during aging and hypoxia. Two groups of six rats (age-matched 3 and 24 months old) were kept in room air as a control groups, the others two groups were kept in a Plexiglas chamber for 12 days in chronic hypoxia (10-12% inspired oxygen). The presence of Ngb in the CB tissue was detected by immunohistochemistry using a polyclonal antibody. Ngb immunoreactivity was significantly higher in CB tissues from young rats exposed to chronic intermittent hypoxia, whereas CB tissues from old rats did not show any significant increase in Ngb levels after hypoxia. Similar to hemoglobin, Ngb may act as a respiratory protein by reversibly binding gaseous ligands NO and O(2) and could act as a NO scavenger and participate in detoxification of Reactive Oxygen Species (ROS) generated under hypoxic conditions.

Sympathetic Peripheral Chemoreflex is Independent of Expiratory Output Neurons in the Cat

Previously we reported that activities of certain chemoreflex sensitive cervical preganglionic sympathetic nerves (PSN) were augmented by carotid chemoreceptor stimulation independently of phrenic nerve (PN) activity in the cat. To test the hypothesis that the PSN carotid chemoreflex could have been mediated by the expiratory neuron activity, we studied the relationship between PSN, internal intercostal expiratory nerve (IICEN) and PN activities in vagotomized, anesthetized, paralysed and artificially ventilated cats. We made the following observations. (1) Hypoxia often inhibited IICEN activity while the PN and PSN activities were stimulated. (2) during normoxia, cyanide strongly stimulated PN and PSN discharges but only moderately IICEN discharges. (3) Hyperventilation hypocapnia suppressed or eliminated PSN and PN rhythms and activities, but made some IICEN fibers fire continuously. (4) During hypocapnic apnea, cyanide stimulated PSN activity before PN and IICEN activities, although some PSN fibers were stimulated simultaneously with PN fibers. Accordingly we conclude that IICEN activity does not significantly influence chemoreflex stimulation of PSN activity and that a direct chemoreflex stimulation of IICEN is minimal in the cat. Thus, the chemoreflex PSN response is in part independent of respiratory chemoreflex pathways.

Sperm forward motility is negatively affected by short-term exposure to altitude hypoxia

Human exposure to altitude is a model to study the role of oxygen in different areas of physiology and pathophysiology. The aim of this study was to evaluate whether a short exposure to hypoxia (5 days) combined with exercise, at altitude ranging from 900 m above sea level to 5895 m above sea level (Kilimanjaro Expedition) can modify seminal and reproductive hormonal parameter levels in human beings. During the ascent, blood oxygen saturation at 3.848 m above sea level was found to be decreased when compared to sea level (P < 0.02). The sperm forward motility at sea level after the expedition showed a significant reduction (P < 0.02). There were no changes in other seminal parameters among those compared. Determination of the hormonal plasma concentrations showed that baseline values of follicle‐stimulating hormone, total testosterone, prolactin and oestradiol were unchanged at sea level after the hypoxic experience, with respect to baseline values at sea level. On the other hand, luteinising hormone levels after altitudes trekking significantly increased compared to levels before the expedition (P < 0.05). Because of the short‐term exposure, we can assume that the reduced forward motility described here may result from the effects of the acute altitude hypoxia on spermatozoa during the epididymal transit where they mature acquiring their motility.

Human carotid body neuroglobin, vascular endothelial growth factor and inducible nitric oxide synthase expression in heroin addiction.

AIMS The carotid body (CB) represents the prime site for detecting and responding to hypoxia. Since the role of heroin in respiratory depression with consequent hypoxia is known, the authors were able to investigate morphological and molecular modifications occurring in the CB of heroin addicted subjects compared to subjects who died because of trauma. METHODS AND RESULTS CB sampled from six 27 year old subjects, slides were treated with Mallory Trichrome staining or used for immunohistochemical analysis to detect Neuroglobin (NGB), Hypoxia Inducible Factor-1 (HIF-1α), Vascular Endothelial Growth Factor (VEGF), Inducible Nitric Oxide Synthase (i-NOS), Bax and cleaved Caspase-3 proteins. Mallory Trichrome staining shows an increase in the connective tissue in heroin subjects compared to controls and a parallel reduction in parenchymal area. Immunohistochemical analyses in heroin subjects found a decrease in NGB and an increase in HIF-1α and VEGF compared to controls; i-NOS expression was not statistically significant. Bax and cleaved caspase-3 were positive only in the heroin subjects. CONCLUSIONS These results could confirm the typical hypoxic condition occurring in heroin addicts. Since NGB may function as a reactive oxygen or nitrogen species scavenger and as apoptotic cell death protector, the decrease in its expression may suggest a key role of this globin in human CB impairment due to heroin addiction.