Ethanol and Opioids Do Not Act Synergistically To Depress Excitation in Carotid Body Type I Cells

The combination of opioids and ethanol can synergistically depress breathing and the acute ventilatory response to hypoxia. Multiple studies have shown that the underlying mechanisms for this may involve calcium channel inhibition in central neurons. But we have previously identified opioid receptors in the carotid bodies and shown that their activation inhibits calcium influx into the chemosensitive cells. Given that the carotid bodies contribute to the drive to breathe and underpin the acute hypoxic ventilatory response, we hypothesized that ethanol and opioids may act synergistically in these peripheral sensory organs to further inhibit calcium influx and therefore inhibit ventilation. Methods Carotid bodies were removed from 56 Sprague–Dawley rats (1021 days old) and then enzymatically dissociated to allow calcium imaging of isolated chemosensitive type I cells. Cells were stimulated with high K+ in the presence and absence of the µ-opioid agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) (10 µM), a maximal sublethal concentration of ethanol (3 g L-1, 65.1 mM) or a combination of both. Results DAMGO alone significantly inhibited Ca2+ influx but this effect was not potentiated by the high concentration of ethanol. Conclusion These results indicate for the first time that while opioids may suppress breathing via an action at the level of the carotid bodies, ethanol is unlikely to potentiate inhibition via this pathway. Thus, the synergistic effects of ethanol and opioids on ventilatory parameters are likely mediated by central rather than peripheral actions

Time-Dependent Alteration in the Chemoreflex Post-Acute Lung Injury

Acute lung injury (ALI) induces inflammation that disrupts the normal alveolar-capillary endothelial barrier which impairs gas exchange to induce hypoxemia that reflexively increases respiration. The neural mechanisms underlying the respiratory dysfunction during ALI are not fully understood. The purpose of this study was to investigate the role of the chemoreflex in mediating abnormal ventilation during acute (early) and recovery (late) stages of ALI. We hypothesized that the increase in respiratory rate (fR) during post-ALI is mediated by a sensitized chemoreflex. ALI was induced in male Sprague-Dawley rats using a single intra-tracheal injection of bleomycin (Bleo: low-dose = 1.25 mg/Kg or high-dose = 2.5 mg/Kg) (day 1) and respiratory variables- fR, Vt (Tidal Volume), and VE (Minute Ventilation) in response to 10% hypoxia (10% O2, 0% CO2) and 5% hypercapnia/21% normoxia (21% O2, 5% CO2) were measured weekly from W0-W4 using whole-body plethysmography (WBP). Our data indicate sensitization (∆fR = 93 ± 31 bpm, p \u3c 0.0001) of the chemoreflex at W1 post-ALI in response to hypoxic/hypercapnic gas challenge in the low-dose bleo (moderate ALI) group and a blunted chemoreflex (∆fR = -0.97 ± 42 bpm, p \u3c 0.0001) at W1 post-ALI in the high-dose bleo (severe ALI) group. During recovery from ALI, at W3-W4, both low-dose and high-dose groups exhibited a sensitized chemoreflex in response to hypoxia and normoxic-hypercapnia. We then hypothesized that the blunted chemoreflex at W1 post-ALI in the high-dose bleo group could be due to near maximal tonic activation of chemoreceptors, called the ceiling effect . To test this possibility, 90% hyperoxia (90% O2, 0% CO2) was given to bleo treated rats to inhibit the chemoreflex. Our results showed no changes in fR, suggesting absence of the tonic chemoreflex activation in response to hypoxia at W1 post-ALI. These data suggest that during the acute stage of moderate (low-dose bleo) and severe (high-dose bleo) ALI, chemoreflex activity trends to be slightly sensitized and blunted, respectively while it becomes significantly sensitized during the recovery stage. Future studies are required to examine the molecular/cellular mechanisms underlying the time-course changes in chemoreflex sensitivity post-ALI

Effect of Administration of Somatostatin Analogue on Blood Pressure in Chronic Intermittent Hypoxic Rats

The cardiorespiratory system in our bodies does not adapt to Chronic Intermittent Hypoxia (CIH) and consequently syndromes such as sleep apnea lead to pathophysiological conditions like Hypertension. It has been demonstrated that the peripheral chemoreceptors underpin the development of these conditions and at present, there are no selective drug therapies for this form of hypertension. However, evidence suggests that peripheral chemoreflex sensitivity to CO2 & hypoxia is reduced by Somatostatin (SST) in humans. Our preliminary in-vitro studies have demonstrated that SST will blunt the response of the carotid body to hypoxia and decrease the baseline activity of the carotid body. We therefore hypothesize that SST analogues given in-vivo via osmotic minipumps will attenuate the increase in BP, thereby preventing systemic hypertension from developing during CIH. Adult male Sprague-Dawley rats were implanted with Osmotic minipumps containing sterile water or SST analogue (Octreotide Acetate) and then were exposed to CIH for ≤35 days to induce hypertension. BPs were measured before, during and after IH conditioning. Each minipump administers the drug for only 28 days. It was predicted that the animals exposed to the SST analogue will be protected from CIH-induced hypertension. Data showed a sudden drop in BP post-surgery in all animals tested. This hypotension may have prevented the ability of chronic intermittent hypoxia to induce hypertension in both experimental and control animals

Effect of Administration of Somatostatin Analogue on Blood Pressure in Chronic Intermittent Hypoxic Rats

The cardiorespiratory system in our bodies does not adapt to Chronic Intermittent Hypoxia (CIH) and consequently syndromes such as sleep apnea lead to pathophysiological conditions like Hypertension. It has been demonstrated that the peripheral chemoreceptors underpin the development of these conditions and at present, there are no selective drug therapies for this form of hypertension. However, evidence suggests that peripheral chemoreflex sensitivity to CO2 & hypoxia is reduced by Somatostatin (SST) in humans. Our preliminary in-vitro studies have demonstrated that SST will blunt the response of the carotid body to hypoxia and decrease the baseline activity of the carotid body. We therefore hypothesize that SST analogues given in-vivo via osmotic minipumps will attenuate the increase in BP, thereby preventing systemic hypertension from developing during CIH. Adult male Sprague-Dawley rats were implanted with Osmotic minipumps containing sterile water or SST analogue (Octreotide Acetate) and then were exposed to CIH for ≤35 days to induce hypertension. BPs were measured before, during and after IH conditioning. Each minipump administers the drug for only 28 days. It was predicted that the animals exposed to the SST analogue will be protected from CIH-induced hypertension. Data showed a sudden drop in BP post-surgery in all animals tested. This hypotension may have prevented the ability of chronic intermittent hypoxia to induce hypertension in both experimental and control animals

Ethanol and Opioids Do Not Act Synergistically To Depress Excitation in Carotid Body Type I Cells

The combination of opioids and ethanol can synergistically depress breathing and the acute ventilatory response to hypoxia. Multiple studies have shown that the underlying mechanisms for this may involve calcium channel inhibition in central neurons. But we have previously identified opioid receptors in the carotid bodies and shown that their activation inhibits calcium influx into the chemosensitive cells. Given that the carotid bodies contribute to the drive to breathe and underpin the acute hypoxic ventilatory response, we hypothesized that ethanol and opioids may act synergistically in these peripheral sensory organs to further inhibit calcium influx and therefore inhibit ventilation. Methods Carotid bodies were removed from 56 Sprague–Dawley rats (1021 days old) and then enzymatically dissociated to allow calcium imaging of isolated chemosensitive type I cells. Cells were stimulated with high K+ in the presence and absence of the µ-opioid agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) (10 µM), a maximal sublethal concentration of ethanol (3 g L-1, 65.1 mM) or a combination of both. Results DAMGO alone significantly inhibited Ca2+ influx but this effect was not potentiated by the high concentration of ethanol. Conclusion These results indicate for the first time that while opioids may suppress breathing via an action at the level of the carotid bodies, ethanol is unlikely to potentiate inhibition via this pathway. Thus, the synergistic effects of ethanol and opioids on ventilatory parameters are likely mediated by central rather than peripheral actions