Peripheral Chemoreflex Sensitivity Research Articles

Tetraplegia is associated with enhanced peripheral chemoreflex sensitivity and ventilatory long-term facilitation.

Cardiorespiratory plasticity induced by acute intermittent hypoxia (AIH) may contribute to recovery following spinal cord injury (SCI). We hypothesized that patients with cervical SCI would demonstrate higher minute ventilation (V̇e) following AIH compared with subjects with thoracic SCI and able-bodied subjects who served as controls. Twenty-four volunteers (8 with cervical SCI, 8 with thoracic SCI, and 8 able-bodied) underwent an AIH protocol during wakefulness. Each subject experienced 15 episodes of isocapnic hypoxia using mixed gases of 100% nitrogen (N2), 8% O2, and 40% CO2 to achieve oxygen saturation ≤90% followed by room air (RA). Measurements were obtained before, during, and 40 min after AIH to obtain ventilation and heart rate variability data [R-R interval (RRI) and low-frequency/high-frequency power (LF/HF)]. AIH results were compared with those of sham studies conducted in RA during the same time period. Individuals with cervical SCI had higher V̇e after AIH compared with able-bodied controls (117.9 ± 23.2% vs. 97.9 ± 11.2%, P < 0.05). RRI decreased during hypoxia in all individuals (those with cervical SCI, from 1,009.3 ± 65.0 ms to 750.2 ± 65.0 ms; those with thoracic SCI, from 945.2 ± 65.0 ms to 674.9 ± 65.0 ms; and those who were able-bodied, from 949 ± 75.0 to 682.2 ± 69.5 ms; P < 0.05). LH/HF increased during recovery in individuals with thoracic SCI and those who were able-bodied (0.54 ± 0.22 vs. 1.34 ± 0.22 and 0.67 ± 0.23 vs. 1.82 ± 0.23, respectively; P < 0.05) but remained unchanged in the group with cervical SCI. Our conclusion is that patients with cervical SCI demonstrate ventilatory long-term facilitation following AIH compared with able-bodied controls. Heart rate responses to hypoxia are acutely present in patients with cervical SCI but are absent during posthypoxic recovery.

Maternal Protein Restriction Increases Respiratory and Sympathetic Activities and Sensitizes Peripheral Chemoreflex in Male Rat Offspring1–3

Background: Maternal protein restriction in rats increases the risk of adult offspring arterial hypertension through unknown mechanisms.Objectives: The aims of the study were to evaluate the effects of a low-protein (LP) diet during pregnancy and lactation on baseline sympathetic and respiratory activities and peripheral chemoreflex sensitivity in the rat offspring.Methods: Wistar rat dams were fed a control [normal-protein (NP); 17% protein] or an LP (8% protein) diet during pregnancy and lactation, and their male offspring were studied at 30 d of age. Direct measurements of baseline arterial blood pressure (ABP), heart rate (HR), and respiratory frequency (Rf) as well as peripheral chemoreflex activation (potassium cyanide: 0.04%) were recorded in pups while they were awake. In addition, recordings of the phrenic nerve (PN) and thoracic sympathetic nerve (tSN) activities were obtained from the in situ preparations. Hypoxia-inducible factor 1α (HIF-1α) expression was also evaluated in carotid bifurcation through a Western blotting assay.Results: At 30 d of age, unanesthetized LP rats exhibited enhanced resting Rf (P = 0.001) and similar ABP and HR compared with the NP rats. Despite their similar baseline ABP values, LP rats exhibited augmented low-frequency variability (∼91%;P = 0.01). In addition, the unanesthetized LP rats showed enhanced pressor (P = 0.01) and tachypnoeic (P = 0.03) responses to peripheral chemoreflex activation. The LP rats displayed elevated baseline tSN activity (∼86%;P = 0.02) and PN burst frequency (45%;P = 0.01) and amplitude (53%;P = 0.001) as well as augmented sympathetic (P = 0.01) and phrenic (P = 0.04) excitatory responses to peripheral chemoreflex activation compared with the NP group. Furthermore, LP rats showed an increase of ∼100% in HIF-1α protein density in carotid bifurcation compared with NP rats.Conclusion: Sympathetic-respiratory overactivity and amplified peripheral chemoreceptor responses, potentially through HIF-1α–dependent mechanisms, precede the onset of hypertension in juvenile rats exposed to protein undernutrition during gestation and lactation.

Efficacy and safety of open lung ventilation in patients with impaired peripheral chemoreflex sensitivity

Mechanical ventilation during anesthesia leads to the development of atelectasis, poor oxygenation and postoperative pulmonary complications. Application of PEEP and recruitment maneuver (RM) can significantly reduce the severity of atelectasis and improve lung function. But the application of this strategy often leads to hemodynamic instability, which may be associated with impaired reactivity of the cardiovascular system. The purpose of this study was to evaluate the efficacy and safety of RM in patients with increased sensitivity of peripheral chemoreceptors (SPCR), which reflects the decreasing reactivity of the cardiovascular system.

Effect of chronic ethanol exposure on rat ventilatory responses to hypoxia and hypercapnia

OBJECTIVE:The effect of chronic ethanol exposure on chemoreflexes has not been extensively studied in experimental animals. Therefore, this study tested the hypothesis that known ethanol-induced autonomic, neuroendocrine and cardiovascular changes coincide with increased chemoreflex sensitivity, as indicated by increased ventilatory responses to hypoxia and hypercapnia.METHODS:Male Wistar rats were subjected to increasing ethanol concentrations in their drinking water (first week: 5% v/v, second week: 10% v/v, third and fourth weeks: 20% v/v). At the end of each week of ethanol exposure, ventilatory parameters were measured under basal conditions and in response to hypoxia (evaluation of peripheral chemoreflex sensitivity) and hypercapnia (evaluation of central chemoreflex sensitivity).RESULTS:Decreased respiratory frequency was observed in rats exposed to ethanol from the first until the fourth week, whereas minute ventilation remained unchanged. Moreover, we observed an increased tidal volume in the second through the fourth week of exposure. The minute ventilation responses to hypoxia were attenuated in the first through the third week but remained unchanged during the last week. The respiratory frequency responses to hypoxia in ethanol-exposed rats were attenuated in the second through the third week but remained unchanged in the first and fourth weeks. There was no significant change in tidal volume responses to hypoxia. With regard to hypercapnic responses, no significant changes in ventilatory parameters were observed.CONCLUSIONS:Our data are consistent with the notion that chronic ethanol exposure does not increase peripheral or central chemoreflex sensitivity.

Assessment of the peripheral ventilatory response to CO2 in heart failure patients: reliability of the single-breath test

The assessment of chemoreflex sensitivity in heart failure patients is gaining increasing interest since recent studies demonstrated that augmented chemosensitivity is an independent predictor of mortality and represents an important pathogenic factor in the development of Cheyne–Stokes respiration. The single-breath CO2 test is a well-established method to quantify peripheral hypercapnic chemoreflex sensitivity. As the original criteria for the computation of the chemoreflex sensitivity in healthy subjects need to be modified in heart failure patients to take into account impaired cardiac function, the effects of such modifications on measurement reliability deserve investigation. Hence, we devised this study to assess the reliability of the single-breath CO2 test in heart failure patients. In 27 clinically stable, mild-to-moderate heart failure patients (age (mean±SD): 64±10 years, left ventricular ejection fraction: 34±7%, NYHA class: 2.7±0.4), the test was administered on two consecutive days in the same conditions. Reliability was assessed by the standard error of measurement (SEM) and by the intraclass correlation coefficient (ICC). The mean value of the chemoreflex sensitivity on the two days was: 0.25 ± 0.12 and 0.24 ± 0.12 l min−1 mmHg−1 (p = 0.45), respectively. The SEM was 0.05 l min−1 mmHg−1, indicating large intra-subject variability. Consequently, in order to be 95% confident that a real change has occurred between two measurements taken on the same individual (test–retest), the observed difference must be higher than ±0.15 l min−1 mmHg−1, which is about 60% of the mean value across our population. The ICC was 0.71, indicating thatintra-subject variability, although high, is a limited (29%) portion of inter-subject variability. Intra-subject variability should be carefully taken into account when using the single-breath CO2 test in assessing changes in individual patients. The observed ICC indicates that this test may provide useful information for diagnostic/classification purposes.

Parasympathetic activation by pyridostigmine on chemoreflex sensitivity in heart-failure rats

We evaluated the effects of parasympathetic activation by pyridostigmine (PYR) on chemoreflex sensitivity in a rat model of heart failure (HF rats). HF rats demonstrated higher pulmonary ventilation (PV), which was not affected by PYR. When HF and control rats treated or untreated with PYR were exposed to 15% O2, all groups exhibited prompt increases in respiratory frequency (RF), tidal volume (TV) and PV. When HF rats were exposed to 10% O2 they showed greater PV response which was prevented by PYR. The hypercapnia triggered by either 5% CO2 or 10% CO2 promoted greater RF and PV responses in HF rats. PYR blunted the RF response in HF rats but did not affect the PV response. In conclusion, PYR prevented increased peripheral chemoreflex sensitivity, partially blunted central chemoreflex sensitivity and did not affect basal PV in HF rats.

Response to Role of the Carotid Body in Obesity-Related Sympathoactivation

We thank Prof Andrea Porzionato1 for her comment and support of our review2 that raises the issue of the role of the carotid body in obesity-related sympathoactivation. In our review,2 we summarized the intriguing association of raised peripheral chemosensitivity in several disease states, including hypertension, heart failure, and sleep apnea. On the basis of our recent preclinical data,3 we emphasized that in addition to increased peripheral chemoreflex sensitivity, the carotid body develops substantial afferent tone in hypertensive (but not normotensive) rats, and that by severing its connection to the central nervous system, arterial pressure falls substantially. This was associated with a reduction in sympathetic vasomotor …

Obstructive sleep apnea is associated with increased chemoreflex sensitivity in patients with metabolic syndrome.

Obstructive sleep apnea (OSA) is often observed in patients with metabolic syndrome (MetS). In addition, the association of MetS and OSA substantially increases sympathetic nerve activity. However, the mechanisms involved in sympathetic hyperactivation in patients with MetS + OSA remain to be clarified. We tested the hypothesis that chemoreflex sensitivity is heightened in patients with MetS and OSA. Prospective clinical study. Forty-six patients in whom MetS was newly diagnosed (ATP-III) were allocated into: (1) MetS + OSA (n = 24, 48 ± 1.8 yr); and (2) MetS - OSA (n = 22, 44 ± 1.7 yr). Eleven normal control subjects were also studied (C, 47 ± 2.3 yr). OSA was defined as an apnea-hypopnea index ≥ 15 events/hr (polysomnography). Muscle sympathetic nerve activity (MSNA) was measured by microneurography technique. Peripheral chemoreflex sensitivity was assessed by inhalation of 10% oxygen and 90% nitrogen (carbon dioxide titrated), and central chemoreflex sensitivity by 7% carbon dioxide and 93% oxygen. Physical characteristics and MetS measures were similar between MetS + OSA and MetS - OSA. MSNA was higher in MetS + OSA patients compared with MetS - OSA and C (33 ± 1.3 versus 28 ± 1.2 and 18 ± 2.2 bursts/min, P < 0.05). Isocapnic hypoxia caused a greater increase in MSNA in MetS + OSA than MetS - OSA and C (P = 0.03). MSNA in response to hyperoxic hypercapnia was greater in MetS + OSA compared with C (P = 0.005). Further analysis showed a significant association between baseline MSNA and peripheral (P < 0.01) and central (P < 0.01) chemoreflex sensitivity. Min ventilation in response to hyperoxic hypercapnia was greater in MetS + OSA compared with C (P = 0.001). OSA increases sympathetic peripheral and central chemoreflex response in patients with MetS, which seems to explain, at least in part, the increase in sympathetic nerve activity in these patients. In addition, OSA increases ventilatory central chemoreflex response in patients with MetS.

A computerized integrated system for the assessment of central and peripheral chemoreflex sensitivity

The assessment of chemoreflex sensitivity (CRS) is of major importance in studies investigating the adaptation of ventilation to the needs of human body. Increased sensitivity of chemoreceptors to both hypoxia and hypercapnia has recently been shown to be a powerful and independent prognosticator in heart failure (HF) patients, thus highlighting the importance of the assessment of CRS also in the clinical setting. In spite of this, the measurement of CRS is currently limited to the research setting. One possible reason might be the lack of suitable commercial equipments.On the basis of these considerations, we designed a system to carry out a comprehensive assessment of CRS, including both central and peripheral chemoreceptors. The system is based on the integration of different commercial devices and is entirely managed by a custom software written in Matlab language. The main features of our system are: (1) the implementation of standard methods (the Read's rebreathing test, the CO2 single breath test and the transient hypoxia test) suitable for both pathological and healthy subjects, (2) data quality assurance and reduction of subjective judgment in the analysis through advanced analysis procedures and statistical outliers rejection, and (3) full interactive control of every step of the recording and analysis procedures.The system is currently used in our Institution in the assessment of CRS in HF patients, chronic obstructive pulmonary disease patients and healthy subjects. It has proven to be very effective and easy to use even by clinical personnel without a specific background in respiratory function assessment.

Redox regulation of neurovascular function by acetazolamide: complementary insight into mechanisms underlying high‐altitude acclimatisation

We read with interest the study by Fan and colleagues describing how the carbonic anhydrase (CA) inhibitor acetazolamide reduced periodic breathing and accelerated acclimatisation to high altitude in native lowlanders (Fan et al. 2012). Intravenous infusion was shown to increase resting cerebral blood flow (CBF) and cerebrovascular reactivity to carbon dioxide () independently of altered peripheral or central chemoreflex sensitivity. The authors concluded that the improvement in breathing stability was attributable to an increase in the ‘CO2 reserve’. We would like to extend their elegant findings by suggesting a complementary mechanism albeit secondary to classical CA inhibition that may have equally contributed to the neurovascular benefits as observed.

Reply from J.‐L. Fan, K. R. Burgess and P. N. Ainslie

We thank Drs Teppema and Berendsen for their interest in our recent paper (Fan et al. 2012). If we interpret their letter correctly, they have raised three noteworthy discussion points. First, why greater elevations in middle cerebral artery blood flow velocity (MCAv) and ventilatory CO2 sensitivities were evident during initial arrival to 5050 m (Fan et al. 2010) compared to those measured 5–12 days at this elevation. Second, they expressed concerns over curve fitting during isocapnic hypoxic rebreathing for the comparison of ventilatory O2 sensitivity between sea level and following ascent to 5050 m. Finally, they expressed skepticism over our use of intravenous acetazolamide to examine its effect on breathing control. Although we feel many of these points are discussed in our paper (Fan et al. 2012), the salient points are outlined below. The differences from during initial arrival to 5050 m (Fan et al. 2010) to those measured 5–12 days at this elevation (Fan et al. 2012) probably reflect partial acclimatization over this time frame. In our more recent study, we observed normalized pH and MCAv to sea level values, whereas our earlier report found these variables to be significantly elevated during initial arrival to 5050 m. Moreover, we found the changes in resting ventilation and with ascent to 5050 m to be greater following 5–12 days compared with initial arrival. This difference in the state of acclimatization would certainly account for the differences in the CO2 sensitivities between our two papers. Another possibility for these apparent discrepant findings may be due to the difference in sample sizes between the two studies. In our more recent report, only 11 subjects were included in the final statistical analysis, resulting in a tendency for the ventilatory CO2 sensitivity to be elevated at 5050 m (P= 0.085). In contrast, our earlier study reported ventilatory CO2 sensitivity in 17 subjects. Therefore, we believe that the lack of change in ventilatory CO2 sensitivity observed in Fan et al. (2012) could be attributed to insufficient statistical power to detect the changes in central chemoreflex following ascent to high altitude. Finally, the transition we used from room air at both altitudes to the end hyperventilation state resulted in a similar degree of mild hyperoxic exposure at both altitudes. We agree that testing peripheral chemoreflex sensitivity is extremely difficult, especially in the field, and additional O2 may be needed inside the rebreathing bag to ensure similar ranges. However, since the ranges assessed pre- and post-acetazolamide were similar at each altitude, we believe that the soda lime rebreathing method was sufficient to identify any potential changes in peripheral chemoreflex associated with our intervention. Moreover, we argue that the ranges assessed were physiologically more relevant at each altitude. We acknowledge that these points raised by Teppema and Berendsen are important considerations when assessing changes in hypoxic ventilatory sensitivities at high altitude. Nevertheless, acute gas control using end-tidal forcing is technologically challenging, especially in real field conditions as opposed to the safe confines of the laboratory (Teppema & Dahan, 2010). Also, although the authors make some interesting points about chemoreflex testing, based on their elegant review paper (Teppema & Dahan, 2010), comparisons with high altitude is almost impossible because of marked acid–base changes and the interactions between the peripheral and central chemoreflexes. Although we would suggest that no approach is perfect, we attempted to target end-tidal CO2 levels for the rebreathing at high altitude so the degree of CO2 washout of all tissues would be similar at the two altitudes. As discussed in our paper, Teppema and Berendsen mention that metabolic acidosis associated with chronic oral acetazolamide ingestion leads to a rise in ventilation and drop in , which independently stabilizes breathing – presumably via an increased plant gain (Dempsey, 2005). However, since the majority of the work on acetazolamide has looked at oral ingestions, our reasoning for using acute intravenous administration was to examine whether acetazolamide may alter ventilatory control and breathing stability by mechanisms other than metabolic acidosis. Oral and i.v. acetazolamide adminstration is clearly physiologically very different and no similarities can be drawn between the two. In summary, whilst thanking Drs Teppema and Berendsen for their interest, we feel their comments do not detract from our salient findings. We do agree, however, that the cerebrovascular response to CO2 may indeed be initiated at the arterial side of the blood–brain barrier.

Peripheral chemoreflex activation contributes to sympathetic baroreflex impairment in chronic heart failure

Chemoreflex-mediated sympathetic activation contributes to both initiation and progression of chronic heart failure (CHF). To study the direct role of increased peripheral chemosensitivity in reducing sympathetic baroreflex function in CHF patients, we compared sympathetic baroreflex function, assessed by the slope of the relationship between muscle sympathetic nerve activity (MSNA) and DBP, in CHF patients with augmented (n = 18) and normal (n = 20) peripheral chemosensitivity. Using a double-blind, randomized, vehicle-controlled study, we examined the effect of chemoreflex deactivation (by breathing 100% oxygen for 15 min) on sympathetic baroreflex function in CHF patients with elevated and with normal chemosensitivity. Baseline MSNA was elevated (60.6 ± 3.2 vs. 48.9 ± 3.7 bursts/min, P < 0.05) and sympathetic baroreflex function impaired (3.06 ± 0.55 vs. 5.51 ± 0.69 % bursts/mmHg, P < 0.05) in CHF patients with augmented peripheral chemosensitivity compared with controls. Administration of 100% oxygen led to a significant decrease in MSNA (from 60.5 ± 3.2 to 52.6 ± 3.2 bursts/min, P < 0.001) and increase in sympathetic baroreflex (from 2.95 ± 0.56 to 6.18 ± 0.77, P < 0.001) in CHF patients with enhanced chemoreflex sensitivity. In contrast, neither room air nor 100% oxygen changed MSNA, hemodynamics or sympathetic baroreflex function in CHF patients with normal chemosensitivity. We report for the first time that increased peripheral chemoreflex sensitivity directly decreases sympathetic baroreflex function in CHF patients. This interaction contributes to sympathetic overactivity and blunted sympathetic baroreflex function of CHF patients and may explain how chemoreceptors contribute to the bad prognosis of CHF patients.

Molecular Mechanisms of Chronic Intermittent Hypoxia and Hypertension

Obstructive sleep apnea (OSA) is characterized by episodes of repeated airway obstruction resulting in cessation (apnea) or reduction (hypopnea) in airflow during sleep. These events lead to intermittent hypoxia and hypercapnia, sleep fragmentation, and changes in intrathoracic pressure, and are associated with a marked surge in sympathetic activity and an abrupt increase in blood pressure. Blood pressure remains elevated during wakefulness despite the absence of obstructive events resulting in a high prevalence of hypertension in patients with OSA. There is substantial evidence that suggests that chronic intermittent hypoxia (CIH) leads to sustained sympathoexcitation during the day and changes in vasculature resulting in hypertension in patients with OSA. Mechanisms of sympathoexcitation include augmentation of peripheral chemoreflex sensitivity and a direct effect on central sites of sympathetic regulation. Interestingly, the vascular changes that occur with CIH have been ascribed to the same molecules that have been implicated in the augmented sympathetic tone in CIH. This review will discuss the hypothesized molecular mechanisms involved in the development of hypertension with CIH, will build a conceptual model for the development of hypertension following CIH, and will propose a systems biology approach in further elucidating the relationship between CIH and the development of hypertension.

Baroreceptor unloading in postural tachycardia syndrome augments peripheral chemoreceptor sensitivity and decreases central chemoreceptor sensitivity

While orthostatic tachycardia is the hallmark of postural tachycardia syndrome (POTS), orthostasis also initiates increased minute ventilation (Ve) and decreased end-tidal CO(2) in many patients. We hypothesized that chemoreflex sensitivity would be increased in patients with POTS. We therefore measured chemoreceptor sensitivity in 20 POTS (16 women and 4 men) and 14 healthy controls (10 women and 4 men), 16-35 yr old by exposing them to eucapneic hyperoxia (30% O(2)), eucapneic hypoxia (10% O(2)), and hypercapnic hyperoxia (30% O(2) + 5% CO(2)) while supine and during 70° head-upright tilt. Heart rate, mean arterial pressure, O(2) saturation, end-tidal CO(2), and Ve were measured. Peripheral chemoreflex sensitivity was calculated as the difference in Ve during hypoxia compared with room air divided by the change in O(2) saturation. Central chemoreflex sensitivity was determined by the difference in Ve during hypercapnia divided by the change in CO(2). POTS subjects had an increased peripheral chemoreflex sensitivity (in l·min(-1)·%oxygen(-1)) in response to hypoxia (0.42 ± 0.38 vs. 0.19 ± 0.17) but a decreased central chemoreflex sensitivity (l·min(-1)·Torr(-1)) CO(2) response (0.49 ± 0.38 vs. 1.04 ± 0.18) compared with controls. CO(2) sensitivity was also reduced in POTS subjects when supine. POTS patients are markedly sensitized to hypoxia when upright but desensitized to CO(2) while upright or supine. The interactions between orthostatic baroreflex unloading and altered chemoreflex sensitivities may explain the hyperventilation in POTS patients.

Role of blood flow in carotid body chemoreflex function in heart failure

Peripheral chemoreflex sensitivity is potentiated in clinical and experimental chronic heart failure (CHF). Blood supply to tissues is inevitably reduced in CHF. However, it remains poorly understood whether the reduced blood flow is the cause of increased peripheral chemoreflex sensitivity in CHF. This work highlights the effect of chronically reduced blood flow to the carotid body (CB) on peripheral chemoreflex function in rabbits. In pacing-induced CHF rabbits, blood flow in the carotid artery was reduced by 36.4 ± 5.2% after 3 weeks of pacing. For comparison, a similar level of blood flow reduction was induced by carotid artery occlusion (CAO) over a similar 3 week time course without pacing. CB blood supply was reduced by similar levels in both CHF and CAO rabbits as measured with fluorescent microspheres. Compared with sham rabbits, CAO enhanced peripheral chemoreflex sensitivity in vivo, increased CB chemoreceptor activity in an isolated CB preparation and decreased outward potassium current (Ik) in CB glomus cells to levels similar to those that were observed in CHF rabbits. In CAO CB compared to sham, neural nitric oxide (NO) synthase (nNOS) expression and NO levels were suppressed, and angiotensin II (Ang II) type 1 receptor (AT1-R) protein expression and Ang II concentration were elevated; these changes were similar to those seen in the CB from CHF rabbits. A NO donor and AT1-R antagonist reversed CAO-enhanced chemoreflex sensitivity. These results suggest that a reduction of blood flow to the CB is involved in the augmentation of peripheral chemoreflex sensitivity in CHF.

Peripheral chemoreflex sensitivity and sympathetic nerve activity are normal in breath hold divers during training season

Breath hold divers are exposed to repeated massive arterial oxygen desaturation, which could perturb chemoreflexes. Therefore, we tested the hypothesis that peripheral chemoreflex regulation of ventilation and sympathetic vasomotor tone is present during the training season. We determined ventilation, heart rate, blood pressure, cardiac stroke volume, and muscle sympathetic nerve activity (MSNA) during isocapnic hypoxia in 10 breath hold divers and 11 matched control subjects at the end of the season of intense apnea trainings. Baseline MSNA frequency was 30±4 bursts/min in control subjects and 25±4 bursts/min in breath hold divers (P=0.053). During hypoxia burst frequency and total sympathetic activity increased similarly in both groups. Sympathetic activity normalized during 30 minute recovery period. Hypoxia‐induced stimulation of minute ventilation was similar in both groups. Hypoxia increased heart rate and cardiac output whereas total peripheral resistance decreased. Blood pressure remained unchanged. We conclude that peripheral chemoreflex regulation of ventilation and sympathetic vasomotor tone is paradoxically preserved in apnea divers during the training season.This study was supported by the Croatian Ministry of Science, Education and Sports.

Baroreflex unloading blunts chemoreceptor sensitivity in Postural Tachycardia Syndrome (POTS)

POTS have increased minute ventilation (VE) and decreased end tidal carbon dioxide (ETCO2) compared to healthy subjects. Chemoreceptor sensitivity was measured in 18 POTS (14F, 4M), 10 healthy controls (6F, 4M) 16–35 years old by exposing them to eucapneic hyperoxia‐30%oxygen, eucapneic hypoxia (10%oxygen) and hypercapnia 30%oxygen+5%carbon dioxide) in supine and HUT70 position. We measured heart Rate (HR), mean arterial pressure (MAP) oxygen saturation, ETCO2, mean cerebral blood flow velocity (mCFV) and VE. Chemoreflex sensitivity was ascertained by comparing slopes determined from eucapneic hypoxia‐hyperoxia to measure peripheral chemoreflex sensitivity, and hyperoxic hypercapnia –eucapnia to measure central chemoreflex sensitivity. POTS had significantly higher resting HR, lower MAP, stroke volume (SV) and mCFV as compared to controls (p&lt;0.05). Hypoxia and hypercapnia increased the HR, MAP, CO, mCFV and VE (p&lt;0.05). POTS had increases in VE during supine hypoxia (POTS vs. controls, 3.6± 0.9 vs. 1.6± 0.2, p=0.003) which reversed in HUT70 (1.96± 0.3 vs. 5.4± 1.2). In both POTS and controls, hypercapnia resulted in similar increases in VE when supine but no further increases when HUT70. POTS have higher peripheral chemoreflex sensitivity than controls which attenuates during unloading of baroreflexes.

Enhanced peripheral chemoreflex function in conscious rats with ligation‐induced heart failure

Our previous studies showed peripheral chemoreflex sensitivity is enhanced in conscious rabbits with pacing‐induced chronic heart failure (CHF), which is mediated by an elevated Angiotensin II (Ang II) effect on the carotid body (CB). Here we investigated whether CB chemoreflex function and CB Ang II are similarly altered in a rat model of 8 week ligation‐induced CHF. Minute ventilation (VE) and renal sympathetic nerve activity (RSNA) in response to stimulation of peripheral chemoreceptor by isocapnic/hypoxic gases were measured in conscious state. The degree of CHF was assessed by echocardiography. It was found that the baselines VE and RSNA at normoxia and graded hypoxia were elevated in CHF rats (&gt; 30% reduction of FS) than those in sham rats. In addition, the concentration of tissue Ang II measured by radioimmunoassay was higher in CHF CBs compared to sham CBs (51.44 ± 0.16 vs. 36.20 ± 1.29 pg/mg protein, p&lt;0.05). Furthermore, protein expression of Ang II type 1 receptor and angiotensin converting enzyme 1 in CHF CBs were increased compared to those in sham CBs. These results suggest that, similar to the pacing model in rabbits, increased Ang II in the CBs may contribute to the enhanced peripheral chemoreflex function in the coronary ligation model of CHF in rats. Supported by NIH grant PO‐1 HL 62222.

Elevated mitochondrial superoxide contributes to enhanced chemoreflex in heart failure rabbits

Peripheral chemoreflex sensitivity is enhanced in both clinical and experimental chronic heart failure (CHF). Here we investigated the role of manganese superoxide dismutase (MnSOD), the SOD isoform specially targeted to mitochondria, and mitochondrial superoxide levels in the enhanced chemoreceptor activity and function of the carotid body (CB) in CHF rabbits. CHF suppressed MnSOD protein expression and elevated mitochondrial superoxide levels in CB compared with that in sham CB. Adenovirus (Ad) MnSOD (1 x 10(8) plaque-forming units/ml) gene transfer selectively to the CBs normalized mitochondrial superoxide levels in glomus cells from CHF CB. In addition, Ad MnSOD reduced the elevation of superoxide level in CB tissue from CHF rabbits. Ad MnSOD significantly increased MnSOD expression in CHF CBs and normalized the baseline renal sympathetic nerve activity and the response of renal sympathetic nerve activity to hypoxia in CHF rabbits. Ad MnSOD decreased baseline single-fiber discharge from CB chemoreceptors compared with Ad Empty (6.3 + or - 1.5 vs. 12.7 + or - 1.4 imp/s at approximately 100-Torr Po(2), P < 0.05) and in response to hypoxia (20.5 + or - 1.8 vs. 32.6 + or - 1.4 imp/s at approximately 40-Torr Po(2), P < 0.05) in CHF rabbits. Compared with Ad Empty, Ad MnSOD reversed the blunted K(+) currents in CB glomus cells from CHF rabbits (385 + or - 11 vs. 551 + or - 20 pA/pF at +70 mV, P < 0.05). The results suggest that decreased MnSOD in the CB and elevated mitochondrial superoxide levels contribute to the enhanced CB chemoreceptor activity and peripheral chemoreflex function in CHF rabbits.

Peripheral chemoreflex sensitivity and sympathetic nerve activity are normal in apnea divers during training season

Apnea divers are exposed to repeated massive arterial oxygen desaturation, which could perturb chemoreflexes. An earlier study suggested that peripheral chemoreflex regulation of sympathetic vasomotor tone and ventilation may have recovered 4 or more weeks into the off season. Therefore, we tested the hypothesis that peripheral chemoreflex regulation of ventilation and sympathetic vasomotor tone is present during the training season. We determined ventilation, heart rate, blood pressure, cardiac stroke volume, and muscle sympathetic nerve activity (MSNA) during isocapnic hypoxia in 10 breath hold divers and 11 matched control subjects. The study was carried out at the end of the season of intense apnea trainings. Baseline MSNA frequency was 30 ± 4 bursts/min in control subjects and 25 ± 4 bursts/min in breath hold divers ( P = 0.053). During hypoxia burst frequency and total sympathetic activity increased similarly in both groups. Sympathetic activity normalized during the 30-minute recovery. Hypoxia-induced stimulation of minute ventilation was similar in both groups, although in divers it was maintained by higher tidal volumes and lower breathing frequency compared with control subjects. In both groups, hypoxia increased heart rate and cardiac output whereas total peripheral resistance decreased. Blood pressure remained unchanged. We conclude that peripheral chemoreflex regulation of ventilation and sympathetic vasomotor tone is paradoxically preserved in apnea divers, both, during the off and during the training season. The observation suggests that repeated arterial oxygen desaturation may not be sufficient explaining sympathetic reflex abnormalities similar to those in obstructive sleep apnea patients.