Correction: Neubert et al. Effects of Normobaric Hypoxia and Adrenergic Blockade over 72 h on Cardiac Function in Rats. Int. J. Mol. Sci. 2023, 24, 11417.

In the original publication [...].

Effects of Normobaric Hypoxia and Adrenergic Blockade over 72 h on Cardiac Function in Rats.

In rats, acute normobaric hypoxia depressed left ventricular (LV) inotropic function. After 24 h of hypoxic exposure, a slight recovery of LV function occurred. We speculated that prolonged hypoxia (72 h) would induce acclimatization and, hence, recovery of LV function. Moreover, we investigated biomarkers of nitrosative stress and apoptosis as possible causes of hypoxic LV depression. To elucidate the role of hypoxic sympathetic activation, we studied whether adrenergic blockade would further deteriorate the general state of the animals and their cardiac function. Ninety-four rats were exposed over 72 h either to normal room air (N) or to normobaric hypoxia (H). The rodents received infusion (0.1 mL/h) with 0.9% NaCl or with different adrenergic blockers. Despite clear signs of acclimatization to hypoxia, the LV depression continued persistently after 72 h of hypoxia. Immunohistochemical analyses revealed significant increases in markers of nitrosative stress, adenosine triphosphate deficiency and apoptosis in the myocardium, which could provide a possible explanation for the absence of LV function recovery. Adrenergic blockade had a slightly deteriorative effect on the hypoxic LV function compared to the hypoxic group with maintained sympathetic efficacy. These findings show that hypoxic sympathetic activation compensates, at least partially, for the compromised function in hypoxic conditions, therefore emphasizing its importance for hypoxia adaptation.

Relaxin does not prevent development of hypoxia-induced pulmonary edema in rats.

Acute hypoxia impairs left ventricular (LV) inotropic function and induces development of pulmonary edema (PE). Enhanced and uneven hypoxic pulmonary vasoconstriction is an important pathogenic factor of hypoxic PE. We hypothesized that the potent vasodilator relaxin might reduce hypoxic pulmonary vasoconstriction and prevent PE formation. Furthermore, as relaxin has shown beneficial effects in acute heart failure, we expected that relaxin might also improve LV inotropic function in hypoxia. Forty-two rats were exposed over 24 h to normoxia or hypoxia (10% N2 in O2). They were infused with either 0.9% NaCl solution (normoxic/hypoxic controls) or relaxin at two doses (15 and 75 µg kg-1 day-1). After 24 h, hemodynamic measurements and bronchoalveolar lavage were performed. Lung tissue was obtained for histological and immunohistochemical analyses. Hypoxic control rats presented significant depression of LV systolic pressure by 19% and of left and right ventricular contractility by about 40%. Relaxin did not prevent the hypoxic decrease in LV inotropic function, but re-increased right ventricular contractility. Moreover, hypoxia induced moderate interstitial PE and inflammation in the lung. Contrasting to our hypothesis, relaxin did not prevent hypoxia-induced pulmonary edema and inflammation. In hypoxic control rats, PE was similarly distributed in the apical and basal lung lobes. In relaxin-treated rats, PE index was 35-40% higher in the apical than in the basal lobe, which is probably due to gravity effects. We suggest that relaxin induced exaggerated vasodilation, and hence pulmonary overperfusion. In conclusion, the results show that relaxin does not prevent but rather may aggravate PE formation.

Left ventricular depression and pulmonary edema in rats after short-term normobaric hypoxia: effects of adrenergic blockade and reduced fluid load.

Acute normobaric hypoxia may induce pulmonary injury with edema (PE) and inflammation. Hypoxia is accompanied by sympathetic activation. As both acute hypoxia and high plasma catecholamine levels may elicit PE, we had originally expected that adrenergic blockade may attenuate the severity of hypoxic pulmonary injury. In particular, we investigated whether administration of drugs with reduced fluid load would be beneficial with respect to both cardiocirculatory and pulmonary functions in acute hypoxia. Rats were exposed to normobaric hypoxia (10% O2) over 1.5 or 6 h and received 0.9% NaCl or adrenergic blockers either as infusion (1 ml/h, increased fluid load) or injection (0.5 ml, reduced fluid load). Control animals were kept in normoxia and received infusions or injections of 0.9% NaCl. After 6 h of hypoxia, LV inotropic function was maintained with NaCl injection but decreased significantly with NaCl infusion. Adrenergic blockade induced a similar LV depression when fluid load was low, but did not further deteriorate LV depression after 6 h of infusion. Reduced fluid load also attenuated pulmonary injury after 6 h of hypoxia. This might be due to an effective fluid drainage into the pleural space. Adrenergic blockade could not prevent PE. In general, increased fluid load and impaired LV inotropic function promote the development of PE in acute hypoxia. The main physiologic conclusion from this study is that fluid reduction under hypoxic conditions has a protective effect on cardiopulmonary function. Consequently, appropriate fluid management has particular importance to subjects in hypoxic conditions.

The effect of motor-respiratory coordination on the precision of tracking movements: influence of attention, task complexity and training.

PURPOSE: We investigated motor-respiratory coordination (MRC) in visually guided forearm tracking movements focusing on two main questions: (1) Does attentional demand, training or complexity of the tracking task have an effect on the degree of MRC? (2) Does MRC impair the precision of those movements? We hypothesized that (1) enhanced attention to the tracking task and training increase the degree of MRC while higher task complexity would reduce it, and (2) MRC impairs tracking precision. METHODS: Thirty-five volunteers performed eight tracking trials with several conditions: positive (direct) signal-response relation (SRR), negative (inverse) SRR to increase task complexity, specific instruction for enhanced attention to maximize tracking precision ("strict" instruction), and specific instruction that tracking precision would not be evaluated ("relaxed" instruction). The trials with positive and negative SRR were performed three times each to study training effects. RESULTS: While the degree of MRC remained in the same range throughout all experimental conditions, a switch in phase-coupling pattern was observed. In conditions with positive SRR or with relaxed instruction, we found one preferred phase relationship per period. With higher task complexity (negative SRR) or increased attentional demand (strict instruction), a tighter coupling pattern with two preferred phase relationships per period was adopted. Our main result was that MRC improved tracking precision in all conditions except for that with relaxed instruction. Reduction of amplitude errors mainly contributed to this precision improvement. CONCLUSION: These results suggest that attention devoted to a precision movement intensifies its phase coupling with breathing and enhances MRC-related improvement of tracking precision.

Scan-associated anxiety (scanxiety): the enigma of emotional breathing oscillations at 0.32 Hz (19 bpm).

MRI-related anxiety in healthy participants is often characterized by a dominant breathing frequency at around 0.32 Hz (19 breaths per minute, bpm) at the beginning but in a few cases also at the end of scanning. Breathing waves at 19 bpm are also observed in patients with anxiety independently of the scanned body part. In patients with medically intractable epilepsy and intracranial electroencephalography (iEEG), spontaneous breathing through the nose varied between 0.24 and 0.37 Hz (~19 bpm). Remarkable is the similarity of the observed breathing rates at around 0.32 Hz during different types of anxiety states (e.g., epilepsy, cancer, claustrophobia) with the preferred breathing frequency of 0.32 Hz (19 bpm), which is predicted by the binary hierarchy model of Klimesch. This elevated breathing frequency most likely reflects an emotional processing state, in which energy demands are minimized due to a harmonic coupling ratio with other brain-body oscillations.

Hypoxia-Induced Pulmonary Injury-Adrenergic Blockade Attenuates Nitrosative Stress, and Proinflammatory Cytokines but Not Pulmonary Edema.

Hypoxia can induce pulmonary edema (PE) and inflammation. Furthermore, hypoxia depresses left ventricular (LV) inotropy despite sympathetic activation. To study the role of hypoxic sympathetic activation, we investigated the effects of hypoxia with and without adrenergic blockade (AB) on cardiovascular dysfunction and lung injury, i.e., pulmonary edema, congestion, inflammation, and nitrosative stress. Eighty-six female rats were exposed for 72 h to normoxia or normobaric hypoxia and received infusions with NaCl, prazosin, propranolol, or prazosin-propranolol combination. We evaluated hemodynamic function and performed histological and immunohistochemical analyses of the lung. Hypoxia significantly depressed LV but not right ventricular (RV) inotropic and lusitropic functions. AB significantly decreased LV function in both normoxia and hypoxia. AB effects on RV were weaker. Hypoxic rats showed signs of moderate PE and inflammation. This was accompanied by elevated levels of tumor necrosis factor α (TNFα) and nitrotyrosine, a marker of nitrosative stress in the lungs. In hypoxia, all types of AB markedly reduced both TNFα and nitrotyrosine. However, AB did not attenuate PE. The results suggest that hypoxia-induced sympathetic activation contributes to inflammation and nitrosative stress in the lungs but not to PE. We suggest that AB in hypoxia aggravates hypoxia-induced inotropic LV dysfunction and backlog into the pulmonary circulation, thus promoting PE.

Analysis of Respiratory Sinus Arrhythmia and Directed Information Flow between Brain and Body Indicate Different Management Strategies of fMRI-Related Anxiety.

BACKGROUND: Respiratory sinus arrhythmia (RSA) denotes decrease of cardiac beat-to-beat intervals (RRI) during inspiration and RRI increase during expiration, but an inverse pattern (termed negative RSA) was also found in healthy humans with elevated anxiety. It was detected using wave-by-wave analysis of cardiorespiratory rhythms and was considered to reflect a strategy of anxiety management involving the activation of a neural pacemaker. Results were consistent with slow breathing, but contained uncertainty at normal breathing rates (0.2-0.4 Hz). OBJECTIVES AND METHODS: We combined wave-by-wave analysis and directed information flow analysis to obtain information on anxiety management at higher breathing rates. We analyzed cardiorespiratory rhythms and blood oxygen level-dependent (BOLD) signals from the brainstem and cortex in 10 healthy fMRI participants with elevated anxiety. RESULTS: Three subjects with slow respiratory, RRI, and neural BOLD oscillations showed 57 ± 26% negative RSA and significant anxiety reduction by 54 ± 9%. Six participants with breathing rate of ~0.3 Hz showed 41 ± 16% negative RSA and weaker anxiety reduction. They presented significant information flow from RRI to respiration and from the middle frontal cortex to the brainstem, which may result from respiration-entrained brain oscillations, indicating another anxiety management strategy. CONCLUSIONS: The two analytical approaches applied here indicate at least two different anxiety management strategies in healthy subjects.

Respiration-entrained brain oscillations in healthy fMRI participants with high anxiety.

Brain-body interactions can be studied by using directed coupling measurements of fMRI oscillations in the low (0.1-0.2 Hz) and high frequency bands (HF; 0.2-0.4 Hz). Recently, a preponderance of oscillations in the information flow between the brainstem and the prefrontal cortex at around 0.15/0.16 Hz was shown. The goal of this study was to investigate the information flow between BOLD-, respiratory-, and heart beat-to-beat interval (RRI) signals in the HF band in healthy subjects with high anxiety during fMRI examinations. A multivariate autoregressive model was concurrently applied to the BOLD signals from the middle frontal gyrus (MFG), precentral gyrus and the brainstem, as well as to respiratory and RRI signals. Causal coupling between all signals was determined using the Directed Transfer Function (DTF). We found a salience of fast respiratory waves with a period of 3.1 s (corresponding to ~ 0.32 Hz) and a highly significant (p < 0.001) top-down information-flow from BOLD oscillations in the MFG to the brainstem. Additionally, there was a significant (p < 0.01) information flow from RRI to respiratory oscillations. We speculate that brain oscillations around 0.32 Hz, triggered by nasal breathing, are projected downwards to the brainstem. Particularly interesting is the driving force of cardiac to respiratory waves with a ratio of 1:1 or 1:2. These results support the binary hierarchy model with preferred respiratory frequencies at 0.32 Hz and 0.16 Hz.

Catecholamines can induce pulmonary remodeling in rats.

BACKGROUND/AIMS: Previously, we found that catecholamine (CA) infusion in rats induced pulmonary injury with edema and inflammation resembling acute lung injury in humans. Here, we examined effects of norepinephrine (NE) and of selective α- and ß-adrenergic agonists on the remodeling of pulmonary extracellular matrix. METHODS: Eighty rats were infused over 8-72 h with NE, phenylephrine (PE), isoproterenol (ISO) or NaCl solution. We investigated mRNA expression of collagen, matrix metalloproteinase (MMP)-2, its tissue inhibitor (TIMP-2) and transforming growth factor (TGF)-ß isoforms in lung tissue. Additionally, lung histology, hemodynamic function and cardiac hypertrophy were evaluated. RESULTS: After 72 h of infusion, lung histology showed beginning fibrosis and vascular hypertrophy. Collagen type I, MMP-2 and TIMP-2 mRNA expression were significantly elevated. All these effects were most pronounced with NE while PE and ISO induced weaker responses. TGF-ß mRNA expression was also elevated after 72 h, predominantly after PE infusion. Cardiac hypertrophy was most pronounced after ISO infusion. CONCLUSION: CA infusion over 72 h may induce pulmonary remodeling. Mainly α-adrenergic but also ß-adrenergic mechanisms contribute to these processes. In contrast, cardiac hypertrophy is predominantly mediated by ß-adrenergic stimulation and hence, is considered to be a direct adrenergic effect rather than a consequence of pulmonary fibrosis.

Negative respiratory sinus arrhythmia (nRSA) in the MRI-scanner - a physiologic phenomenon observed during elevated anxiety in healthy persons.

Recently, we reported on a rare manifestation of respiratory sinus arrhythmia (RSA), namely the "switched-off" RSA (Rassler et al., 2018), also called negative RSA (nRSA). It was found in a minority of healthy persons during elevated fMRI-related anxiety characterized by slow spontaneous breathing and synchronous slow beat-to-beat interval (RRI) oscillations. From 23 healthy scanner naïve participants of an fMRI study consisting of 4 resting states, we selected resting states with highest state anxiety (AS) from 10 participants (AS=24.6±2.5) and compared them to those with lowest AS of the same participants (AS=15.1±3.8, p<0.001). During elevated anxiety, the percentage of nRSA (nRSA%) was more than twice of RSA (p=0.045), while RSA prevailed during low anxiety. This indicates that nRSA might be related to elevated anxiety. Interestingly, nRSA was not only associated with slow RRI and breathing oscillations, but also occurred at "normal" breathing rates in the 0.20-0.35 Hz range. We often observed coupled RRI oscillations at 0.1 or 0.15 Hz and respiration at 0.3 Hz (rate ratio 1:3 or 1:2) with respiration-synchronous 0.3 Hz-wavelets in the RRI rhythm (termed "superposition") indicating a reduced dominance of the respiratory rhythm over the RRI rhythm. This novel finding is supported by the work of Perlitz et al., (2004) on a "0.15 Hz rhythm" in brainstem. The concept behind such a 1:n ratio is a pacemaker-like rhythm in the brainstem that "drives" the cardiac RRI signal and secondarily also respiration as reflected in the 1:n rate ratio.

How Do Young and Old Spontaneously Hypertensive Rats Respond to Antihypertensive Therapy? Comparative Studies on the Effects of Combined Captopril and Nifedipine Treatment.

Numerous studies on the effects of antihypertensive treatment in young spontaneously hypertensive rats (SHRs) have shown that early-onset therapy may effectively reduce their blood pressure (BP) even to normotensive values. In contrast, only a few studies investigated the effects of treatment started at an advanced age. These studies revealed that antihypertensive effects are lower in adult or even in senescent SHRs compared with young SHRs. Even more, prevention of cardiac sequelae of hypertension such as hypertrophy and fibrosis is less effective when treatment starts late in life. Because, in patients, combination therapies with calcium antagonists are favored, we studied the efficacy of a combination therapy with captopril and nifedipine in young and old SHRs. We directly compared the treatment effects on BP as well as on cardiac hypertrophy and remodeling between these two animal cohorts. With antihypertensive treatment, significantly lower BP values were achieved in young SHRs despite a shorter treatment period compared with old SHRs. Although treatment effects on cardiac hypertrophy were greater in old than in young SHRs, cardiac fibrosis was significantly attenuated only in young but not in old SHRs. The results emphasize the value of antihypertensive therapy and particularly accentuate the importance of an early-onset therapy. With respect to problems such as late diagnosis and poor therapy adherence, these results may have great importance for the treatment of human hypertension.

Processing of fMRI-related anxiety and information flow between brain and body revealed a preponderance of oscillations at 0.15/0.16 Hz.

Slow oscillations of different center frequencies and their coupling play an important role in brain-body interactions. The crucial question analyzed by us is, whether the low frequency (LF) band (0.05-0.15 Hz) or the intermediate frequency (IMF) band (0.1-0.2 Hz) is more eminent in respect of the information flow between body (heart rate and respiration) and BOLD signals in cortex and brainstem. A recently published study with the LF band in fMRI-naïve subjects revealed an intensive information flow from the cortex to the brainstem and a weaker flow from the brainstem to the cortex. The comparison of both bands revealed a significant information flow from the middle frontal gyrus (MFG) to the precentral gyrus (PCG) and from brainstem to PCG only in the IMF band. This pattern of directed coupling between slow oscillations in the cortex and brainstem not only supports the existence of a pacemaker-like structure in brainstem, but provides first evidence that oscillations centered at 0.15/0.16 Hz can also emerge in brain networks. BOLD oscillations in resting states are dominating at ~ 0.08 Hz and respiratory rates at ~ 0.32 Hz. Therefore, the frequency component at ~ 0.16 Hz (doubling-halving 0.08 Hz or 0.32 Hz) is of special interest, because phase coupled oscillations can reduce the energy demand.

Antihypertensive and cardioprotective effects of different monotherapies and combination therapies in young spontaneously hypertensive rats - A pilot study.

Spontaneously hypertensive rats (SHR) are an established animal model for antihypertensive treatment. The aim of this pilot study was a systematic search for two lines of antihypertensive treatment - a monotherapy and a combination of two drugs - to be applied in a future study on old SHR. Originally, representatives of three drug classes recommended for antihypertensive therapy in humans should be applied, namely captopril (CAP) as an antagonist of the renin-angiotensin-aldosterone system, nifedipine (NIF) as calcium channel blocker and propranolol (PROP) as ß-adrenergic blocker. As we observed that PROP had been poorly ingested, all groups with PROP therapy were excluded from the study. CAP (60 mg kg-1 d-1), NIF (10 mg kg-1 d-1) or both were administered orally to seven-week-old SHR over 3 weeks. A further group of SHR received no treatment (SHR/CTRL). Age-matched normotensive Wistar-Kyoto rats served as normotensive controls. We examined the effect of the antihypertensive therapies on systolic blood pressure, heart weight and on histological and biochemical markers of cardiac hypertrophy and fibrosis. CAP proved to be the most effective treatment reducing blood pressure and relative heart weight significantly compared to SHR/CTRL without reaching normotensive values. Beginning cardiac fibrosis observed in SHR/CTRL was completely abrogated with CAP treatment. Similar effects were achieved with a combination of CAP and NIF. CAP as monotherapy and CAP + NIF as combination therapy were chosen for the forthcoming study on old SHR.

How Effective Is a Late-Onset Antihypertensive Treatment? Studies with Captopril as Monotherapy and in Combination with Nifedipine in Old Spontaneously Hypertensive Rats.

Background: A major problem in the treatment of human hypertension is the late diagnosis of hypertension and, hence, the delayed start of treatment. Very often, hypertension has existed for a long time and cardiac damage has already developed. Therefore, we tested whether late-onset antihypertensive treatment is effective in lowering blood pressure (BP) and in reducing or even preventing left ventricular hypertrophy and fibrosis. Methods: Twenty-one male 60-week-old spontaneously hypertensive rats (SHR) were included. Fourteen rats received oral treatment with captopril (CAP) either as monotherapy or combined with nifedipine (CAP + NIF) over 22 weeks. Seven untreated SHR served as controls. We examined the therapeutic effects on BP, heart weight and histological and biochemical markers of left ventricular remodeling and fibrosis. Results: At 82 weeks of age, BP was reduced in the CAP and CAP + NIF groups by 44 and 51 mmHg, respectively (p < 0.001), but not in untreated controls. Despite the late therapy start, cardiac hypertrophy and fibrosis were attenuated compared to controls. Both treatments reduced heart weight by 1.2 mg/g (25%, p = 0.001) and collagens I and III by 66% and 60%, respectively (p < 0.001), thus proving nearly equivalent cardioprotective efficacy. Conclusion: These data clearly emphasize the benefit of antihypertensive treatment in reducing BP and mitigating the development of cardiac damage even when treatment is started late in life.

Processing of fMRI-related anxiety and bi-directional information flow between prefrontal cortex and brain stem.

Brain-heart synchronization is fundamental for emotional-well-being and brain-heart desynchronization is characteristic for anxiety disorders including specific phobias. Recording BOLD signals with functional magnetic resonance imaging (fMRI) is an important noninvasive diagnostic tool; however, 1-2% of fMRI examinations have to be aborted due to claustrophobia. In the present study, we investigated the information flow between regions of interest (ROI's) in the cortex and brain stem by using a frequency band close to 0.1 Hz. Causal coupling between signals important in brain-heart interaction (cardiac intervals, respiration, and BOLD signals) was studied by means of Directed Transfer Function based on the Granger causality principle. Compared were initial resting states with elevated anxiety and final resting states with low or no anxiety in a group of fMRI-naïve young subjects. During initial high anxiety the results showed an increased information flow from the middle frontal gyrus (MFG) to the pre-central gyrus (PCG) and to the brainstem. There also was an increased flow from the brainstem to the PCG. While the top-down flow during increased anxiety was predominant, the weaker ascending flow from brainstem structures may characterize a rhythmic pacemaker-like activity that (at least in part) drives respiration. We assume that these changes in information flow reflect successful anxiety processing.

Verification of a Central Pacemaker in Brain Stem by Phase-Coupling Analysis Between HR Interval- and BOLD-Oscillations in the 0.10-0.15 Hz Frequency Band.

The origin of slow intrinsic oscillations in resting states of functional magnetic resonance imaging (fMRI) signals is still a matter of debate. The present study aims to test the hypothesis that slow blood oxygenation level-dependent (BOLD) oscillations with frequency components greater than 0.10 Hz result from a central neural pacemaker located in the brain stem. We predict that a central oscillator modulates cardiac beat-to-beat interval (RRI) fluctuations rapidly, with only a short neural lag around 0.3 s. Spontaneous BOLD fluctuations in the brain stem, however, are considerably delayed due to the hemodynamic response time of about ∼2-3 s. In order to test these predictions, we analyzed the time delay between slow RRI oscillations from thorax and BOLD oscillations in the brain stem by calculating the phase locking value (PLV). Our findings show a significant time delay of 2.2 ± 0.2 s between RRI and BOLD signals in 12 out of 23 (50%) participants in axial slices of the pons/brain stem. Adding the neural lag of 0.3 s to the observed lag of 2.2 s we obtain 2.5 s, which is the time between neural activity increase and BOLD increase, termed neuro-BOLD coupling. Note, this time window for neuro-BOLD coupling in awake humans is surprisingly of similar size as in awake head-fixed adult mice (Mateo et al., 2017).

Crucial role of interleukin-6 in the development of norepinephrine-induced left ventricular remodeling in mice.

BACKGROUND: Elevated serum concentration of interleukin (IL)-6 is a predictor for poor prognosis in congestive heart failure. It was shown previously in rats, that IL-6 expression in the left ventricle (LV) was followed by LV hypertrophy. METHODS: Using IL-6 deficient mice (IL-6(-/-)), we studied the role of IL-6 in a model of norepinephrine (NE)-induced LV hypertrophy. RESULTS: In wild type (WT) mice, IL-6 mRNA expression and its concentration in the serum were elevated after 4 h of NE-treatment (s.c. 0.25 mg.h)./kg Further, NE-induced LV hypertrophy was detected: LV weight/body weight (LVW/BW) ratio (+12.3+/-3%, p < 0.05) and mRNA expression of atrial natriuretic peptide (ANP) in WT mice (+120+/-25%, p < 0.05) after 3 days were increased. In contrast, NE did not induce elevation of LVW/BW ratio and ANP expression in IL-6(-/-) mice. Replacement with recombinant IL-6 restored the hypertrophy-inducing effect of NE in IL-6(-/-) mice. As to the extracellular matrix (ECM) proteins, NE increased collagen type I and III expression only in WT mice and not in IL-6(-/-) mice. The addition of recombinant IL-6 elevated the expression of the ECM proteins to the WT level. CONCLUSION: IL-6 is a major player in the development of NE-induced LV hypertrophy in mice.

Effects of Adrenergic Agonists and Antagonists on Cardiopulmonary Function During Normobaric Hypoxia in Rat.

Pulmonary edema (PE) is an issue widely noted in acute exposure to hypoxia as seen in high altitude climbers, yet the etiology of this is not defined. Previous studies in rats showed that both hypoxia and strong sympathetic activation may induce PE. As acute exposure to hypoxia is accompanied by sympathetic activation, we assume that this may impair pulmonary circulation and contribute to the development of hypoxic PE. The aim of the present study was to investigate the effects of adrenergic agonists and antagonists as models for overstimulation and suppression, respectively, of sympathetic activity on cardiovascular function and formation of PE in hypoxic rats. Norepinephrine or adrenergic blockers were infused to rats exposed to normobaric hypoxia with 10% O2 over time intervals up to 24 h. Normoxic and hypoxic controls received 0.9% NaCl infusion. We evaluated hemodynamic function and lung histology. A significant decrease of left ventricular systolic function was observed after 6 h of hypoxia. This effect was less pronounced with α-adrenergic blockade but was more severe with combined α-plus ß-adrenergic blockade. Norepinephrine delayed the onset of hypoxic left ventricular depression but did not reduce its degree. Significant PE developed after 16 h of hypoxia. It regressed under α- but not with ß-adrenergic blockade, and was aggravated by combining hypoxia with norepinephrine. Almost half of the animals exposed to hypoxia over 16-24 h suffered cardiorespiratory arrest during the experiment and presented with signs of acute right ventricular failure. They had significantly elevated serum catecholamine concentrations and significantly stronger PE than the others. Notably, most of them had received norepinephrine or combined adrenergic blockade. Mild changes in serum catecholamine concentrations indicated that hypoxic sympathoadrenergic activation was only weak. Hence, it was not sufficient to prevent left ventricular depression. However, the results show that α-adrenergic mechanisms contribute to the formation of hypoxic PE. Adrenergic blockade but also sympathetic overactivity may induce pulmonary congestion, PE and acute right ventricular failure indicating that a fine balance of sympathetic activation under hypoxic conditions is crucial. This has important implications for climbers to high altitude as well as for patients suffering from hypoxia.

"Switch-Off" of Respiratory Sinus Arrhythmia May Be Associated With the Activation of an Oscillatory Source (Pacemaker) in the Brain Stem.

Recently, we reported on the unusual "switch-off" of respiratory sinus arrhythmia (RSA) by analyzing heart rate (HR) beat-to-beat interval (RRI) signals and respiration in five subjects during a potentially anxiety-provoking first-time functional magnetic resonance imaging (fMRI) scanning with slow spontaneous breathing waves (Rassler et al., 2018). This deviation from a fundamental physiological phenomenon is of interest and merits further research. Therefore, in this study, the interplay between blood-oxygen level-dependent (BOLD) activity in the cerebellum/brain stem, RRI, and respiration was probed. Both the cardiovascular and the respiratory centers are located in the medulla oblongata and pons, indicating that dominant slow rhythmic activity is present in the brain stem. The recording of BOLD signals provides a way to investigate associated neural activity fluctuation in the brain stem. We found slow spontaneous breathing waves associated with two types of slow BOLD oscillations with dominant frequencies at 0.10 and 0.15 Hz in the brain stem. Both BOLD oscillations were recorded simultaneously. One is hypothesized as vessel motion-based phenomenon (BOLDv) associated with the start of expiration; the other one as pattern associated with neural activity (BOLDn) acting as a driving force for spontaneous inspiration and RRI increase (unusual cessation of RSA) about 2-3 s after BOLDv. This time delay of 2-3 s corresponds to the neurovascular coupling time.