Respiratory sinus arrhythmia in the immediate post-exercise period: correlation with breathing-specific heart rate.

BACKGROUND: Although the absolute values of pulmonary ventilation and cardiac output are similar, the designs of the respiratory and cardiovascular systems imply major differences in flow patterns, airflow being intermittent by comparison to the quasi-continuous pulmonary blood flow. PURPOSE: We hypothesized that respiratory sinus arrhythmia (RSA, difference in heart rate (fH) between inspiration and expiration, as percent of mean fH) ameliorates the inevitable differences between air- and blood-flow patterns. Specifically, we hypothesized RSA to correlate more closely to the ratio between fH and breathing frequency (fR) (fH/fR "breathing-specific heart rate", a proxy for cardio-respiratory coupling) than to either fH or fR alone. Hence, we designed protocols to change independently fH or fR. METHODS: We measured RSA breath-by-breath in 145 young men and women during spontaneous breathing, breathing under cues at different fR (to modify the denominator of fH/fR) and immediately post-exercise while breathing freely or by keeping fR as at rest (to modify the nominator of fH/fR). RESULTS: RSA had no significant correlation with fH, and a better correlation with fH/fR (r2 = 0.92) than with fR alone (r2 = 0.75); the variance of the Y values of the fH/fR-RSA correlation was ~ half that of the fR/RSA correlation (P < 0.002). CONCLUSIONS: We propose that the fH/fR-RSA relationship reflects a central process that ameliorates gas exchange against the difference between air- and blood-flow patterns. The neurological mechanisms are still conjectural. Measurements of RSA could offer a glimpse of the degree of cardio-respiratory central compensation in face of the inequality between blood flow and airflow.

Respiratory sinus arrhythmia in young men and women at different chest wall configurations.

Respiratory sinus arrhythmia (RSA) is an acceleration of heart rate during inspiration and deceleration with expiration. We asked whether or not in humans some of the volume-related information necessary for RSA originated from the chest wall. Men and women, 19-20 years old, were breathing supine. Rib cage and abdomen displacement provided an index of tidal volume (VT) and RSA was computed breath-by-breath from the peak and trough of instantaneous heart rate. First, measurements were taken during breathing at rest (protocol a, 129 male and 164 female). Then, in subgroups of the original subject population, measurements were collected for the first five breaths immediately following a brief breath-hold period (protocol b), predominantly with the rib cage or predominantly with the abdomen (protocol c), above functional residual capacity or below it (protocol d). As long as VT was constant, severe chest wall distortion (protocol c) did not modify RSA. A drop in absolute lung volume (protocol d) or an increase in VT (protocol b) respectively decreased and increased RSA. The results, globally taken, are compatible with the notion that in humans changes in lung volume are detected by lung mechanoreceptors, whereas chest wall reflexes play no role in RSA. No difference in RSA emerged between genders during resting breathing or modest breath-hold hyperventilation.

Defective Fas expression exacerbates neurotoxicity in a model of Parkinson's disease.

Fas (CD95), a member of the tumor necrosis factor-receptor superfamily, has been studied extensively as a death-inducing receptor in the immune system. However, Fas is also widely expressed in a number of other tissues, including in neurons. Here, we report that defects in the Fas/Fas ligand system unexpectedly render mice highly susceptible to neural degeneration in a model of Parkinson's disease. We found that Fas-deficient lymphoproliferative mice develop a dramatic phenotype resembling clinical Parkinson's disease, characterized by extensive nigrostriatal degeneration accompanied by tremor, hypokinesia, and loss of motor coordination, when treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose that causes no neural degeneration or behavioral impairment in WT mice. Mice with generalized lymphoproliferative disease, which express a mutated Fas ligand, display an intermediate phenotype between that of lymphoproliferative and WT mice. Moreover, Fas engagement directly protects neuronal cells from MPTP/1-methyl-4-phenylpyridinium ion toxicity in vitro. Our data show that decreased Fas expression renders dopaminergic neurons highly susceptible to degeneration in response to a Parkinson-causing neurotoxin. These findings constitute the first evidence for a neuroprotective role for Fas in vivo.

Respiratory sinus arrhythmia during a mental attention task: the role of breathing-specific heart rate.

It is known that a mental attention task (MAT) can modify the magnitude of the increase in instantaneous heart rate (HR) with inspiration, or Respiratory Sinus Arrhythmia (RSA). Here, we asked whether the RSA changes were mediated by the changes in HR, breathing frequency (f) or HR/f ('breathing specific heart rate'). This latter reflects the degree of coupling between pulmonary blood and air flows, the optimization of which may be the function of RSA. RSA (computed as the difference between peak and trough instantaneous HR of each breath, in percent of mean HR) was measured breath-by-breath in 119 young men and women (19.6 ± 0.1 year old) during spontaneous breathing and during a MAT, which consisted in finger tapping at acoustic cues delivered in various patterns. During MAT, breathing became more rapid (+2.2 breaths/min, P < 0.001) and shallow (78% of rest, P < 0.001) and HR decreased slightly (-1 beats/min, P < 0.05). RSA dropped from 13.4 ± 0.7 to 11.6 ± 0.7% (P < 0.0001), because of the drop in the inspiratory peak of instantaneous HR, and so did HR/f, from 5.8 ± 0.2 to 4.9 ± 0.2 beats/breath (P < 0.0001).The results were very similar between genders. The magnitude of the changes in HR/f correlated linearly with those of RSA, so that those subjects who decreased HR/f the most also had the largest decrease in RSA and the few who increased HR/f during MAT also increased RSA. We conclude that this type of mental task changed RSA by a magnitude that depended on its effect on HR/f. The results support the concept that RSA is a central cardio-respiratory mechanism to ameliorate the matching between pulmonary blood and air flows, whether the ventilatory drive originates spontaneously or is under cortical influences.

Fas expression promotes proteasomal activity in toxin-induced parkinsonism.

OBJECTIVE: Fas (CD95), commonly categorised as a death receptor due to its well-defined role in apoptosis, can paradoxically also promote neuroprotection. We have previously found that defects in Fas signalling render mice highly susceptible to neural degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease (PD). Decreased activity of the ubiquitin proteasome system and accumulation of protein aggregates are implicated in PD pathogenesis. Here, we investigate the relationship between Fas and ubiquitin proteasomal activity in neuronal cells. METHODS: We performed proteasome assays in neuroblastoma cells and in midbrain cultures of wild-type and Fas-deficient mice. RESULTS: Neuroblastoma cells upregulated proteasomal activity in response to an activating Fas antibody in vitro. Furthermore, neural tissue from Fas-deficient mice showed decreased proteasomal activity compared with the tissue from wild-type mice when exposed to a PD-inducing toxin in vivo. CONCLUSION: These findings suggest that mechanisms for Fas-mediated neuroprotection may include Fas-induced upregulation of proteasomal activity, and consequently less accumulation of toxic protein aggregates.

Proteasome inhibitor model of Parkinson's disease in mice is confounded by neurotoxicity of the ethanol vehicle.

Defects in the ubiquitin-proteasome system have been implicated in Parkinson's Disease (PD). Recently, a rat model of PD was developed using a synthetic proteasome inhibitor (PSI), (Z-lle-Glu(OtBu)-Ala-Leu-al). We attempted to transfer this model to mouse studies, where genetics can be more readily investigated due to the availability of genetically modified mice. We treated C57BL/6 (B6) mice with six intraperitoneal injections of 6 mg/kg PSI in 50 mul of 70% ethanol over a 2-week-period. We found significant decreases in nigrostriatal dopamine in PSI-treated mice compared with saline-treated mice. However, we observed similar decreases in the ethanol-treated vehicle control group. Administration of ethanol alone led to significant long-term alterations in dopamine levels. Ethanol significantly eclipses the effects of PSI in the dopamine system, and therefore is a confounding vehicle for this model.