Respiratory-sympathetic Coupling Research Articles

Respiratory modulation of muscle sympathetic nerve activity is not increased in essential hypertension or chronic obstructive pulmonary disease

We examined cardiac and respiratory modulation of muscle sympathetic nerve activity (MSNA) in 13 patients with essential hypertension (HT) and 15 with chronic obstructive pulmonary disease (COPD), and compared these with a group of young healthy controls (YHC) and older healthy controls (OHC). There were no significant differences in age of the OHC and HT subjects. MSNA was recorded via a tungsten microelectrode inserted percutaneously into the common peroneal nerve. Respiration was recorded by a strain-gauge transducer around the chest and ECG recorded by surface electrodes. Cardiac and respiratory modulation of MSNA was quantified by fitting polynomials to the cross-correlation histograms constructed between the sympathetic spikes and ECG or respiration. Cardiac modulation was high across all groups, but was significantly lower in COPD (75.9 ± 4.4%) than in the HT (92.4 ± 3.0%), OHC (93.7 ± 1.3%) or YHC (89.1 ± 1.6%) groups. Across all groups, respiratory modulation was significantly lower than cardiac modulation. Respiratory modulation in HT (45.2 ± 5.7%) and COPD (37.5 ± 6.3%) was not higher than in the OHC (47.2 ± 5.4%) or YHC (49.5 ± 6.0%) groups. We have shown that respiratory modulation of MSNA is present in all groups, is consistently lower than the magnitude of cardiac modulation, and is not increased in HT or COPD, arguing against an amplified respiratory-sympathetic coupling in hypertension. Moreover, given that patients with COPD are chronically asphyxic, these data indicate that an increased chemical drive does not increase respiratory modulation of MSNA.

Sympathetic overactivity coupled with active expiration in rats submitted to chronic intermittent hypoxia

It is well known that the respiration modulates sympathetic outflow in basal conditions. Recordings of sympathetic nerve activity demonstrated that central respiratory activity produces rhythmical oscillations in sympathetic discharge that appear mainly during inspiratory phase. This led us to hypothesize that changes in the mechanisms regulating the central entrainment between respiratory and sympathetic activities may contribute to sympathetic overactivity and hypertension. This issue was addressed using rats submitted to chronic intermittent hypoxia (CIH), in which we evaluated whether or not the sympathetic overactivity and hypertension observed in these animals were linked to changes in respiratory pattern. We verified that under baseline conditions, CIH rats exhibited a reduction in post-inspiratory activity of vagus nerve and an enhanced late-expiratory activity in abdominal motor nerve. As a consequence of this altered expiratory pattern, we observed that CIH rats showed an additional burst in sympathetic activity phase-locked with the enhanced late-E expiratory activity. These findings pointed out that the entrainment between pontine-medullary expiratory and sympathetic neurons of CIH rats is strengthened, indicating for the first time in this experimental model that changes in the coupling of respiratory and sympathetic activities may contribute to hypertension. Subsequent studies performed in other models of hypertension also demonstrated similar changes, supporting the concept that alterations in central mechanisms of respiratory-sympathetic coupling is a novel and important mechanism to be considered in the pathogenesis of hypertension.

Acute intermittent hypoxia in ratin vivoelicits a robust increase in tonic sympathetic nerve activity that is independent of respiratory drive

Acute intermittent hypoxia (AIH) elicits long-term increases in respiratory and sympathetic outflow (long-term facilitation, LTF). It is still unclear whether sympathetic LTF is totally dependent on changes in respiration, even though respiratory drive modulates sympathetic nerve activity (SNA). In urethane-anaesthetized, vagotomized mechanically ventilated Sprague-Dawley rats, we investigated the effect of ten 45 s episodes of 10% O2-90% N(2) on splanchnic sympathetic nerve activity (sSNA) and phrenic nerve activity (PNA). We then tested whether or not hypoxic sympathetic chemoreceptor and baroreceptor reflexes were changed 60 min after AIH. We found that 17 animals manifested a sustained increase of sSNA (+51.2+/-4.7%) 60 min after AIH, but only 10 of these rats also expressed phrenic LTF compared with the time controls (rats not exposed to hypoxia, n=5). Inspiratory triggered averages of integrated sSNA showed respiratory modulation of SNA regardless of whether or not phrenic LTF had developed. The hypoxic chemoreceptor reflex was enhanced by 60 min after the development of AIH (peak change from 76.9+/-13.9 to 159.5+/-24.9%). Finally, sympathetic baroreceptor reflex sensitivity increased after sympathetic LTF was established (Gainmax from 1.79+/-0.18 to 2.60+/-0.28% mmHg1). Our findings indicate that respiratory-sympathetic coupling does contribute to sympathetic LTF, but that an additional tonic increase of sympathetic tone is also present that is independent of the level of PNA. Sympathetic LTF is not linked to the change in baroreflex function, since the baroreflex appears to be enhanced rather than impaired, but does play an important role in the enhancement of the hypoxic chemoreflex.

Sympathetic‐mediated hypertension of awake juvenile rats submitted to chronic intermittent hypoxia is not linked to baroreflex dysfunction

In the present study, we evaluated the mechanisms underpinning the hypertension observed in freely moving juvenile rats submitted to chronic intermittent hypoxia (CIH). Male juvenile Wistar rats (20-21 days old) were submitted to CIH (6% O(2) for 40 s every 9 min, 8 h day(1)) for 10 days while control rats were maintained in normoxia. Prior to CIH, baseline systolic arterial pressure (SAP), measured indirectly, was similar between groups (86 +/- 1 versus 87 +/- 1 mmHg). After exposure to CIH, SAP recorded directly was higher in the CIH (n = 28) than in the control group (n = 29; 131 +/- 3 versus 115 +/- 2 mmHg, P < 0.05). This higher SAP of CIH rats presented an augmented power of oscillatory components at low (10.05 +/- 0.91 versus 5.02 +/- 0.63 mmHg(2), P < 0.05) and high (respiratory-related) frequencies (12.42 +/- 2.46 versus 3.28 +/- 0.61 mmHg(2), P < 0.05) in comparison with control animals. In addition, rats exposed to CIH also exhibited an increased cardiac baroreflex gain (3.11 +/- 0.08 versus 2.1 +/- 0.10 beats min(1) mmHg(1), P < 0.0001), associated with a shift to the right of the operating point, in comparison with control rats. Administration of hexamethonium (ganglionic blocker, i.v.), injected after losartan (angiotensin II type 1 receptor antagonist) and [beta-mercapto-beta,beta-cyclopenta-methylenepropionyl(1), O-Me-Tyr(2), Arg(8)]-vasopressin (vasopressin type 1a receptor antagonist), produced a larger depressor response in the CIH (n = 8) than in the control group (n = 9; 49 +/- 2 versus 39 +/- 2 mmHg, P < 0.05). Fifteen days after the cessation of exposure to CIH, the mean arterial pressure of CIH rats returned to normal levels. The data indicate that the sympathetic-mediated hypertension observed in conscious juvenile rats exposed to CIH is not secondary to a reduction in cardiac baroreflex gain and exhibits a higher respiratory modulation, indicating that an enhanced respiratory-sympathetic coupling seems to be the major factor contributing to hypertension in rats exposed to CIH.

Mechanisms underpinning the hypertension in juvenile rats submitted to chronic intermittent hypoxia

Neural and/or hormonal mechanisms underlying the hypertension of juvenile male Wistar rats (20‐21 days) exposed to chronic intermittent hypoxia (CIH, 6% O2 for 40 s every 9 min, 8 h/day) for 10 days were evaluated. Prior to CIH, baseline systolic arterial pressure (SAP), measured indirectly, was similar between CIH and control rats. After CIH, SAP recorded directly was higher in CIH (n=28) than in control group [n=29, (131±3 vs 115±2 mmHg, P&lt;0.05)]. This higher SAP of CIH rats was associated with increases in the power of oscillatory components at low and high (respiratory‐related) frequencies, but not with changes in spontaneous cardiac baroreflex, in comparison to controls. Sequential i.v. injections of losartan (AT1 receptor antagonist) and AVPx (Vasopressin1a receptor antagonist) did not affect baseline mean arterial pressure (MAP) in either CIH (n=8) or control groups (n=9), while hexamethonium (ganglionic blocker), injected after losartan and AVPx, produced a larger depressor response in CIH than in control group (‐53±2 vs ‐42±2 mmHg, P&lt;0.05). Fifteen days after the cessation of CIH exposure MAP of CIH rats returned to normal levels. The data indicate that the hypertension observed in CIH‐treated juvenile rats is mainly dependent on sympathetic overactivity and is under a higher respiratory modulation, suggesting augmented respiratory‐sympathetic coupling in CIH‐induced hypertension. Supported by FAPESP and CNPq.

Amplified respiratory–sympathetic coupling in the spontaneously hypertensive rat: does it contribute to hypertension?

Sympathetic nerve activity (SNA) is elevated in established hypertension. We tested the hypothesis that SNA is elevated in neonate and juvenile spontaneously hypertensive (SH) rats prior to the development of hypertension, and that this may be due to augmented respiratory-sympathetic coupling. Using the working heart-brainstem preparation, perfusion pressure, phrenic nerve activity and thoracic (T8) SNA were recorded in male SH rats and normotensive Wistar-Kyoto (WKY) rats at three ages: neonates (postnatal day 9-16), 3 weeks old and 5 weeks old. Perfusion pressure was higher in SH rats at all ages reflecting higher vascular resistance. The amplitude of respiratory-related bursts of SNA was greater in SH rats at all ages (P < 0.05). This was reflected in larger Traube-Hering pressure waves in SH rats (1.4 +/- 0.8 versus 9.8 +/- 1.5 mmHg WKY versus SH rat, 5 weeks old, n = 5 per group, P < 0.01). Recovery from hypocapnic-induced apnoea and reinstatement of Traube-Hering waves produced a significantly greater increase in perfusion pressure in SH rats (P < 0.05). Differences in respiratory-sympathetic coupling in the SH rat were not secondary to changes in central or peripheral chemoreflex sensitivity, nor were they related to altered arterial baroreflex function. We have shown that increased SNA is already present in SH rats in early postnatal life as revealed by augmented respiratory modulation of SNA. This is reflected in an increased magnitude of Traube-Hering waves resulting in elevated perfusion pressure in the SH rat. We suggest that the amplified respiratory-related bursts of SNA seen in the neonate and juvenile SH rat may be causal in the development of their hypertension.

Increased sympathetic outflow in juvenile rats submitted to chronic intermittent hypoxia correlates with enhanced expiratory activity

Chronic intermittent hypoxia (CIH) in rats produces changes in the central regulation of cardiovascular and respiratory systems by unknown mechanisms. We hypothesized that CIH (6% O(2) for 40 s, every 9 min, 8 h day(-1)) for 10 days alters the central respiratory modulation of sympathetic activity. After CIH, awake rats (n = 14) exhibited higher levels of mean arterial pressure than controls (101 +/- 3 versus 89 +/- 3 mmHg, n = 15, P < 0.01). Recordings of phrenic, thoracic sympathetic, cervical vagus and abdominal nerves were performed in the in situ working heart-brainstem preparations of control and CIH juvenile rats. The data obtained in CIH rats revealed that: (i) abdominal (Abd) nerves exhibited an additional burst discharge in late expiration; (ii) thoracic sympathetic nerve activity (tSNA) was greater during late expiration than in controls (52 +/- 5 versus 40 +/- 3%; n = 11, P < 0.05; values expressed according to the maximal activity observed during inspiration and the noise level recorded at the end of each experiment), which was not dependent on peripheral chemoreceptors; (iii) the additional late expiratory activity in the Abd nerve correlated with the increased tSNA; (iv) the enhanced late expiratory activity in the Abd nerve unique to CIH rats was accompanied by reduced post-inspiratory activity in cervical vagus nerve compared to controls. The data indicate that CIH rats present an altered pattern of central sympathetic-respiratory coupling, with increased tSNA that correlates with enhanced late expiratory discharge in the Abd nerve. Thus, CIH alters the coupling between the central respiratory generator and sympathetic networks that may contribute to the induced hypertension in this experimental model.

Increased sympathetic activity in rats submitted to chronic intermittent hypoxia (CIH) is coupled to enhanced late expiratory activity

The mechanisms triggering the sympathetic overactivity in CIH rats are not understood. In the present study, we explored whether juvenile rats exposed to CIH exhibit changes in central respiratory‐sympathetic coupling. CIH was induced with 6% O2 for 40 s every 9 min, 8 h/day for 10 days. On the 11th day, awake CIH rats breathing room air showed a higher mean arterial pressure than controls (101 ± 3 vs 89 ± 3 mmHg, n = 14). Recordings of phrenic, thoracic sympathetic (tSNA), cervical vagus (cVN) and abdominal nerve (Abd) activities were made in the working heart‐brainstem preparation. During late expiration (Late E), tSNA was greater in CIH (n = 9) than in control rats (52 ± 5 vs 40 ± 3%, n = 11; P &lt; 0.05). Moreover, CIH rats (n = 6), but not controls (n = 5), also exhibited a peak of activity in Abd during Late E with reduced post‐inspiratory activity in cVN. These observations suggest that CIH alters the breathing pattern evoking Late E activity in the Abd. We propose that this Late E discharge in CIH rats contributes with an additional excitatory synaptic drive to the sympathetic outflow and, in turn, raises arterial pressure. Further studies are required to identify the neuronal populations and the correspondent neurochemical mechanisms responsible for the altered respiratory‐sympathetic entrainment in CIH rats. Supported by CNPq and FAPESP (Brazil) and BHF (UK).