Published online before print March 28, 2005, doi: 10.1161/01.HYP.0000161875.32767.ac
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(Hypertension. 2005;45:894.)
© 2005 American Heart Association, Inc.
Original Articles |
Effects of Peripheral Chemoreceptors Deactivation on Sympathetic Activity in Heart Transplant Recipients
From the Department of Cardiology (A.C., B.N., N.C., M.L., O.X., J.-P.D., P.v.d.B.) and the Department of Cardiac Surgery (M.A.), Erasme University Hospital, Brussels, Belgium; and the Department of Hypertension and Diabetology (K.N.), Medical University of Gdansk, Poland.
Correspondence to Agnieszka Ciarka, Department of Cardiology, Erasme Hospital, 808, Lennik Road, 1070 Brussels, Belgium. E-mail Agnieszka.Ciarka{at}ulb.ac.be
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Abstract |
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Heart transplantation initially normalizes sympathetic hyperactivity directed at the muscle circulation. However, sympathetic activity increases with time after transplantation and the exact mechanisms responsible for sympathetic control in heart transplant recipients remain unclear. We examined the effects of peripheral chemoreflex deactivation caused by breathing 100% oxygen on muscle sympathetic nerve activity (expressed as number of burst per minute and mean burst amplitude), heart rate, and mean blood pressure in 13 heart transplant recipients, 13 patients with essential hypertension, and 10 controls. Heart transplant recipients disclosed the highest sympathetic activity, whereas it did not differ between controls and patients with essential hypertension (51±16 versus 37±14 versus 39±12 burst/min, respectively; P<0.05). Breathing 100% oxygen, in comparison with 21% oxygen, reduced sympathetic activity (–4±4 versus –1±2 burst/min, P<0.01; 85±9 versus101±8% of amplitude at baseline, P<0.001) and mean blood pressure (–4±5 versus +3±6 mm Hg; P<0.05) in heart transplant recipients, decreased sympathetic activity (–4±4 versus 0±3 burst/min, P<0.05; 90±16 versus101±9% of amplitude at baseline, P<0.05) in patients with essential hypertension, but did not reduce sympathetic activity (2±4 versus 3±3 burst/min, P=NS; 95±11 versus 95±13% of amplitude at baseline, P=NS) in control subjects. The sympathetic response to hyperoxia was more marked in heart transplant recipients than in controls (85±9 versus 95±11% of baseline amplitude; P<0.05). The decrease in sympathetic activity was most evident in patients with the longest time after heart transplantation (r=–0.75, P<0.01). In conclusion, tonic chemoreflex activation increases resting muscle sympathetic nerve activity and favors blood pressure elevation after heart transplantation.
Key Words: chemoreceptors • sympathetic nervous system • transplantation
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Introduction |
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Congestive heart failure is associated with remarkably elevated muscle sympathetic nerve activity (MSNA).1 Heart transplantation restores a close to normal cardiac function but does not always normalize MSNA.2–5 Elevated MSNA after heart transplantation is associated with cyclosporine therapy3 and increases as a function of time after transplantation.2
Increased peripheral chemoreflex sensitivity has been demonstrated in humans and experimental animals with congestive heart failure.6–9 Whether this alteration in chemoreflex function is reversible when cardiac function is restored by heart transplantation is unknown. We hypothesized that increased peripheral chemoreceptor activation, possibly a lingering effect of heart failure, contributes to elevated MSNA in heart transplant recipients (HTRs). Accordingly, we studied the effects of hyperoxia, an intervention that acutely reduces afferent nerve traffic from the peripheral chemoreceptors, on MSNA in HTRs. Because the majority of HTRs are hypertensive10 and enhanced peripheral chemoreflex sensitivity has been observed in hypertensive humans and in animal models of hypertension,11–13 we also studied the effects of hyperoxia on MSNA in essential hypertension patients (EHPs). Last, we examined effects of hyperoxia on MSNA in 10 healthy subjects to determine whether tonic drive from peripheral chemoreceptors is increased in HTRs.
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Methods |
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Subjects
Thirteen HTRs participated in the study (58±10 years, all men, body mass index [BMI]) 26±4 kg/m2). Mean time after heart transplantation was 9±5 years (range, 2 to 15 years). All patients were on various combinations of immunosuppressive treatment including cyclosporine (n=12), methylprednisolone (n=10), tacrolimus (n=1), and mofetil mycofenolate (n=3), and had a normal left ventricular ejection fraction of 60±9% (range, 50% to 75%) determined by resting radionuclide angiography. Hypertension was treated with diuretics (n=8), ß-blockers (n=5), calcium channel-blockers (n=8), angiotensin-converting enzyme inhibitors, and angiotensin II receptor antagonists (n=8). The origin of heart failure was ischemic heart disease (n=5), idiopathic dilated cardiomyopathy (n=5), valvular heart disease (n=2) and congenital heart defect (n=1). Patients had either no or modest left ventricular hypertrophy (both interventricular and posterior end diastolic thickness were 11±1 mm), as measured by routine echocardiography according to European Society of Cardiology Guidelines.14
Thirteen closely matched EHPs (aged 61±11 years, all men, BMI 28±4 kg/m2) also agreed to participate in the study. They were using antihypertensive treatment and were receiving diuretics (n=9), ß-blockers (n=8), calcium channel-blockers (n=9), angiotensin-converting enzyme inhibitors, and angiotensin II receptor antagonists (n=7). The control group consisted of 10 control subjects (all men, aged 50±10 years, BMI 25±4 kg/m2).
The study protocol was approved by institutional review committee (Ethical Committee of Erasme Hospital). All patients and subjects gave informed consent for the study.
Protocol and Procedures
All measurements were taken in a quiet room after 15 minutes of supine rest. We obtained continuous recording of the ECG (Siemens) and O2 blood saturation (Nellcor). Mean arterial blood pressure (MBP) was measured every minute using an oscillometric sphygmomanometer (Physiocontrol Colin BP-880). MSNA was recorded continuously using multiunit recordings of postganglionic sympathetic activity, measured from a nerve fascicle in the peroneal nerve posterior to the fibular head.15 Respiratory movements were recorded continuously by Respitrace.
The study was double-blinded, randomized, placebo-controlled, and crossover. All patients and controls underwent baseline recordings before placement of a nonrebreathing mask. They started to breathe air containing 21% oxygen through a nonrebreathing mask for 10 minutes. After this baseline mask period, subjects were randomly allocated to breathe either 100% oxygen or air containing 21% oxygen for 15 minutes. This was followed by a 30-minute period without a mask. The mask was then replaced and air containing 21% oxygen was administered for 10 minutes. This was followed by 15 minutes of breathing either air containing 21% oxygen or 100% oxygen, the opposite to that which the subject had received in the first part of the study. The flow rate in the nonrebreathing mask was maintained constant throughout the study.
Analyses
Measurements were averaged during the last 3 minutes of the baseline period before placement of the nonrebreathing mask, during the last 5 minutes of the 10-minute baseline mask periods, and during the last 5 minutes of the 15-minute intervention periods. Sympathetic bursts were carefully identified by voltage neurogram inspection by a single trained observer blinded to subject and intervention. Sympathetic activity was expressed as burst frequency per minute. The amplitude of each burst was determined and sympathetic activity was expressed as burst per minute multiplied by mean burst amplitude (arbitrary units). Burst amplitude depends on neural signal amplification, which varies from one subject to another but is kept constant throughout each experiment. Burst frequency permits comparison of sympathetic nerve activity between different subjects (HTRs versus EHPs versus control subjects), whereas both burst frequency and amplitude were used to assess the effects of hyperoxia on sympathetic activity in the patients and controls. Changes in burst amplitudes during interventions were expressed as a percentage of baseline values.
Respiratory rate was expressed as number of respirations per minute. The amplitude of respiratory movements was calculated as the difference between maximal and minimal thoracic cage expansion during each respiratory cycle assessed by the Respitrace and was expressed in arbitrary units. Plasma creatinin levels were determined routinely in the HTRs.
All data are expressed as mean±SD. The comparison of mean burst amplitude was not possible in 1 HTR and 1 EHP because of a shift in the microneurographic recording site during the study. Statistical analysis was performed with Statview 5.0 (SAS). Baseline variables in HTRs, EHPs, and the controls were compared by ANOVA, with Bonferoni contrasts a posteriori. Effects of 100% oxygen breathing in each group were examined by repeated measurement ANOVA with gas (21% or 100% oxygen) as the factor. Comparison of effects of 100% oxygen breathing between HTR and control group was performed by ANOVA for repeated measurements with group and time (baseline before 100% oxygen and 100% oxygen) as factors. Relationships between variables were estimated by linear regression analysis. A 
2 test was used to compare the proportion of patients on different classes of hypertensive treatment in the HTRs and EHPs.
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Results |
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HTRs, EHPs, and control subjects were matched for gender, age, and BMI (P
0.07). There was no difference in the antihypertensive treatment regimen between HTRs and EHPs (P>0.24). HTRs and EHPs presented the same MBP, which was increased in both groups in comparison with the control subjects (Figure 1). HTRs disclosed a higher MSNA than the controls, and also had faster heart rates (HRs) and slightly larger arterial blood oxygen saturations in comparison with the EHPs (Figure 1).
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Breathing 100% oxygen decreased MSNA and MBP in HTRs (Table 1, Figure 2). Peripheral chemoreceptor inhibition with 100% oxygen decreased MSNA, but did not change MBP and HR in EHPs (Table 2, Figure 3). In control subjects, 100% oxygen in comparison with 21% oxygen provoked a decrease in HR and did not change MSNA or blood pressure (Table 3, Figure 4). Acute hyperoxia did not change respiratory rate and respiratory movement amplitude in HTRs, EHPs, and controls (Table 1, Table 2, and Table 3).
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The reduction in MSNA during 100% oxygen breathing was not different between HTRs and EHPs (ANOVA P=0.29 for percent of baseline burst amplitude), whereas the MSNA response to hyperoxia was more marked in the HTRs than in the control subjects (85±9 versus 95±11% of baseline burst amplitude, ANOVA P<0.05).
The reduction in MSNA during 100% oxygen breathing was most evident in patients with the longest time after transplantation (Figure 5). Oxygen saturation was not related to transplantation time (r=–0.33). The decrease in MBP was not related to the decrease in MSNA (r0.16).
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In HTRs, plasma creatinine was 1.9±0.6 mg/dL (range, 1.3 to 3.4 mg/dL), and there was no relation between plasma creatinine and MSNA at baseline (r0.05).
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Discussion |
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This is the first study to our knowledge to demonstrate that peripheral chemoreflex deactivation by hyperoxia decreases MSNA and MBP after cardiac transplantation. Heart transplantation initially decreases the MSNA related to the heart failure state, because it returns to normal values within 1 year after the surgical procedure,16 although this normalization does not seem to be permanent.2,3 Only a few studies have used direct recording of nerve traffic to unravel sympathetic activation after heart transplantation. These studies revealed that cyclosporine and time from heart transplantation contribute to MSNA increase in HTRs.2,3 Our study confirms previous observations of increased MSNA in long-term HTRs. It provides a new insight into sympathetic regulation after heart transplantation. The demonstration that peripheral chemoreceptor deactivation decreases resting MSNA and blood pressure in normoxemic HTRs is the first main finding of our study. The demonstration of a higher peripheral chemoreceptor contribution to MSNA in HTRs than in healthy controls is the second important finding of our study. The reduction in MSNA in response to hyperoxia was nearly 3-times larger in the HTRs than in the controls, despite the fact that both groups disclosed strictly identical baseline arterial blood oxygen saturations. This suggests that the tonic peripheral chemoreceptor drive to MSNA is increased in HTR. Moreover, the concomitant decrease in MSNA and MBP in response to hyperoxia in HTR suggests a causal interaction, because an isolated reduction in MBP rather would be expected to elicit a baroreflex-related increase in MSNA.
Animal studies also reveal that acute hyperoxia decreases HR and blood pressure probably through changes in sympathetic activity.17 Human studies report a decrease in MSNA during short breathing periods of 3 to 4 minutes of hyperoxia.18 However, longer exposure to oxygen was reported to decrease heart rate but not MSNA in healthy subjects.19,20 Previous observations of MSNA reduction during hyperoxia in humans18 could be explained by acclimatization to the laboratory environment. Our control subjects decreased their MSNA during 100% oxygen breathing; however, their MSNA decreased also during 21% oxygen, similar to what was observed in the study by Narkiewicz et al.20
HTRs are at risk for systemic hypertension. The cumulative probability of hypertension reaches up to 77% at the fourth year after transplantation.10 Hypertension appears within weeks or months after the surgical procedure and is of multifactorial origin.10 Moreover, it does not respond to single antihypertensive agents and requires combined antihypertensive therapy.10 Cyclosporine is implicated in the pathogenesis of hypertension, because it has been demonstrated to cause sympathetic nerve activation3 and is also well-documented as a cause of chronic nephropathy.21 However, patients who underwent transplantation who do not receive cyclosporine can also have hypertension develop.10 Alternative mechanisms such as abnormal renin-angiotensin-aldosterone system responsiveness to fluid retention are therefore also postulated to contribute to the pathogenesis of blood pressure elevation.22 Our study further improves the understanding of the physiopathology of arterial hypertension after heart transplantation by demonstrating that tonic peripheral chemoreceptor activation contributes to sympathetic activity and blood pressure in these patients.
The third important finding of our study is that there is no difference in the MSNA response to peripheral chemoreceptor deactivation between HTRs and treated elderly patients with essential arterial hypertension. We also report for the first time to our knowledge that acute hyperoxia decreases MSNA in patients with essential hypertension but fails to decrease arterial blood pressure in this clinical setting.
Several studies have investigated chemoreceptor function in animal models of hypertension and in hypertensive patients. Spontaneously hypertensive rats exposed to hypoxia present increased carotid chemoreceptor discharge in comparison with normotensive Wistar rats and Wistar–Kyoto rats.23 Studies in young, untreated, borderline hypertensive humans demonstrated exaggerated ventilatory and MSNA response to hypoxia11,12,24 and also a decrease in arterial blood pressure and total peripheral resistance during peripheral chemoreceptor deactivation by acute hyperoxia.13 None of these studies determined, however, the effects of hyperoxia on MSNA in EHPs.
From our present data, it is impossible to state whether the observed increased peripheral chemoreceptor drive in HTRs is caused by heart transplantation per se or by post-transplant hypertension. Although increased peripheral chemoreceptor drive could be a lingering effect of heart failure, it could also be a result of hypertension, which commonly develops in HTRs. The observation that hyperoxia decreases MSNA in both HTRs and EHPs supports the latter hypothesis. However, the finding that hyperoxia decreased MBP only in HTR suggests an impact of other factors specific to patients after heart transplantation.
Studies in young patients with borderline hypertension showed increased MSNA25 and elevated plasma norepinephrine levels,26 whereas MSNA was not increased in elderly hypertensive patients.27,28 In our study, we did not find a difference in baseline MSNA between EHPs and matched control subjects. This finding, however, is not unexpected, because our EHPs were of an advanced age, with established arterial hypertension, and were using antihypertensive treatment. Although diuretics do not seem to affect sympathetic activity29 and calcium channel-blockers tend to increase MSNA,30,31 some studies demonstrated beneficial effects of beta-blockers,32 angiotensin-converting enzyme II inhibitors,33 and selective angiotensin II receptor blockade29,31 on sympathetic activity in hypertensive subjects. Therefore, we cannot exclude that normalization of MSNA in our EHPs was caused by pharmacological antihypertensive treatment. The decrease in MSNA in response to chemoreflex inhibition was positively related to the duration after heart transplantation. We speculate that cyclosporine-related arterial baroreceptor attenuation,34 and possibly the duration of systemic hypertension after the surgical procedure, may play a role.
End-stage renal failure is accompanied by increased MSNA, which remains elevated in patients after renal transplantation with diseased native kidneys,35 but decreases during peripheral chemoreceptor deactivation by acute hyperoxia.36 In our study, HTRs presented moderately elevated plasma creatinine levels. However, renal failure does not seem to be a key component of sympathetic activation in HTR, because creatinine levels did not correlate with sympathetic overactivity.
Peripheral chemoreceptors are primarily influenced by a decrease in arterial blood oxygen saturation, but they respond also to an increase in arterial carbon dioxide content.37 Acute hyperoxia selectively suppresses the activity of peripheral chemoreceptors.20,37,38 This allows the contribution of resting peripheral chemoreflex drive on MSNA and blood pressure to be determined.20 However, breathing 100% oxygen can also increase ventilation in normal subjects.39 Central chemoreceptor activation during hyperoxia, known as the Haldane effect,40 may play a role because oxygenated hemoglobin has a lower transport capacity for tissue CO2 than does nonoxygenated hemoglobin. Subsequently, an increase of CO2 in brain tissue may result in stimulation of central chemoreceptors. In mitigation, however, first, it is very unlikely that central chemoreflex activation played an important role in our study because this reflex increases not only ventilation but also MSNA and MBP,41 in contrast to what we observed in our HTRs and EHPs. We cannot exclude, however, the possibility that the Haladane effect may have limited the size of the decrease in MSNA and MBP we observed.
Sympathetic nerve traffic to the periphery is modulated by respiration.42 In normal individuals and in patients with heart failure, MSNA is affected by the breathing pattern and is inversely related to tidal volume and is directly related to breathing frequency.43,44 Thus, changes in pulmonary stretch receptor activation affects MSNA.43,45 However, the reduction in MSNA we observed during peripheral chemoreflex suppression cannot be explained by an augmented stimulation of pulmonary stretch receptors, because hyperoxia did not affect respiratory rate or the amplitude of respiratory movements in our study.
Perspectives
Heart transplantation decreases but does not normalize the ventilatory response to exercise,46 which remains excessive in comparison with healthy subjects.46 Peripheral chemoreceptors are known to intervene in exercise hyperpnea.47 Whether peripheral chemoreceptor sensitivity is increased in HTRs is unknown, and this will need further studies on the ventilatory and MSNA response to hypoxia. We speculate that increased peripheral chemoreceptor sensitivity could correlate with the excessive ventilatory response to exercise48 in HTRs. In conclusion, our study demonstrates that peripheral chemoreceptors contribute to MSNA and blood pressure in HTRs, as well as to MSNA in elderly patients with essential arterial hypertension. Effects of hyperoxia on MSNA are more marked in HTRs than in control subjects. The contribution of peripheral chemoreceptors to MSNA is directly related to the time from heart transplantation.
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Acknowledgments |
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This study was supported by Sankyo (C.A.), the Stefan Batory Foundation (C.A.), the Foundation for Cardiac Surgery (C.A.), by Astra Zeneca (B.N.), and the National Fund for Research-Belgium (P.v.d.B.). We are indebted to Francoise Pignez for drawing the figures and to Annette Fiasse for the technical assistance.
Received January 9, 2005; first decision January 9, 2005; accepted February 28, 2005.
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References |
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1. Leimbach WN, Jr, Wallin BG, Victor RG, Aylward PE, Sundlof G, Mark AL. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation. 1986; 73: 913–919.
2. van de Borne P, Neubauer J, Rahnama M, Jansens JL, Montano N, Porta A, Somers VK, Degaute JP. Differential characteristics of neural circulatory control: early versus late after cardiac transplantation. Circulation. 2001; 104: 1809–1813.
3. Scherrer U, Vissing SF, Morgan BJ, Rollins JA, Tindall RS, Ring S, Hanson P, Mohanty PK, Victor RG. Cyclosporine-induced sympathetic activation and hypertension after heart transplantation. N Engl J Med. 1990; 323: 693–699.[Abstract]
4. Elam M, Casale R, La Rovere MT, Mortara A, Tavazzi L. Is sympathetic neural hyperactivity in chronic heart failure affected by heart transplantation? Eur Heart J. 1993; 14: 521–525.
5. Rundqvist B, Elam M, Eisenhofer G, Friberg P. Normalization of total body and regional sympathetic hyperactivity in heart failure after heart transplantation. J Heart Lung Transplant. 1996; 15: 516–526.[Medline] [Order article via Infotrieve]
6. Narkiewicz K, Pesek CA, van de Borne PJ, Kato M, Somers VK. Enhanced sympathetic and ventilatory responses to central chemoreflex activation in heart failure. Circulation. 1999; 100: 262–267.
7. Ponikowski P, Chua TP, Anker SD, Francis DP, Doehner W, Banasiak W, Poole-Wilson PA, Piepoli MF, Coats AJ. Peripheral chemoreceptor hypersensitivity: an ominous sign in patients with chronic heart failure. Circulation. 2001; 104: 544–549.
8. Sun SY, Wang W, Zucker IH, Schultz HD. Enhanced peripheral chemoreflex function in conscious rabbits with pacing-induced heart failure. J Appl Physiol. 1999; 86: 1264–1272.
9. Sun SY, Wang W, Zucker IH, Schultz HD. Enhanced activity of carotid body chemoreceptors in rabbits with heart failure: role of nitric oxide. J Appl Physiol. 1999; 86: 1273–1282.
10. Ozdogan E, Banner N, Fitzgerald M, Musumeci F, Khaghani A, Yacoub M. Factors influencing the development of hypertension after heart transplantation. J Heart Transplant. 1990; 9: 548–553.[Medline] [Order article via Infotrieve]
11. Trzebski A, Tafil M, Zoltowski M, Przybylski J. Increased sensitivity of the arterial chemoreceptor drive in young men with mild hypertension. Cardiovasc Res. 1982; 16: 163–172.[Medline] [Order article via Infotrieve]
12. Somers VK, Mark AL, Abboud FM. Potentiation of sympathetic nerve responses to hypoxia in borderline hypertensive subjects. Hypertension. 1988; 11: 608–612.
13. Izdebska E, Izdebski J, Trzebski A. Hemodynamic responses to brief hyperoxia in healthy and in mild hypertensive human subjects in rest and during dynamic exercise. J Physiol Pharmacol. 1996; 47: 243–256.[Medline] [Order article via Infotrieve]
14. Feigenbaum H. Echocardiographic evaluation of cardiac chambers and hemodynamic information derived from echocardiography. Echocardiography. Baltimore: Williams & Wilkins; 2004: 134–215.
15. Mark AL, Victor RG, Nerhed C, Wallin BG. Microneurographic studies of the mechanisms of sympathetic nerve responses to static exercise in humans. Circ Res. 1985; 57: 461–469.
16. Rundqvist B, Casale R, Bergmann-Sverrisdottir Y, Friberg P, Mortara A, Elam M. Rapid fall in sympathetic nerve hyperactivity in patients with heart failure after cardiac transplantation. J Card Fail. 1997; 3: 21–26.[CrossRef][Medline] [Order article via Infotrieve]
17. Przybylski J, Trzebski A, Czyzewski T, Jodkowski J. Responses to hyperoxia, hypoxia, hypercapnia and almitrine in spontaneously hypertensive rats. Bull Eur Physipathol Respir. 1982; 18: 145–154.
18. Seals DR, Johnson DG, Fregosi RF. Hyperoxia lowers sympathetic activity at rest but not during exercise in humans. Am J Physiol. 1991; 260: R873–R878.[Medline] [Order article via Infotrieve]
19. Heindl S, Lehnert M, Criee CP, Hasenfuss G, Andreas S. Marked sympathetic activation in patients with chronic respiratory failure. Am J Respir Crit Care Med. 2001; 164: 597–601.
20. Narkiewicz K, van de Borne PJ, Montano N, Dyken ME, Phillips BG, Somers VK. Contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea. Circulation. 1998; 97: 943–945.
21. Myers BD, Sibley R, Newton L, Tomlanovich SJ, Boshkos C, Stinson E, Luetscher JA, Whitney DJ, Krasny D, Coplon NS. The long-term course of cyclosporine-associated chronic nephropathy. Kidney Int. 1988; 33: 590–600.[Medline] [Order article via Infotrieve]
22. Braith RW, Mills RM, Wilcox CS, Davis GL, Hill JA, Wood CE. High-dose angiotensin-converting enzyme inhibition restores body fluid homeostasis in heart-transplant recipients. J Am Coll Cardiol. 2003; 41: 426–432.
23. Fukuda Y, Sato A, Trzebski A. Carotid chemoreceptor discharge responses to hypoxia and hypercapnia in normotensive and spontaneously hypertensive rats. J Auton Nerv Syst. 1987; 19: 1–11.[CrossRef][Medline] [Order article via Infotrieve]
24. Matsumoto H, Osanai S, Nakano H, Akiba Y, Onodera S. Ventilatory responses in patients with essential hypertension. Jpn J Physiol. 1991; 41: 831–842.[CrossRef][Medline] [Order article via Infotrieve]
25. Anderson EA, Sinkey CA, Lawton WJ, Mark AL. Elevated sympathetic nerve activity in borderline hypertensive humans. Evidence from direct intraneural recordings. Hypertension. 1989; 14: 177–183.
26. Esler M, Jennings G, Biviano B, Lambert G, Hasking G. Mechanism of elevated plasma noradrenaline in the course of essential hypertension. J Cardiovasc Pharmacol. 1986; 8 (suppl 5): S39–S43.
27. Wallin BG, Delius W, Hagbarth KE. Comparison of sympathetic nerve activity in normotensive and hypertensive subjects. Circ Res. 1973; 33: 9–21.
28. Wallin BG, Sundlof G. A quantitative study of muscle nerve sympathetic activity in resting normotensive and hypertensive subjects. Hypertension. 1979; 1: 67–77.
29. Grassi G, Seravalle G, Dell’Oro R, Trevano FQ, Bombelli M, Scopelliti F, Facchini A, Mancia G. Comparative effects of candesartan and hydrochlorothiazide on blood pressure, insulin sensitivity, and sympathetic drive in obese hypertensive individuals: results of the CROSS study. J Hypertens. 2003; 21: 1761–1769.[CrossRef][Medline] [Order article via Infotrieve]
30. Binggeli C, Corti R, Sudano I, Luscher TF, Noll G. Effects of chronic calcium channel blockade on sympathetic nerve activity in hypertension. Hypertension. 2002; 39: 892–896.
31. Struck J, Muck P, Trubger D, Handrock R, Weidinger G, Dendorfer A, Dodt C. Effects of selective angiotensin II receptor blockade on sympathetic nerve activity in primary hypertensive subjects. J Hypertens. 2002; 20: 1143–1149.[CrossRef][Medline] [Order article via Infotrieve]
32. Wallin BG, Sundlof G, Stromgren E, Aberg H. Sympathetic outflow to muscles during treatment of hypertension with metoprolol. Hypertension. 1984; 6: 557–562.
33. Klein IH, Ligtenberg G, Oey PL, Koomans HA, Blankestijn PJ. Enalapril and losartan reduce sympathetic hyperactivity in patients with chronic renal failure. J Am Soc Nephrol. 2003; 14: 425–430.
34. Shaltout HA, Abdel-Rahman AA. Cyclosporine induces progressive attenuation of baroreceptor heart rate response and cumulative pressor response in conscious unrestrained rats. J Pharmacol Exp Ther. 2003; 305: 966–973.
35. Hausberg M, Kosch M, Harmelink P, Barenbrock M, Hohage H, Kisters K, Dietl KH, Rahn KH. Sympathetic nerve activity in end-stage renal disease. Circulation. 2002; 106: 1974–1979.
36. Hering D, Zdrojewski Z, Kara T, Krol E, Somers VK, Wyrzykowski B, Rutkowski B, Narkiewicz K. Tonic chemoreflex activation contributes to the elevated muscle sympathetic nerve activity in patients with chronic heart failure. J Hypertens. 2004; 22 (suppl 2): S80.
37. Duffin J. The chemoreflex control of breathing and its measurement. Can J Anaesth. 1990; 37: 933–942.[Medline] [Order article via Infotrieve]
38. Velez-Roa S, Ciarka A, Najem B, Vachiery JL, Naeije R, van de Borne P. Increased sympathetic nerve activity in pulmonary artery hypertension. Circulation. 2004; 110: 1308–1312.
39. Becker HF, Polo O, McNamara SG, Berthon-Jones M, Sullivan CE. Effect of different levels of hyperoxia on breathing in healthy subjects. J Appl Physiol. 1996; 81: 1683–1690.
40. Siggaard-Andersen O, Garby L. The Bohr effect and the Haldane effect. Scand J Clin Lab Invest. 1973; 31: 1–8.[Medline] [Order article via Infotrieve]
41. Tamisier R, Nieto L, Anand A, Cunnington D, Weiss JW. Sustained muscle sympathetic activity after hypercapnic but not hypocapnic hypoxia in normal humans. Respir Physiol Neurobiol. 2004; 141: 145–155.[CrossRef][Medline] [Order article via Infotrieve]
42. Guyenet PG, Koshiya N, Huangfu D, Verberne AJ, Riley TA. Central respiratory control of A5 and A6 pontine noradrenergic neurons. Am J Physiol. 1993; 264: R1035–R1044.[Medline] [Order article via Infotrieve]
43. Goso Y, Asanoi H, Ishise H, Kameyama T, Hirai T, Nozawa T, Takashima S, Umeno K, Inoue H. Respiratory modulation of muscle sympathetic nerve activity in patients with chronic heart failure. Circulation. 2001; 104: 418–423.
44. Naughton MT, Floras JS, Rahman MA, Jamal M, Bradley TD. Respiratory correlates of muscle sympathetic nerve activity in heart failure. Clin Sci (Lond). 1998; 95: 277–285.[Medline] [Order article via Infotrieve]
45. Seals DR, Suwarno NO, Joyner MJ, Iber C, Copeland JG, Dempsey JA. Respiratory modulation of muscle sympathetic nerve activity in intact and lung denervated humans. Circ Res. 1993; 72: 440–454.
46. Marzo KP, Wilson JR, Mancini DM. Effects of cardiac transplantation on ventilatory response to exercise. Am J Cardiol. 1992; 69: 547–553.[CrossRef][Medline] [Order article via Infotrieve]
47. Whipp BJ. Peripheral chemoreceptor control of exercise hyperpnea in humans. Med Sci Sports Exerc. 1994; 26: 337–347.[Medline] [Order article via Infotrieve]
48. Chua TP, Clark AL, Amadi AA, Coats AJ. Relation between chemosensitivity and the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol. 1996; 27: 650–657.[Abstract]
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 B. Najem, A. Houssiere, A. Pathak, C. Janssen, D. Lemogoum, O. Xhaet, N. Cuylits, and P. van de Borne Acute Cardiovascular and Sympathetic Effects of Nicotine Replacement Therapy Hypertension, June 1, 2006; 47(6): 1162 - 1167. [Abstract] [Full Text] [PDF]
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 A. Ciarka, N. Cuylits, J.-L. Vachiery, M. Lamotte, J.-P. Degaute, R. Naeije, and P. van de Borne Increased Peripheral Chemoreceptors Sensitivity and Exercise Ventilation in Heart Transplant Recipients Circulation, January 17, 2006; 113(2): 252 - 257. [Abstract] [Full Text] [PDF]
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