Background-This study tested the hypothesis that sympathetic nerve activity is increased in pulmonary artery hypertension (PAH), a rare disease of poor prognosis and incompletely understood pathophysiology. We subsequently explored whether chemoreflex activation contributes to sympathoexcitation in PAH. Methods and Results-We measured muscle sympathetic nerve activity (MSNA) by microneurography, heart rate (HR), and arterial oxygen saturation (SaO 2 ) in 17 patients with PAH and 12 control subjects. The patients also underwent cardiac echography, right heart catheterization, and a 6-minute walk test with dyspnea scoring. Circulating catecholamines were determined in 8 of the patients. Chemoreflex deactivation by 100% O 2 was assessed in 14 patients with the use of a randomized, double-blind, placebo-controlled, crossover study design. Sympathetic hyperactivity in PAH is partially chemoreflex mediated and may be related to disease severity.

Abstract-Sympathetic overactivity is implicated in the increased cardiovascular risk of cigarette smokers. Excitatory nicotinic receptors are present on peripheral chemoreceptor cells. Chemoreceptors located in the carotid and aortic bodies increase ventilation (Ve), blood pressure (BP), heart rate (HR), and sympathetic nerve activity to muscle circulation (MSNA) in response to hypoxia. We tested the hypothesis that nicotine replacement therapy (NRT) increases MSNA and chemoreceptor sensitivity to hypoxia. Sixteen young healthy smokers were included in the study (8 women). After a randomized and blinded sublingual administration of a 4-mg tablet of nicotine or placebo, we measured minute Ve, HR, mean BP, and MSNA during normoxia and 5 minutes of isocapnic hypoxia. Maximal voluntary end-expiratory apneas were performed at baseline and at the end of the fifth minute of hypoxia. Nicotine increased HR by 7Ϯ3 bpm, mean BP by 5Ϯ2 mm Hg, and MSNA by 4Ϯ1 bursts/min, whereas subjects breathed room air (all PϽ0.05). During hypoxia, nicotine also raised HR by 8Ϯ2 bpm, mean BP by 2Ϯ1 mm Hg, and MSNA by 7Ϯ2 bursts/min (all PϽ0.05). Nicotine increased MSNA during the apneas performed in normoxia and hypoxia (PϽ0.05). Nicotine also raised the product of systolic BP and HR, a marker of cardiac oxygen consumption, during normoxia, hypoxia, and the apneas (PϽ0.05). Ve, apnea duration, and O 2 saturation during hypoxia and the apneas remained unaffected. In conclusion, sympathoexcitatory effects of NRT are not because of an increased chemoreflex sensitivity to hypoxia. NRT increases myocardial oxygen consumption in periods of reduced oxygen availability.

Aging reduces sympathetic reactivity to isometric handgrip, but does not prevent the metaboreceptors to remain the main determinant of sympathetic activation during exercise in hypoxia.

Houssière, Anne, Boutaina Najem, Nicolas Cuylits, Sophie Cuypers, Robert Naeije, and Philippe van de Borne. Hyperoxia enhances metaboreflex sensitivity during static exercise in humans. Am J Physiol Heart Circ Physiol 291: H210 -H215, 2006; doi:10.1152/ajpheart.01168.2005.-Peripheral chemoreflex inhibition with hyperoxia decreases sympathetic nerve traffic to muscle circulation [muscle sympathetic nerve activity (MSNA)]. Hyperoxia also decreases lactate production during exercise. However, hyperoxia markedly increases the activation of sensory endings in skeletal muscle in animal studies. We tested the hypothesis that hyperoxia increases the MSNA and mean blood pressure (MBP) responses to isometric exercise. The effects of breathing 21% and 100% oxygen at rest and during isometric handgrip at 30% of maximal voluntary contraction on MSNA, heart rate (HR), MBP, blood lactate (BL), and arterial O 2 saturation (SaO 2 ) were determined in 12 healthy men. The isometric handgrips were followed by 3 min of postexercise circulatory arrest (PE-CA) to allow metaboreflex activation in the absence of other reflex mechanisms. Hyperoxia lowered resting MSNA, HR, MBP, and BL but increased Sa O 2 compared with normoxia (all P Ͻ 0.05). MSNA and MBP increased more when exercise was performed in hyperoxia than in normoxia (MSNA: hyperoxic exercise, 255 Ϯ 100% vs. normoxic exercise, 211 Ϯ 80%, P ϭ 0.04; and MBP: hyperoxic exercise, 33 Ϯ 9 mmHg vs. normoxic exercise, 26 Ϯ 10 mmHg, P ϭ 0.03). During PE-CA, MSNA and MBP remained elevated (both P Ͻ 0.05) and to a larger extent during hyperoxia than normoxia (P Ͻ 0.05). Hyperoxia enhances the sympathetic and blood pressure (BP) reactivity to metaboreflex activation. This is due to an increase in metaboreflex sensitivity by hyperoxia that overrules the sympathoinhibitory and BP lowering effects of chemoreflex inhibition. This occurs despite a reduced lactic acid production.handgrip; muscle sympathetic nerve activity; metaboreceptors; chemoreceptors MUSCLE METABORECEPTORS regulate sympathetic activation during exercise (19,25). This reflex is activated by metabolites released from exercising skeletal muscle. Several substances, such as lactic acid, phosphate, K ϩ , H ϩ , adenosine, prostaglandins, and bradykinin, are now identified as stimulators of this pressor reflex (35,37,40).These metabolites stimulate group III and IV chemosensitive afferents in the working muscles (32). These afferent fibers can also be activated by injection of lactic acid or a hyperosmolar solution of potassium chloride, and their activity is modulated by endogenous nitric oxide in resting and contracting muscle (3,6,11,13,16). This activation in both nonexercising and exercising limbs (32) provokes a rise in cardiac output and vasoconstriction of the nonischemic vascular beds. As a result, blood pressure (BP) and perfusion pressure increase and correct blood flow deficits during exercise (32,35,40,43).There are several reasons to believe that hyperoxia may affect sympathetic regulation during exercise.First, hyp...

To investigate the effects of muscle metaboreceptor activation during hypoxic static exercise, we recorded muscle sympathetic nerve activity (MSNA), heart rate, blood pressure, ventilation, and blood lactate in 13 healthy subjects (22 +/- 2 yr) during 3 min of three randomized interventions: isocapnic hypoxia (10% O(2)) (chemoreflex activation), isometric handgrip exercise in normoxia (metaboreflex activation), and isometric handgrip exercise during isocapnic hypoxia (concomitant metaboreflex and chemoreflex activation). Each intervention was followed by a forearm circulatory arrest to allow persistent metaboreflex activation in the absence of exercise and chemoreflex activation. Handgrip increased blood pressure, MSNA, heart rate, ventilation, and lactate (all P < 0.001). Hypoxia without handgrip increased MSNA, heart rate, and ventilation (all P < 0.001), but it did not change blood pressure and lactate. Handgrip enhanced blood pressure, heart rate, MSNA, and ventilation responses to hypoxia (all P < 0.05). During circulatory arrest after handgrip in hypoxia, heart rate returned promptly to baseline values, whereas ventilation decreased but remained elevated (P < 0.05). In contrast, MSNA, blood pressure, and lactate returned to baseline values during circulatory arrest after hypoxia without exercise but remained markedly increased after handgrip in hypoxia (P < 0.05). We conclude that metaboreceptors and chemoreceptors exert differential effects on the cardiorespiratory and sympathetic responses during exercise in hypoxia.

Cardiac resynchronization therapy (CRT) decreases muscle sympathetic nerve activity (MSNA) in patients with severe congestive heart failure (CHF) and cardiac asynchrony. Whether this affects equally patients who clinically respond or not to CRT is unknown. We tested the hypothesis that the favorable effects of CRT on MSNA disappear on CRT interruption only in those who respond to CRT. Twenty-three consecutive CHF patients participated in the study, among whom 16 presented a symptomatic improvement by one or more New York Heart Association (NYHA) functional classes 15 +/- 5 mo after CRT (responders), and seven had not improved after 12 +/- 4 mo of CRT (nonresponders). MSNA and echocardiographic recordings were obtained in random order during atrio-right ventricular pacing (ARV), without stimulation in patients who were not pacemaker dependent (OFF, n = 17), and during atrio-biventricular pacing (BIV). Responders had a longer 6-min walking distance, a lower NYHA class and brain natriuretic peptide levels, and a better quality of life than did nonresponders (all P < 0.05). MSNA increased by 25 +/- 7% in the responders, whereas it remained unchanged in the nonresponders, when shifting from the BIV mode to a nonsynchronous condition (ARV and OFF modes) (P < 0.01). Cardiac output decreased by 0.7 +/- 0.2 l/min in the responders but did not change when shifting from the BIV mode to the nonsynchronous pacing mode in the nonresponders (P < 0.01). In conclusion, reversible sympathoinhibition is a marker of the clinical response to CRT.

Abstract-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 (51Ϯ16 versus 37Ϯ14 versus 39Ϯ12 burst/min, respectively; PϽ0.05). Breathing 100% oxygen, in comparison with 21% oxygen, reduced sympathetic activity (Ϫ4Ϯ4 versus Ϫ1Ϯ2 burst/min, PϽ0.01; 85Ϯ9 versus101Ϯ8% of amplitude at baseline, PϽ0.001) and mean blood pressure (Ϫ4Ϯ5 versus ϩ3Ϯ6 mm Hg; PϽ0.05) in heart transplant recipients, decreased sympathetic activity (Ϫ4Ϯ4 versus 0Ϯ3 burst/min, PϽ0.05; 90Ϯ16 versus101Ϯ9% of amplitude at baseline, PϽ0.05) in patients with essential hypertension, but did not reduce sympathetic activity (2Ϯ4 versus 3Ϯ3 burst/min, PϭNS; 95Ϯ11 versus 95Ϯ13% of amplitude at baseline, PϭNS) in control subjects. The sympathetic response to hyperoxia was more marked in heart transplant recipients than in controls (85Ϯ9 versus 95Ϯ11% of baseline amplitude; PϽ0.05). The decrease in sympathetic activity was most evident in patients with the longest time after heart transplantation (rϭϪ0.75, PϽ0.01).In conclusion, tonic chemoreflex activation increases resting muscle sympathetic nerve activity and favors blood pressure elevation after heart transplantation. Key Words: chemoreceptors Ⅲ sympathetic nervous system Ⅲ transplantation C ongestive 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 therapy 3 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 hypertensive 10 and enhanced peripheral chemoreflex sensitivity has been observed in hypertensive humans and in animal m...

Abstract-We tested the hypothesis that lower blood pressure and increased vasodilatation reported in sickle cell disease (SCD) patients with hemoglobin SS genotype (SS) are translated by lower arterial stiffness determined by pulse wave velocity (PWV) and wave reflections assessed by augmentation index (AI). We enrolled 20 SS (8 females; 12 male) patients closely matched for age, gender, height, and body mass index to 20 subjects with hemoglobin AA genotype (AA). Carotid-femoral PWV (PWV CF ) and carotid-radial PWV (PWV CR ) were recorded with the Complior device. Aortic AI was derived from pressure wave analysis (SphygmocoR). PWV CF and PWV CR were lower in SS than in AA (4.5Ϯ0.7 m/s versus 6.9Ϯ0.9 m/s, PϽ0.0001 and 6.6Ϯ1.2 m/s versus 9.5Ϯ1.4 m/s, PϽ0.0001, respectively). AI was lower in SS than in AA (2Ϯ14% versus 11Ϯ8%, Pϭ0.02). Multivariate analysis revealed that both PWV CF and PWV CR were negatively associated with hemoglobin SS type and positively related to mean arterial pressure (MAP), whereas AI was positively associated with MAP and total cholesterol (all PϽ0.0001). Multivariate analysis restricted to SS indicated a positive association between PWV CF and PWV CR with age but a negative association with MAP (R 2 ϭ0.57 and 0.51, respectively, both PϽ0.001), whereas MAP and heart rate were independently associated with AI (R 2 ϭ0.65, PϽ0.001). This study provides the first evidence that SCD is associated with both lower arterial stiffness and wave reflections. SS patients have a paradoxical negative association between PWV and MAP, suggesting that low MAP does not protect them against arterial stiffness impairment.