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.