N-Acetylcysteine reduces hyperacute intermittent hypoxia-induced sympathoexcitation in human subjects.

NEW FINDINGS: What is the central question of this study? This study evaluated the following central question: does N-acetylcysteine (N-AC), an antioxidant that readily penetrates the blood-brain barrier, have the capability to reduce the increase in sympathetic nerve activity observed during hyperacute intermittent hypoxia? What is the main finding and its importance? We demonstrate that N-AC decreases muscle sympathetic nerve activity in response to hyperacute intermittent hypoxia versus placebo control. This finding suggests that antioxidants, such as N-AC, have therapeutic potential in obstructive sleep apnoea. This investigation tested the following hypotheses: that (i) N-acetylcysteine (N-AC) attenuates hyperacute intermittent hypoxia-induced sympathoexcitation, (ii) without elevating superoxide measured in peripheral venous blood. Twenty-eight healthy human subjects were recruited to the study. One hour before experimentation, each subject randomly ingested either 70 mg kg(-1) of N-AC (n = 16) or vehicle placebo (n = 12). Three-lead ECG and arterial blood pressure, muscle sympathetic nerve activity (n = 17) and whole-blood superoxide concentration (using electron paramagnetic resonance spectroscopy; n = 12) were measured. Subjects underwent a 20 min hyperacute intermittent hypoxia training (hAIHT) protocol that consisted of cyclical end-expiratory apnoeas with 100% nitrogen. N-AC decreased muscle sympathetic nerve activity after hAIHT compared with placebo (P < 0.02). However, N-AC did not alter superoxide concentrations in venous blood compared with placebo (P > 0.05). Moreover, hAIHT did not increase superoxide concentrations in the peripheral circulation as measured by electron paramagnetic resonance (P > 0.05). Based on these findings, we contend that (i) hAIHT and (ii) the actions of N-AC in hAIHT are primarily mediated centrally rather than peripherally, although central measurements of reactive oxygen species are difficult to obtain in human subjects, thus making this assertion difficult to verify. This investigation suggests the possibility of developing a pharmaceutical therapy to inhibit the sympathoexcitation associated with obstructive sleep apnoea.

α1-Adrenergic receptor control of the cerebral vasculature in humans at rest and during exercise.

We tested the hypothesis that pharmacological blockade of α(1)-adrenoreceptors (by prazosin), at rest and during steady-state dynamic exercise, would impair cerebral autoregulation and result in cerebral vasodilatation in healthy humans. In 10 subjects, beat-to-beat mean arterial pressure and mean middle cerebral artery blood velocity were determined at rest and during low (Ex90) and moderate workload (Ex130) on an upright bicycle ergometer without and with prazosin. Plasma noradrenaline concentrations increased significantly from rest to Ex130 during control conditions (from 1.8 ± 0.2 to 3.2 ± 0.3 pmol (ml plasma)(-1)). In the control conditions, the transfer function gain between mean arterial pressure and mean middle cerebral artery blood velocity in the low-frequency range was decreased at Ex90 (P = 0.035) and Ex130 (P = 0.027) from rest. A significant increase in critical closing pressure (CCP) was also observed in the control conditions from rest to Ex90 to Ex130 (from 18 ± 3 to 24 ± 4 to 31 ± 4 mmHg). An average of 74 ± 2% blockade of blood pressure response was achieved with oral prazosin. Following blockade, plasma noradrenaline concentrations further increased at rest and during Ex130 from the control value (from 2.6 ± 0.3 to 4.4 ± 0.5 pmol (ml plasma)(-1)). Prazosin also resulted in an increase in low-frequency gain (P < 0.003) compared with the control conditions. Prazosin blockade abolished the increases in CCP during Ex130 and increased the cerebrovascular conductance index (P = 0.018). These data indicate that in the control conditions a strengthening of cerebral autoregulation occurred with moderate dynamic exercise that is associated with an increase in CCP as a result of the exercise-mediated augmentation of sympathetic activity. Given that α(1)-adrenergic receptor blockade attenuated the increase in dynamic cerebral autoregulation and CCP, we conclude that increases in sympathetic activity have a role in establishing cerebral vascular tone in humans.

Resetting of the sympathetic baroreflex is associated with the onset of hypertension during chronic intermittent hypoxia.

Chronic intermittent hypoxia (CIH) is a model of arterial hypoxemia that accompanies sleep apnea and increases resting arterial pressure (AP). We examined the effects of 7 days of exposure to CIH on arterial baroreflex control of renal sympathetic nerve activity (RSNA) and heart rate (HR) in rats. Sprague-Dawley rats (15±2 weeks old) were exposed to CIH (9% oxygen for 3 min every 10 min, 8 h per day) for 7 days (n=16) while control rats (n=18) were maintained in normoxia. Baroreflex regulation of RSNA and HR were estimated in Inactin anesthetized and artificially ventilated rats during infusions of phenylephrine and nitroprusside to manipulate AP. After exposure to CIH, resting mean AP was higher in CIH than that in control group (115±7 vs. 105±7, P<0.001). Resting HR did not differ between the two groups. Exposure to CIH shifted the AP-RSNA relationship rightward (approximately 10 mm Hg, P<0.01). CIH did not alter maximum gain of the baroreflex control of RSNA (-2.6±0.6 vs. -2.5±0.6 arbitrary units (a.u.)/mm Hg) and HR (-1.8±0.6 vs. -1.8±0.7 bpm/mm Hg, CIH vs. control). In addition, cardiac spontaneous baroreflex sensitivity in conscious rats (n=8) also did not change during exposure to CIH. These results indicate that resetting of the sympathetic baroreflex control, rather than an impairment of its sensitivity, is associated with an onset of hypertension induced by CIH.

Carotid baroreflex responsiveness is impaired in normotensive African American men.

There are important differences in autonomic function and cardiovascular responsiveness between African Americans (AA) and Caucasian Americans (CA). This study tested the hypothesis that carotid baroreflex (CBR) responsiveness is impaired in normotensive AA compared with normotensive CA at rest. CBR control of heart rate (HR) and mean arterial blood pressure (MAP) was assessed in 30 nonhypertensive male subjects (15 AA; 15 CA; age 18-33 yr) with 5-s periods of neck pressure (NP; simulated hypotension) and neck suction (NS; simulated hypertension) ranging from +45 to -80 Torr during rest. Carotid-cardiac stimulus-response curves revealed a significantly lower minimum HR response in the CA compared with AA (40.8 ± 2.4 vs. 49.8 ± 2.9 beats/min, respectively; P < 0.05). In addition, the magnitude of the mean HR response to all trials of NS (-20, -40, -60, and -80 Torr) was attenuated in the AA group (AA, -10.1 ± 1.7 vs. CA, -14.9 ± 2.2 beats/min; P < 0.05), while no significant differences were found in the magnitude of the mean HR response to NP (+15, +30, and +45 Torr) between racial groups. There were no significant differences in the carotid-vasomotor stimulus-response curves between racial groups. Also, while no racial differences were found in the magnitude of the mean MAP response to all trials of NS, the magnitude of the mean MAP response to all trials of NP was attenuated in the AA group (AA, 7.2 ± 1.3 vs. CA, 9.3 ± 1.1 mmHg; P < 0.05). Together, these findings support inherent differences in short-term blood pressure regulation between racial groups that exhibit different relative risk for the development of hypertension.

The effects of aerobic fitness and beta1-adrenergic receptor blockade on cardiac work during dynamic exercise.

The purpose of this investigation was to determine whether cardiovascular adaptations characteristic of long-term endurance exercise compensate more effectively during cardioselective beta(1)-adrenergic receptor blockade-induced reductions in sympathoadrenergic-stimulated contractility. Endurance-trained (ET) athletes (n = 8) and average-trained (AT; n = 8) subjects performed submaximal cycling exercise at moderate [45% maximum oxygen uptake (Vo(2max))] and heavy (70% Vo(2max)) workloads, with and without metoprolol. Cardiac output (Qc), heart rate (HR), and systolic blood pressure were recorded at rest and during exercise. Cardiac work was calculated from the triple product of HR, stroke volume, and systolic blood pressure, and myocardial efficiency is represented as cardiac work for a given total body oxygen consumption. Metoprolol reduced Qc at 45% Vo(2max) (P = 0.004) and 70% Vo(2max) (P = 0.022) in ET subjects, but did not alter Qc in the AT subjects. In ET subjects at 45% Vo(2max), metoprolol-induced reductions in Qc were a result of decreases in HR (P < 0.05) and the absence of a compensatory increase in stroke volume (P > 0.05). The cardiac work and calculated cardiac efficiency were reduced with metoprolol in ET subjects at both exercise intensities and in the AT subjects during the high-intensity workload (P < 0.01). The cardiac work and the calculated cardiac efficiency were not affected by metoprolol in the AT subjects during the 45% Vo(2max) exercise. Therefore, in AT subjects, beta-blockade reduced the amount of pressure generation necessary to produce the same amount of work during moderate-intensity exercise. In patients with heart disease receiving metoprolol, a decrease in the generation of cardiac pressure necessary to perform a given amount of work during mild-to-moderate exercise would prove to be beneficial.

Autonomic neural control of the cerebral vasculature: acute hypotension.

BACKGROUND AND PURPOSE: The effect of antihypertensive drugs on autonomic neural control of the cerebral circulation remains unclear. This study was designed to compare middle cerebral artery mean blood velocity responses to acute hypotension with and without alpha(1)-adrenoreceptor blockade (Prazosin) in young, healthy humans. METHODS: Acute hypotension was induced nonpharmacologically in 6 healthy subjects (mean+/-SE; 28+/-2 years) by releasing bilateral thigh cuffs after 9 minutes of suprasystolic resting ischemia before and after an oral dose of Prazosin (1 mg/20 kg body weight). RESULTS: Prazosin had no effect on thigh cuff release-induced reductions in mean arterial pressure and middle cerebral artery mean blood velocity. However, Prazosin attenuated the amount of peripheral vasoconstriction through the arterial baroreflex as evidenced by a slower return of mean arterial pressure to baseline (P=0.03). Immediately after cuff release, cerebral vascular conductance index increased through cerebral autoregulation and returned to resting values as a result of an increased perfusion pressure mediated through arterial baroreflex mechanisms. The rate of regulation, an index of cerebral autoregulation, was attenuated with Prazosin (control versus Prazosin; rate of regulation=0.204+/-0.020 versus 0.006+/-0.053/s, P=0.037). In addition, as mean arterial pressure was returning to resting values, the rate of change in cerebral vascular conductance index was decreased with Prazosin (0.005+/-0.006/s) compared with control (0.025+/-0.005/s; P=0.010). CONCLUSIONS: These data suggest that during recovery from acute hypotension, decreases in cerebral vascular conductance index were mediated by increases in arterial blood pressure and sympathetically mediated cerebral vasoconstriction.

Effects of changes in central blood volume on carotid-vasomotor baroreflex sensitivity at rest and during exercise.

The purpose of this investigation was to examine whether the effect of changes in central blood volume on carotid-vasomotor baroreflex sensitivity at rest was the same during exercise. Eight men (means +/- SE: age 26 +/- 1 yr; height 180 +/- 3 cm; weight 86 +/- 6 kg) participated in the present study. Sixteen Torr of lower body negative pressure (LBNP) were applied to decrease central venous pressure (CVP) at rest and during steady-state leg cycling at 50% peak O2 uptake (104 +/- 20 W). Subsequently, infusions of 25% human serum albumin solution were administered to increase CVP at rest and during exercise. During all protocols, heart rate, arterial blood pressure, and CVP were recorded continuously. At each stage of LBNP or albumin infusion, the maximal gain (G(max)) of the carotid-vasomotor baroreflex function curve was measured using the neck pressure and neck suction technique. LBNP reduced CVP and increased the G(max) of the carotid-vasomotor baroreflex function curve at rest (+63 +/- 25%, P = 0.006) and during exercise (+69 +/- 19%, P = 0.002). In contrast to the LBNP, increases in CVP resulted in the G(max) of the carotid-vasomotor baroreflex function curve being decreased at rest -8 +/- 4% and during exercise -18 +/- 5% (P > 0.05). These findings indicate that the relationship between CVP and carotid-vasomotor baroreflex sensitivity was nonlinear at rest and during exercise and suggests a saturation load of the cardiopulmonary baroreceptors at which carotid-vasomotor baroreflex sensitivity remains unchanged.

Cardiopulmonary baroreflex is reset during dynamic exercise.

The purpose of this study was to examine the hypothesis that the operating point of the cardiopulmonary baroreflex resets to the higher cardiac filling pressure of exercise associated with the increased cardiac filling volumes. Eight men (age 26 +/- 1 yr; height 180 +/- 3 cm; weight 86 +/- 6 kg; means +/- SE) participated in the present study. Lower body negative pressure (LBNP) was applied at 8 and 16 Torr to decrease central venous pressure (CVP) at rest and during steady-state leg cycling at 50% peak oxygen uptake (104 +/- 20 W). Subsequently, two discrete infusions of 25% human serum albumin solution were administered until CVP was increased by 1.8 +/- 0.6 and 2.4 +/- 0.4 mmHg at rest and 2.9 +/- 0.9 and 4.6 +/- 0.9 mmHg during exercise. During all protocols, heart rate, arterial blood pressure, and CVP were recorded continuously. At each stage of LBNP or albumin infusion, forearm blood flow and cardiac output were measured. During exercise, forearm vascular conductance increased from 7.5 +/- 0.5 to 8.7 +/- 0.6 U (P = 0.024) and total systemic vascular conductance from 7.2 +/- 0.2 to 13.5 +/- 0.9 l.min(-1).mmHg(-1) (P < 0.001). However, there was no significant difference in the responses of both forearm vascular conductance and total systemic vascular conductance to LBNP and the infusion of albumin between rest and exercise. These data indicate that the cardiopulmonary baroreflex had been reset during exercise to the new operating point associated with the exercise-induced change in cardiac filling volume.

The effect of changes in cardiac output on middle cerebral artery mean blood velocity at rest and during exercise.

We examined the relationship between changes in cardiac output and middle cerebral artery mean blood velocity (MCA V(mean)) in seven healthy volunteer men at rest and during 50% maximal oxygen uptake steady-state submaximal cycling exercise. Reductions in were accomplished using lower body negative pressure (LBNP), while increases in were accomplished using infusions of 25% human serum albumin. Heart rate (HR), arterial blood pressure and MCA V(mean) were continuously recorded. At each stage of LBNP and albumin infusion was measured using an acetylene rebreathing technique. Arterial blood samples were analysed for partial pressure of carbon dioxide tension (P(a,CO2). During exercise HR and were increased above rest (P < 0.001), while neither MCA V(mean) nor P(a,CO2) was altered (P > 0.05). The MCA V(mean) and were linearly related at rest (P < 0.001) and during exercise (P = 0.035). The slope of the regression relationship between MCA V(mean) and at rest was greater (P = 0.035) than during exercise. In addition, the phase and gain between MCA V(mean) and mean arterial pressure in the low frequency range were not altered from rest to exercise indicating that the cerebral autoregulation was maintained. These data suggest that the associated with the changes in central blood volume influence the MCA V(mean) at rest and during exercise and its regulation is independent of cerebral autoregulation. It appears that the exercise induced sympathoexcitation and the change in the distribution of between the cerebral and the systemic circulation modifies the relationship between MCA V(mean) and .