Age-dependent sympathetic neural responses to ß1 selective beta-blockade in untreated hypertension-related tachycardia.

BACKGROUND: Elevated heart rate (HR) increases cardiovascular morbidity and mortality in hypertension. The impact of beta-blockers on patient prognosis in hypertension is controversial. This study examined the age-related effects of betaxolol on HR, muscle sympathetic nerve activity (MSNA), blood pressure (BP) and sympathovagal balance in untreated males with hypertension and tachycardia. METHODS: Ten young (age 26 ± 1 years) and seven older (age 50 ± 4 years) males underwent measurement of BP, HR, HR variability (Poincare plot) and MSNA before and after 8 weeks treatment with betaxolol at the initial starting dose of 10 mg/day, which was increased to 20 mg/day once daily after 4 weeks in all subjects. RESULTS: In younger subjects, betaxolol decreased systolic BP (-13 ± 4 mm Hg, p = .01) and HR (-29 ± 4 bpm, p < .001) but not MSNA (3 ± 3 burst/min., p = 0.47) after 8 weeks. In older subjects a pronounced reduction in BP (-27 ± 7, p = .007) was accompanied by a significant decrease in MSNA (-13 ± 5 burst/min., p < .05) and HR (-17 ± 4 bpm, p = .002). SD1/SD2 ratio of Poincare plot increased in younger (0.36 ± 0.03 vs 0.51 ± 0.05, p = .004), but not in older (0.43 ± 0.08 vs 0.54 ± 0.12, p = .50) subjects. CONCLUSION: Autonomic neural responses to betaxolol are age-dependent in hypertension-related tachycardia. Betaxolol reduces sympathetic drive to the heart, but not to the peripheral vessels confirming the contribution of augmented cardiac sympathetic activity to disease pathophysiology in younger adults. In older hypertensives, the sympathovagal balance is not influenced by betaxolol. The paradoxical reduction in MSNA despite lowering of BP and HR in older patients may suggest age-related functional decrements in autonomic control and/or inhibitory effects of betaxolol on the central nervous system.

Longitudinal tracking of muscle sympathetic nerve activity and its relationship with blood pressure in subjects with prehypertension.

Prehypertension is associated with increased cardiovascular events. While the "tracking phenomenon" is an important longitudinal characteristic of blood pressure (BP), changes in muscle sympathetic nerve activity (MSNA) over time remain unclear. This study tested the hypothesis that MSNA tracking contributes to BP trends in prehypertension. BP and MSNA were assessed in 13 prehypertensive males at rest, during hand grip and mental stressors at baseline and after 8 years. Baseline office BP averaged 127 ± 2/81 ± 2 mmHg and MSNA 24 ± 4 bursts/min. BP increased by 7 ± 2/5 ± 2 mmHg (P < 0.01) and MSNA by 11 ± 2 bursts/min (P < 0.001) at follow-up. SBP and DBP were interrelated at baseline (r = 0.65, P = 0.02) and at follow-up (r = 0.78, P = 0.002). MSNA tracking (r = 0.82; P < 0.001) was similar to BP. MSNA was strongly related to DBP at baseline (r = 0.73; P < 0.01) and follow-up (r = 0.64; P = 0.01), more so than SBP. BMI increased (P < 0.001) at follow-up but was unrelated to BP or MSNA. Despite comparable pressor and cardiac increases to handgrip and mental stressors, sympathetic responses were blunted, more pronounced to isometric test (P < 0.006) at follow-up. In conclusion, the trend in MSNA corresponds with BP changes over time suggesting that tonic sympathetic activation may contribute to time-related increase in resting BP and the development of sustained hypertension in prehypertension.

High-normal blood pressure is associated with increased resting sympathetic activity but normal responses to stress tests.

OBJECTIVE: High-normal blood pressure (BP) increases the risk of cardiovascular (CV) disease. The mechanisms underlying this increased risk are not clear. Sympathetic activation appears to be a potential mechanism linking high-normal BP to CV disease. This study examined whether high-normal BP compared with optimal BP is linked to sympathoexcitation at rest and/or during laboratory stressors. METHODS: Heart rate (HR), BP and muscle sympathetic nerve activity (MSNA) were obtained at rest and during stress tests (sustained handgrip and mental stress) in 18 subjects (15 males and three females) with high-normal BP (systolic BP of 130-139 mmHg, diastolic BP of 85-89 mmHg, or both) and in 12 subjects (10 males and two females) with optimal BP (< 120/80 mmHg) matched for age (34 ± 3 years in both groups) and body mass index (25 ± 2 kg/m(2) in both groups). RESULTS: Despite the higher resting BP levels, MSNA was higher in subjects with high-normal BP than in the optimal BP group (26 ± 3 vs 18 ± 2 bursts/min, p< 0.05). During sustained handgrip, MSNA increased by 37 ± 14% in high-normal BP group compared with an increase of 49 ± 15% in optimal BP group (p = 0.55). Changes during mental stress were 50 ± 28% and 37 ± 12%, respectively (p = 0.73). There were no significant differences in SBP responses to handgrip and mental stress between the high-normal and optimal BP groups. Baseline HR and chronotropic responses to stress tests were comparable between the two groups. CONCLUSION: In comparison with optimal BP, high-normal BP is associated with increased resting MSNA, but normal neural and circulatory responses to stress tests. These findings suggest that tonic activation of the sympathetic nervous system may precede overt arterial hypertension and contribute to an excess risk of CV disease in subjects with high-normal BP.

Smoking is associated with chronic sympathetic activation in hypertension.

OBJECTIVE: Previous studies have shown that smoking contributes importantly to short-term modulation of sympathetic nerve traffic. However, effect of smoking status on resting muscle sympathetic nerve activity (MSNA) in hypertension is unknown. Therefore, we tested the hypothesis that smoking is associated with chronic sympathetic activation in patients with essential hypertension. METHODS: We measured MSNA, heart rate (HR) and blood pressure during undisturbed supine rest and in 30 hypertensive smokers (22 males, age 38+/-4 years, body mass index, BMI 27+/-1 kg/m(2), mean+/-SEM). These measurements were compared with those obtained 38 non-smoking hypertensive patients matched for gender, age and BMI. All hypertensives underwent 24-h ambulatory blood pressure monitoring. Patients were newly diagnosed, never treated for hypertension and were free of any other known diseases. RESULTS: In comparison with non-smokers, smokers had smaller office-daytime systolic blood pressure difference (6+/-2 vs 15+/-3 mmHg, respectively; p<0.01). Despite similar resting values, HR in smokers was greater than in non-smokers during both daytime (86+/-3 vs 77+/-2 beats/min, respectively; p< 0.001) and night-time (73+/-3 vs 66+/-2 beats/min, respectively; p<0.01). MSNA was elevated in smokers (36+/-3 bursts/min) compared with non-smokers (28+/-3 bursts/min; p<0.01). Similar results were obtained when MSNA was expressed as bursts/100 heart beats. Multiple linear regression analysis revealed that only age and smoking status were linked independently to MSNA (R(2)=0.42, p< 0.001). CONCLUSIONS: In patients with essential hypertension, smoking is independently associated with chronic increase in MSNA. These findings may have implications for our understanding of the mechanisms linking smoking to cardiovascular events.

Tonic chemoreflex activation contributes to the elevated muscle sympathetic nerve activity in patients with chronic renal failure.

OBJECTIVE: Sympathetic activation may contribute to both cardiovascular morbidity and the progression of chronic kidney disease. The role of the chemoreceptors in determining sympathetic nerve discharge in patients with chronic renal failure (CRF) is unknown. We tested the hypothesis that tonic activation of excitatory chemoreceptor afferents contributes to the elevated sympathetic activity in patients with CRF. METHODS: Utilizing a double-blind, randomized, vehicle-controlled design, we examined the effects of chemoreflex deactivation on muscle sympathetic nerve activity (MSNA). We compared effects of breathing 100% oxygen for 15 min with effects of breathing room air for 15 min in 12 stable patients with CRF and in 12 control individuals with similar age, gender, blood pressure and body mass index. RESULTS: The baseline MSNA was elevated significantly in the patients with CRF as compared with the control individuals (50 +/- 2 vs 42 +/- 2 bursts/min; P < 0.05). Reductions in systolic blood pressure and pulse pressure in response to the administration of 100% oxygen were significantly different from those observed during administration of room air in patients with CRF. In patients with CRF, MSNA decreased by 29 +/- 7% (P < 0.01) during hyperoxia but did not change during administration of room air (5 +/- 6%; P = NS). By contrast, neither 100% oxygen or room air changed any measures in control individuals. CONCLUSIONS: Tonic activation of excitatory chemoreflex afferents contributes to increased efferent sympathetic activity to muscle circulation and to blood pressure control in patients with CRF. These findings may have important implications for understanding mechanisms underlying the link between CRF and cardiovascular disease.

Acute hypoxia diminishes the relationship between blood pressure and subarachnoid space width oscillations at the human cardiac frequency.

BACKGROUND: Acute hypoxia exerts strong effects on the cardiovascular system. Heart-generated pulsatile cerebrospinal fluid motion is recognised as a key factor ensuring brain homeostasis. We aimed to assess changes in heart-generated coupling between blood pressure (BP) and subarachnoid space width (SAS) oscillations during hypoxic exposure. METHODS: Twenty participants were subjected to a controlled decrease in oxygen saturation (SaO2 = 80%) for five minutes. BP and heart rate (HR) were measured using continuous finger-pulse photoplethysmography, oxyhaemoglobin saturation with an ear-clip sensor, end-tidal CO2 with a gas analyser, and cerebral blood flow velocity (CBFV), pulsatility and resistive indices with Doppler ultrasound. Changes in SAS were recorded with a recently-developed method called near-infrared transillumination/backscattering sounding. Wavelet transform analysis was used to assess the relationship between BP and SAS oscillations. RESULTS: Gradual increases in systolic, diastolic BP and HR were observed immediately after the initiation of hypoxic challenge (at fifth minute +20.1%, +10.2%, +16.5% vs. baseline, respectively; all P<0.01), whereas SAS remained intact (P = NS). Concurrently, the CBFV was stable throughout the procedure, with the only increase observed in the last two minutes of deoxygenation (at the fifth minute +6.8% vs. baseline, P<0.05). The cardiac contribution to the relationship between BP and SAS oscillations diminished immediately after exposure to hypoxia (at the fifth minute, right hemisphere -27.7% and left hemisphere -26.3% vs. baseline; both P<0.05). Wavelet phase coherence did not change throughout the experiment (P = NS). CONCLUSIONS: Cerebral haemodynamics seem to be relatively stable during short exposure to normobaric hypoxia. Hypoxia attenuates heart-generated BP SAS coupling.

Sympathetic neural responses to smoking are age dependent.

OBJECTIVE: Smoking is an important risk factor for cardiovascular disease. Sympathetic responses to cigarette smoking may be implicated in the link between smoking and cardiovascular disease. We tested the hypothesis that the sympathetic neural responses to smoking are age dependent. METHODS: We examined the effects of cigarette smoking and sham smoking on muscle sympathetic nerve activity, blood pressure and heart rate in 14 normotensive middle-aged (49 +/- 4 years) and 12 young (29 +/- 4 years) habitual smokers matched for body mass index (25 +/- 2 kg/m2 in both groups). RESULTS: Sham smoking had no significant effect on sympathetic drive, blood pressure or heart rate in either group. Cigarette smoking increased heart rate in both middle-aged subjects and young subjects. In comparison to younger subjects, middle-aged smokers showed similar smoking-related increases in systolic blood pressure (SBP) [10 +/- 3 versus 12 +/- 2 mmHg, respectively, not significant (NS)]. Smoking decreased sympathetic nerve activity by 28 +/- 12% of baseline values (P < 0.01) in young subjects. However, muscle sympathetic nerve activity did not change significantly after smoking in middle-aged subjects (5 +/- 8%, NS), despite the increased blood pressures, which would be expected to inhibit sympathetic activity. By contrast, in young subjects, the heart rate increase (22 +/- 2 bpm) was greater than that seen in middle-aged subjects (13 +/- 2 bpm, P < 0.01). CONCLUSIONS: The autonomic responses to smoking are age dependent. While blood pressure increases are similar in both groups, young subjects respond to smoking by marked increases in heart rate and suppression of central sympathetic outflow. In middle-aged subjects, the heart rate increase is less marked, but sympathetic vasoconstrictor activity is not suppressed.

[Intrathecal baclofen in severe spasticity due to multiple sclerosis]. / Dokanalowy baklofen w leczeniu ciezkiej spastycznosci w przebiegu stwardnienia rozsianego.

Intrathecal administration of baclofen via programmable pump is a highly effective treatment method in severe spasticity resistant to oral medications. The authors describe a case of severe spasticity with tetraplegia and painful (> 10 a day) muscle spasms in the upper and lower limbs and paraspinal muscles, in a patient with clinically definite diagnosis of multiple sclerosis (MS). The 34-year-old female patient with a 15-year history of MS, suffering from lower limb spasticity with pes equinovarus since 1995, was treated with very good results with botulinum toxin injections of calf muscles (14 sessions of Dysport 1500iu till 2002). In the early 2002 she developed tetraplegia with severe, generalized and intractable spasticity. After 4 months of ineffective polytherapy (with high doses of oral baclofen, tizanidine, gabapentine, clonidine, diazepam) and the patient's enormous sufferings (she could neither sit up nor voluntarily change her position in bed), a programmable baclofen pump (Medtronic) was implanted. As soon as a few days after the surgery she could stand, sit and move voluntarily, her painful spasms disappeared, and her bladder catheter was removed. At a 6-month follow-up the effect was stable--she was able to walk a long distance outdoors with the aid of a crutch. The daily dose of the drug is 500 micrograms. No side effects of complications were noted.

Effects of acute and long-term slow breathing exercise on muscle sympathetic nerve activity in untreated male patients with hypertension.

OBJECTIVE: Acute slow breathing (SLOWB) affects sympathetic cardiovascular regulation, but its long-term effects are unknown. Using device-guided breathing we explored short-term and long-term SLOWB effects on blood pressure (BP), heart rate (HR) and muscle sympathetic nerve activity (MSNA) in essential hypertension. METHODS: We measured BP, HR and MSNA in 10 hypertensive individuals at rest, during laboratory stressors, before and after acute SLOWB, and 8 weeks after SLOWB exercise. Twelve matched hypertensive controls underwent a similar protocol excluding SLOWB intervention. Office and 24-h BP were obtained at baseline and at follow-up. RESULTS: Acute SLOWB had no influence on BP, HR, but decreased MSNA (P < 0.01). BP, HR, MSNA responses to handgrip were comparable before and after acute SLOWB. Acute SLOWB tended to reduce SBP (P = 0.09), HR (P = 0.08), but not MSNA (P = 0.20) responses to mental stress. Long-term SLOWB decreased office SBP (P < 0.001), DBP (P < 0.01), HR (P = 0.004), but not 24-h BP. Resting MSNA was unchanged after long-term SLOWB (P = 0.68). Long-term SLOWB did not influence BP, HR or MSNA responses to handgrip and cold pressor, but reduced SBP (P = 0.03), HR (P = 0.03) responses to mental stress without MSNA changes. In controls BP, HR, MSNA responses to laboratory stressors remained unchanged at baseline and at follow-up. CONCLUSION: In essential hypertension, MSNA is reduced during acute SLOWB, but remains unaltered following long-term SLOWB. Long-term SLOWB reduces office, but not ambulatory BP and HR. SLOWB attenuates cardiovascular response to mental stress, but not physical stressors. These findings may be indicative of beneficial SLOWB effects on stress reduction in essential hypertension.

Relationship between heart rate variability, blood pressure and arterial wall properties during air and oxygen breathing in healthy subjects.

Previous studies reported that normobaric hyperoxia influences heart rate, arterial pressure, cardiac output and systemic vascular resistance, but the mechanisms underlying these changes are still not fully understood. Several factors are considered including degeneration of endothelium-derived nitric oxide by reactive oxygen species, the impact of oxygen-free radicals on tissues and alterations of autonomic nervous system function. Recently, new devices for the detailed non-invasive assessment of large and small arteries have been developed. Therefore, the aim of our study was to assess heart rate variability (HRV) as a potential indicator of autonomic balance and its relation to blood pressure and vascular properties during medical air (MAB) and 100% oxygen breathing (OXB) in healthy volunteers. In 12 healthy subjects we assessed heart rate and blood pressure variability, baroreflex sensitivity, respiratory frequency, common carotid artery diameter and its wall distensibility, as well as changes in the digital artery pulse waveform, stroke index and systemic vascular resistance during MAB and OXB. Mean and systolic blood pressure have increased significantly while digital pulse amplitude and carotid artery diameter were significantly lower during hyperoxia. Heart rate variability measures did not differ during MAB and OXB. However, the correlations between spectral HRV components and those hemodynamic parameters which have changed due to hyperoxia varied substantially during MAB (correlated significantly) and OXB (no significant correlations were noted). Our findings suggest that autonomic nervous system might not be the main mediator of the cardiovascular changes during 100% oxygen breathing in healthy subjects. It seems that the direct vascular responses are initial consequences of hyperoxia and other cardiovascular parameter alterations are secondary to them.

Potentiated sympathetic and hemodynamic responses to alcohol in hypertensive vs. normotensive individuals.

OBJECTIVE: Alcohol is associated with acute increases in muscle sympathetic nerve activity (MSNA) in normal individuals. The effects of alcohol on MSNA in patients with hypertension are unknown. Using a randomized, placebo-controlled study design, we tested the hypothesis that there is a differential effect of acute alcohol consumption on cardiovascular function in hypertensive patients compared with normotensive controls. METHODS: We examined the effects of oral alcohol intake (1.0 g/kg body weight) and placebo on blood pressure, heart rate, and MSNA in 13 newly diagnosed hypertensive patients and 11 normotensive controls. The two sessions were performed in random order, each study on a separate day. RESULTS: Baseline MSNA was significantly elevated in the hypertensive patients as compared to the controls (38 ± 2 vs. 28 ± 2 bursts/min; P < 0.01). Placebo had no significant effect on MSNA, blood pressure, or heart rate in either group. In normotensive individuals, alcohol had no significant effect on blood pressure (SBP increased by 1 ± 4 mmHg). By contrast, SBP increased after alcohol in hypertensive patients by 24 ± 6 mmHg (P < 0.001 vs. controls). MSNA increased after alcohol in controls by 83 ± 34% (P < 0.01 vs. baseline). MSNA did not change significantly after alcohol in hypertensive patients (16 ± 7%, not significant), despite a profound blood pressure increase, which would be expected to inhibit sympathetic activity. CONCLUSION: Pressor responses to acute alcohol consumption are potentiated in hypertensive patients compared with normotensive controls. Vasoconstrictor sympathetic tone is not suppressed in hypertensive patients after alcohol, despite the enhanced pressor response. Sympathetic neural mechanisms might contribute to both alcohol-related blood pressure increases and cardiovascular events in hypertensive patients.

Resting sympathetic outflow does not predict the morning blood pressure surge in hypertension.

OBJECTIVE: The blood pressure (BP) rise on awakening (morning surge) might be a predictor of hypertension-related cardiovascular complications. Previous studies suggest that the autonomic nervous system may contribute to the early morning BP increase. We tested the hypothesis that resting sympathetic outflow [assessed by direct measures of intraneural sympathetic nerve activity (SNA)] may help predict the morning BP surge in hypertension. METHODS: We measured muscle SNA (MSNA), heart rate (HR) and BP during undisturbed supine rest in 68 newly diagnosed untreated hypertensive patients (53 men and 15 women, age 40 ±â€Š3 years, BMI 27 ±â€Š1 kg/m(2), mean ±â€ŠSEM). The morning BP surge was defined as the difference between the morning BP and the pre-awake BP. RESULTS: SBP averaged 143 ±â€Š3 mmHg for daytime and 126 ±â€Š2 mmHg for night-time. Mean HR was 81 ±â€Š2 beats/min for daytime and 69 ±â€Š2 beats/min for night-time. Average MSNA was 32 ±â€Š2 bursts/min., SBP morning surge 19 ±â€Š2 mmHg and HR morning surge 14 ±â€Š2 beats/min. In univariate analysis, MSNA correlated with daytime SBP (r = 0.28, P = 0.02); night-time SBP (r = 0.26, P = 0.03); daytime HR (r = 0.28, P = 0.02); and night-time HR (r = 0.26, P = 0.03). Multivariate analysis, taking into consideration age, BMI and sex, revealed that MSNA was independently related to both daytime (P = 0.006) and night-time HR (P = 0.02), but not to ambulatory SBP. The morning surge of SBP and HR was not related to MSNA (r = 0.01 and r = 0.07, respectively, P = NS). CONCLUSION: In patients with essential hypertension, MSNA is related to both daytime and night-time HR, but not to the morning BP surge.

Heightened acute circulatory responses to smoking in women.

Objective. Smoking, a major risk factor for cardiovascular morbidity and mortality, may be particularly harmful to women. Sympathetic and hemodynamic responses to cigarette smoking may be implicated in the link between smoking and acute cardiovascular events. We tested the hypothesis that acute effects of smoking on cardiovascular function are potentiated in women compared with men. Methods. We examined the effects of cigarette smoking and sham smoking on muscle sympathetic nerve activity, blood pressure and heart rate in 20 female and 20 male middle-aged healthy habitual smokers. Results. Sham smoking had no effect on muscle sympathetic nerve activity, blood pressure, or heart rate. Although cigarette smoking increased average systolic blood pressure and heart rate in both females and males, systolic blood pressure increased more in women (12+/-2 mmHg) than in men (6+/-2 mmHg; p = 0.02), as did heart rate (16+/-2 beats/min in women vs 9+/-2 beats/min in men; p = 0.002). Female smokers also had greater smoking-related increases in systolic blood pressure variability compared with males (2.2+/-0.6 vs 0.4+/-0.4 mmHg, respectively; p = 0.01) and greater decreases in RR variability (-28+/-5 vs -7+/-4 ms; p = 0.002). Despite the potentiated blood pressure increase in females, which would be expected to inhibit sympathetic activity to a greater extent in females than in males, changes in muscle sympathetic nerve activity during smoking were similar in both sexes. Conclusions. Acute pressor and tachycardic effects of smoking are potentiated in women compared with men. These findings may have important implications for understanding increased vulnerability to acute cardiovascular events in women who smoke.