Impaired cardiovagal and vasomotor responses to baroreceptor stimulation in type II diabetes mellitus

BACKGROUND: In diabetic patients, impairment of the cardiovagal limb of the baroreflex has been well established. However, the role of sympathetic mediated baroreflex vasomotor control of the blood vessels is not well defined. We therefore assessed the vasomotor responses to sinusoidal baroreceptor stimulation in diabetic patients. MATERIALS AND METHODS: We studied 14 type II diabetic patients (age; 57 +/- 7 years) and 18 healthy controls (age; 59 +/- 11 years). Oscillatory neck suction was applied at 0.1 Hz to assess the sympathetic modulation of the heart and blood vessels, and at 0.2 Hz to assess the effect of parasympathetic stimulation on the heart. Breathing was paced at 0.25 Hz. Spectral analysis was used to evaluate the oscillatory responses of RR-interval and blood pressure. RESULTS: The diabetic patients showed a significantly lower RR-interval response (P < 0.05) to the 0.1 Hz neck suction (2.52 +/- 0.50-3.62 +/- 0.54 ln ms2) than the controls (4.23 +/- 0.31-6.74 +/- 0.36 ln ms2). The increase in power of 0.1 Hz systolic blood pressure oscillations during 0.1 Hz suction was also significantly smaller (P < 0.05) in the diabetics (1.17 +/- 0.44-1.69 +/- 0.44 mmHg2) than in the controls (1.60 +/- 0.29 mmHg2-5.87 +/- 1.25 mmHg2). The magnitude of the peak of the 0.2 Hz oscillation in the RR-interval in response to 0.2 Hz neck stimulation was significantly greater (P < 0.05) in the controls (3.42 +/- 0.46 ln ms2) than in the diabetics (1.58 +/- 0.44 ln ms2). CONCLUSION: In addition to cardiovagal dysfunction, baroreflex-mediated sympathetic modulation of the blood vessels is impaired in type II diabetic patients.     

Effects of euglycaemic and hypoglycaemic hyperinsulinaemia on sympathetic and parasympathetic regulation of haemodynamics in healthy subjects

The effects of hypoglycaemia during hyperinsulinaemia, occurring under various pathophysiological conditions, on the cardiovascular regulatory system and vasculature are largely unknown. The aim of the present study was to investigate regulatory and haemodynamic responses to acute hyperinsulinaemia and consequent hypoglycaemia in 18 healthy subjects. Blood sampling and 5 min ECG and blood pressure recordings were performed at baseline and during the euglycaemic and hypoglycaemic phases of a hyperinsulinaemic clamp. Heart rate variability (HRV) and blood pressure variability (BPV) were assessed by using power spectral analysis, and baroreflex sensitivity (BRS) was assessed using the cross-spectral method. Stroke volume was assessed from the non-invasive blood pressure signal by the arterial pulse contour method. Euglycaemic hyperinsulinaemia did not change plasma catecholamine concentrations, HRV, BPV, BRS, heart rate, blood pressure, stroke volume, cardiac output or peripheral resistance. However, hyperinsulinaemic hypoglycaemia resulted in an 11.7-fold increase in the plasma adrenaline concentration (from 0.19+/-0.03 to 1.68+/-0.32 nmol/l; P <0.001), and a modest 1.3-fold increase in the plasma noradrenaline concentration (from 1.74+/-0.22 to 2.02+/-0.19 nmol/l; P <0.05) compared with baseline. Furthermore, we observed significant decreases in diastolic blood pressure (from 68+/-3 to 60+/-3 mmHg; P <0.05) and peripheral resistance (from 24.1+/-1.2 to 18.5+/-1.1 mmHg.min(-1) x l(-1); P <0.01). Stroke volume and cardiac output increased markedly from the euglycaemic to the hypoglycaemic period only ( P <0.01 for both). Hypoglycaemia did not influence HRV, BPV or BRS. Our findings indicate that hyperinsulinaemic hypoglycaemia is characterized by a significant increase in the plasma adrenaline concentration and by decreases in peripheral resistance and blood pressure. Counter-regulation during hyperinsulinaemic hypoglycaemia involves selective adrenomedullary sympathetic activation, and does not influence cardiac parasympathetic regulation or baroreflex control of heart rate.     

Role of nitric oxide and oxidative stress in baroreceptor dysfunction in patients with chronic heart failure

Abnormalities of autonomic control of the cardiovascular system are seen in chronic heart failure (CHF) and confer a poor prognosis. Nitric oxide appears to be important in the regulation of baroreflex control in health and in disease states. The antioxidant vitamin C increases nitric oxide bioavailability in CHF. We evaluated the effects of vitamin C on baroreceptor sensitivity (BRS) by sequence analysis in 100 CHF patients and 44 control subjects. Groups of 55 CHF patients and 22 controls were randomly allocated to receive a single intravenous injection of vitamin C (2 g) or placebo. In addition, 45 CHF patients were randomly allocated to receive a 4-week course of oral vitamin C (4 g/day) or placebo. An age-related reference range for BRS was developed in 22 healthy controls matched for age and gender to the CHF group. BRS was significantly impaired in the CHF group compared with age-matched older controls and young controls (6.9 +/- 3.1, 12.5 +/- 4.9 and 21.7 +/- 9.1 mmHg/ms respectively; P < 0.001 between groups). Intravenous vitamin C acutely improved BRS in CHF patients by 24% (by 1.8 +/- 4.1 mmHg/ms; P < 0.05), but not in controls. There was no improvement in BRS in CHF patients given chronic oral vitamin C. Thus acute intravenous, but not chronic oral, vitamin C improved BRS in CHF patients. There was no effect of intravenous vitamin C in healthy subjects, suggesting that the mechanism was either by free radical scavenging or due to central effects.     

Role of aortic baroreceptors in ethanol-induced impairment of baroreflex control of heart rate in conscious rats.

This study investigated the relative contribution of aortic baroreceptors to the depressant effect of ethanol on arterial baroreceptor function. The acute hemodynamic effects of ethanol were studied in conscious freely moving aortic baroreceptor denervated (ABD) and sham-operated (SO) rats. ABD but not the sham operation caused immediate and significant (P less than .05) increases in mean arterial pressure and heart rate (HR) and an impairment of the baroreflex-mediated control of HR (baroreflex sensitivity, BRS). Two to three days after ABD, these parameters, except the BRS, subsided to near-control levels. Both operations (ABD and sham) significantly reduced the daily water intake but the reduction was significantly greater in ABD rats. Intravenous administration of ethanol (0.1, 0.5 or 1.0 g/kg) to either SO or ABD rats produced short-lived dose-related pressor and bradycardiac responses which correlated well with blood ethanol concentration. In SO rats, ethanol caused dose-related decreases in the slopes of the curves relating increments in mean arterial pressure induced by phenylephrine to corresponding bradycardiac responses; the higher dose significantly (P less than .05) reduced the slope from -2.03 +/- 0.14 to -1.28 +/- 0.18 beats/min/mm Hg, indicating an impairment of BRS. Conversely, in ABD rats, ethanol failed to influence the BRS; the slopes before and after ethanol (1 g/kg) were similar (-1.1 +/- 0.07 vs. -1.0 +/- 0.23 beats/min/mm Hg). The lack of ethanol effect in ABD rats cannot be accounted for by the assumption that aortic barodenervation depressed the baroreceptor reflex to its nadir or by a difference in concentration of blood ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of noradrenaline on human vagal baroreflexes

BACKGROUND: Baroreflex sensitivity (BRS) is depressed in conditions associated with high sympathetic nerve activity in proportion to circulating noradrenaline (NA) levels. Despite the prognostic importance of measurements of BRS in patients, there is little information on how high NA levels affect arterial baroreflex function. AIM: To understand better the role of NA in cardiovascular homeostasis. METHODS: We gave incremental intravenous NA infusions (at 50 and 100 ng/kg/min) to 12 healthy young men. We measured RR intervals and photoplethysmographic arterial pressures and estimated BRS with cross-spectral and sequence methods during metronome-guided respiration at 0.25 Hz. RESULTS: The high NA infusion rate significantly increased respiratory-frequency (0.15-0.40 Hz) RR interval spectral power and decreased low-frequency (0.04-0.15 Hz) systolic pressure spectral power compared with baseline levels (P < 0.05 for both). Cross-spectral BRS increased from an average (+/- SD) baseline level of 17.3+/-6.6 to 34.1+/-20.8 ms/mmHg at the high NA infusion rate (P < 0.05). Sequence BRS values did not increase significantly during NA infusions. The percentage of sequences with parallel changes in systolic pressures and RR intervals decreased progressively from a baseline level of 16.0+/-12.9 to 10.1+/-7.4 during the low NA infusion rate and to 6.2+/-6.2% during the high rate (P < 0.05 and 0.01, respectively). CONCLUSIONS: Increases in circulating NA to high physiological levels do not depress BRS but interfere with the close baroreflex-mediated coupling that is usually present between arterial pressure and heart rate.     

Impact of age on the vasovagal response provoked by sublingual nitroglycerine in routine tilt testing

NTG (nitroglycerine) is used in routine tilt testing to elicit a vasovagal response. In the present study we hypothesized that with increasing age NTG triggers a more gradual BP (blood pressure) decline due to a diminished baroreflex-buffering capacity. The purpose of the present study was to examine the effect of NTG on baroreflex control of BP in patients with distinct age-related vasovagal collapse patterns. The study groups consisted of 29 patients (16-71 years old, 17 females) with clinically suspected VVS (vasovagal syncope) and a positive tilt test. Mean FAP (finger arterial pressure) was monitored continuously (Finapres). Left ventricular SV (stroke volume), CO (cardiac output) and SVR (systemic vascular resistance) were computed from the pressure pulsations (Modelflow). BRS (baroreflex sensitivity) was estimated in the time domain. In the first 3 min after NTG administration, BP was well-maintained in all patients. This implied an adequate arterial resistance response to compensate for steeper reductions in SV and CO with increasing age. HR (heart rate) increased and the BRS decreased after NTG administration. The rate of mean FAP fall leading to presyncope was inversely related to age (r=0.51, P=0.005). Accordingly, patients with a mean FAP fall >1.44 mmHg/s (median) were generally younger compared with patients with a slower mean FAP-fall (30+/-10 years compared with 51+/-17 years; P=0.001). The main determinant of the rate of BP fall on approach of presyncope was the rate of fall in HR (r=0.75, P<0.001). It was concluded that, in older patients, sublingual NTG provokes a more gradual BP decline compared with younger patients. This gradual decline cannot be ascribed to failure of the baroreflex-buffering capacity with increasing age. Age-related differences in the laboratory presentation of a vasovagal episode depend on the magnitude of the underlying bradycardic response.     

Afferent baroreflex dysfunction and age-related orthostatic hypotension.

1. To test the hypothesis that in apparently healthy elderly subjects with orthostatic hypotension there is afferent baroreflex dysfunction, cardiovascular and neurohumoral responses were measured after separate stimuli which activated baroreceptor (head-up tilt) and non-baroreceptor (cold stress, isometric exercise) afferent pathways. 2. In 15 healthy elderly control subjects blood pressure did not change with 60 degrees head-up tilting and there was a moderate increase in heart rate, whereas in 13 subjects with age-related orthostatic hypotension head-up tilting was associated with a marked fall in blood pressure but a similar heart rate response to that in the elderly control group. In contrast, both groups of subjects had similar blood pressure and heart rate responses to cold stress and sustained isometric exercise. 3. Nine subjects with autonomic neuropathy also showed a marked hypotensive response to head-up tilt, but produced no pressor response to cold stress or isometric exercise. 4. The plasma concentrations of noradrenaline, adrenaline and neuropeptide-Y-like immunoreactivity rose and that of atrial natriuretic peptide fell after head-up tilt in the study population as a whole. There were no significant differences between groups despite the much greater blood pressure drops in the subjects with autonomic neuropathy and in those with age-associated orthostatic hypotension. 5. The aorto-iliac pulse wave velocity index was significantly higher in subjects with age-associated orthostatic hypotension compared with that in control subjects. 6. The pattern of responses to the separate stresses observed in the group with age-associated orthostatic hypotension is characteristic and different from that in the elderly control subjects and the subjects with autonomic neuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Carotid artery stiffening does not explain baroreflex impairment in pre-eclampsia

Stiffening of the barosensory vessel wall in hypertension has been suggested to play a role in the associated baroreflex impairment. The carotid distensibility-BRS (baroreflex sensitivity) relationship, however, has not been studied in pre-eclampsia, a condition where hypertension is spontaneously reversible. Twelve normotensive pregnant women and 12 patients with pre-eclampsia matched for maternal age and week of gestation were studied in the third trimester and 3 months postpartum. Carotid artery diastolic diameter and pulsatile distension was measured by echo-wall tracking and carotid pulse pressure by applanation tonometry, and the carotid distensibility coefficient was calculated. Spontaneous BRS was determined by the sequence and spectral methods from 10 min continuous recording of ECG and finger arterial blood pressure. In the third trimester, carotid distensibility was lower in patients with pre-eclampsia than in normotensive pregnant women (2.47+/-0.17 compared with 4.08+/-0.16 x 10(-3)/mmHg); postpartum, it increased moderately in patients, but remained below normotensive values (3.25+/-0.12 compared with 4.25+/-0.19 x 10(-3)/mmHg). In the third trimester, both patients and healthy pregnant women had equally low BRS values; postpartum, the various BRS indices increased markedly (by 60-190%) and to the same level in both groups. No correlation was found between changes in carotid artery distensibility and those in BRS from the third trimester to postpartum period in patients and healthy pregnant women. The lack of association between changes in carotid distensibility and BRS suggest that stiffening of the carotid artery in pre-eclampsia is not responsible for baroreflex dysfunction.     

Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans.

Animal studies have demonstrated that activation of the baroreflex by increases in arterial pressure inhibits cardiovascular and ventilatory responses to activation of peripheral chemoreceptors (PC) with hypoxia. In this study, we examined the influences of baroreflex activation on the sympathetic response to stimulation of PC and central chemoreceptors in humans. PC were stimulated by hypoxia (10% O2/90% N2) (n = 6) and central chemoreceptors by hypercapnia (7% CO2/93% O2) (n = 6). Responses to a cold pressor stimulus were also obtained as an internal reflex control to determine the selectivity of the interactive influence of baroreflex activation. Baroreflex activation was achieved by raising mean blood pressure by greater than 10 mmHg with intravenous infusion of phenylephrine (PE). Sympathetic nerve activity (SNA) to muscle was recorded from a peroneal nerve (microneurography). During hypoxia alone, SNA increased from 255 +/- 92 to 354 +/- 107 U/min (P less than 0.05). During PE alone, mean blood pressure increased and SNA decreased to 87 +/- 45 U/min (P less than 0.05). With hypoxia during baroreflex activation with PE, SNA did not increase (50 +/- 23 U/min). During hypercapnia alone, SNA increased from 116 +/- 39 to 234 +/- 72 U/min (P less than 0.01). Hypercapnia during baroreflex activation with PE increased SNA from 32 +/- 25 U/min during PE alone to 61 +/- 26 U/min during hypercapnia and PE (P less than 0.05). Like hypercapnia (but unlike hypoxia) the cold pressor test also increased SNA during PE. We conclude that baroreflex activation selectively abolishes the SNA response to hypoxia but not to hypercapnia or the cold pressor test. The inhibitory interaction of the baroreflex and the peripheral chemoreflex may be explained by convergence of baroreceptor and peripheral chemoreceptor afferents on neurons in the medulla.     

Disparities in circulatory adjustment to standing between young and elderly subjects explained by pulse contour analysis.

1. The circulatory adjustment to standing was investigated in two age groups. Young subjects consisted of 20 healthy 10-14-year-old girls and boys. Elderly subjects consisted of 40 70-86-year-old healthy and active females and males. Continuous responses of blood pressure and heart rate were recorded by Finapres. A pulse contour algorithm applied to the finger arterial pressure waveform was used to assess stroke volume responses. 2. During the first 30s (initial phase), an almost identical drop in mean blood pressure was found in both age groups (young, 16 +/- 10 mmHg; old, 17 +/- 10 mmHg), but the initial heart rate increase was attenuated in the elderly subjects (young, 29 +/- 7 beats/min; old, 17 +/- 7 beats/min). 3. During the period from 30 s to 10 min of standing, mean blood pressure increased from 96 +/- 12 to 106 +/- 12 mmHg in the elderly subjects compared with almost no change in the young subjects (from 82 +/- 8 to 84 +/- 7 mmHg). In the elderly subjects a progressive increase in total peripheral resistance (from 114 +/- 14% to 146 +/- 29%) was found, compared with an initial rapid increase in total peripheral resistance (126 +/- 18% after 30 s) with no further change during prolonged standing (124 +/- 17% after 10 min) in the young subjects. In this age group the decrease in stroke volume and the increase in heart rate after 10 min of standing were large (young, -37 +/- 11% and 27 +/- 11 beats/min; old, -31 +/- 9% and 7 +/- 6 beats/min, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Arterial baroreflex function determines the survival time in lipopolysaccharide-induced shock in rats

Lipopolysaccharide (LPS) mimics many of the effects of septic shock. LPS-induced death has been attributed to systemic hypotension, hyporeactiveness to vasoconstrictors, metabolic acidosis, and organ damage. However, there is no research directed to the involvement of the baroreflex sensitivity (BRS) in LPS-induced death. The purpose of this study was to evaluate the effect of BRS on the survival time after lethal LPS challenge. Four groups of rats were used. Each rat received an equivalent dose of intravenous LPS (50 mg/kg). It was found that the anesthetized sinoaortic-denervated (SAD) rats (representative of the lowest BRS, BRS = 0.022 +/- 0.015 ms/mmHg) survived the shortest time (36 +/- 11.1 min). The conscious SAD rats (BRS = 0.198 +/- 0.035 ms/mmHg) and the anesthetized sham-operated rats (BRS = 0.304 +/- 0.072 ms/mmHg) were alive a relatively long time (101 +/- 11.5 min and 110 +/- 12.4 min, respectively). The conscious sham-operated rats (BRS = 0.943 +/- 0.097 ms/mmHg) survived the longest time (148 +/- 6.5 min). These results demonstrated that arterial baroreflex function determined the survival time in the LPS-induced lethal shock.     

Adaptation of baroreflex function to increased carotid artery stiffening in patients with transposition of great arteries

We have shown previously that TGA (transposition of great arteries) is associated with increased carotid artery stiffness. It has been established that stiffening of the barosensory vessel wall results in reduced baroreceptor activation and impaired BRS (baroreflex sensitivity). In the present study we tested the hypothesis that the increased carotid artery stiffness in TGA patients was associated with reduced cardiovagal BRS. We studied 32 TGA patients aged 9-19 years, 12+/-3 years after surgical repair and 32 age-matched healthy control subjects. Carotid artery diastolic diameter and pulsatile distension was determined by echo wall tracking; carotid blood pressure was measured by tonometry. BRS was measured using spontaneous techniques [BRS(seq) and LF(gain) (low-frequency transfer function gain)] and by the phenylephrine method (BRS(phe)). Carotid artery distensibility was markedly reduced in patients as compared with controls (5.6+/-1.9 x 10(-3) compared with 8.7+/-2.7 x 10(-3)/mmHg P<0.05, as determined using an unpaired Student's t test), but BRS was not different in patients and controls (20.3+/-14.7 compared with 21.7+/-12.7 for BRS(seq); 13.1+/-9.2 compared with 10.6+/-4.5 for LF(gain); and 19.1+/-8.6 compared with 24.8+/-7.2 for BRS(phe) respectively). Carotid artery elastic function was markedly impaired in patients with TGA, but the increased stiffness of the barosensory vessel wall was not associated with reduced BRS. It appears that attenuation of baroreceptor stimulus due to arterial stiffening may be compensated by other, possibly neural, mechanisms when it exists as a congenital abnormality.     

Advanced analysis of spontaneous baroreflex sensitivity, blood pressure and heart rate variability in patients with dilated cardiomyopathy

Baroreflex sensitivity (BRS) is an important parameter in the classification of patients with reduced left ventricular function. This study aimed at investigating BRS in patients with dilated cardiomyopathy (DCM) and in healthy subjects (controls), as well as comparing the values of BRS parameters with parameters of heart rate variability (HRV) and blood pressure variability (BPV). ECG, continuous blood pressure and respiration curves were recorded for 30 min in 27 DCM patients and 27 control subjects. The Dual Sequence Method (DSM) includes the analysis of spontaneous fluctuations in systolic blood pressure and the corresponding beat-to-beat intervals of heart rate to estimate bradycardic, opposite tachycardic and delayed baroreflex fluctuations. The number of systolic blood pressure/beat-to-beat interval fluctuations in DCM patients was reduced in comparison with controls (DCM patients: male, 154.4+/-93.9 ms/mmHg; female, 93.7+/-40.5 ms/mmHg; controls: male, 245.5+/-112.9 ms/mmHg; female, 150.6+/-55.8 ms/mmHg, P<0.05). The average slope in DCM patients was lower than in controls (DCM, 5.3+/-1.9 ms/mmHg; controls, 8.0+/-5.4 ms/mmHg; P<0.05). Discriminant function analysis showed that, in the synchronous range of the standard sequence method, the DCM and control groups could be discriminated to only 76% accuracy, whereas the DSM gave an improved accuracy of 84%. The combination of six parameters of HRV, BPV and DSM gives an accuracy of classification of 96%, whereas six parameters of HRV and BPV could separate the two groups to only 88% accuracy. Thus the DSM leads to an improved characterization of autonomous regulation in order to differentiate between DCM patients and healthy subjects. BRS in DCM patients is significantly reduced and apparently less effective.     

Effect of age and posture on human lymphocyte adenylate cyclase activity

1. A number of age-related changes have been reported in the catecholamine-adrenoceptor-adenylate cyclase system. Most of the data available on these alterations come from resting subjects; the response to acute stress may provide additional insights into the age effect on these responses. 2. We measured supine and 10 min upright plasma noradrenaline and lymphocyte adenylate cyclase activity in ten healthy elderly subjects (age 66-80 years) and seven healthy young subjects (age 27-34 years). 3. Isoprenaline stimulation of lymphocyte adenylate cyclase activity was not significantly different between supine and upright positions or between elderly and young subjects. There was a marked increase in forskolin-stimulated adenylate cyclase activity in the upright posture in both elderly and young subjects. The increment over supine levels was 70% in the elderly (P less than 0.025) and 73% in the young (P less than 0.05). This enhanced forskolin activity was not seen in two young subjects who became syncopal. 4. These data suggest that enhanced forskolin-stimulated adenylate cyclase activity occurs after 10 min of upright posture in both elderly and young subjects, and may be relevant to immediate blood pressure regulation. We were unable to demonstrate any age-related differences in these acute adrenergic responses.     

Effects of extracellular pH on tumour necrosis factor-alpha production by resident alveolar macrophages

Aging reduces cardiac baroreflex sensitivity. Our primary aim in the present study was to assess the effects of aging on cardiac baroreflex sensitivity, as determined by power spectral analysis (alpha index), in a large population of healthy subjects. We also compared the alpha indexes determined by power spectral analysis with cardiac baroreflex sensitivity measured by the phenylephrine method (BS(phen)). We studied 142 subjects (79 males/63 females; age range 9-94 years), who were subdivided into five groups according to percentiles of age (25, 50, 75 and 95). Power spectral analysis yields three alpha indexes: an alpha low-frequency (LF) index of cardiac baroreflex sensitivity that ranges around 0.1 Hz; an alpha high-frequency (HF) index reflecting cardiac baroreflex sensitivity corresponding to the respiratory rate; and alpha total frequency (alpha TF), a new index whose spectral window includes all power in the range 0.03-0.42 Hz. Spectra were recorded during controlled and uncontrolled respiration. Under both conditions, all three alpha indexes were higher in the youngest age group (< or =34 years old) than in the three oldest groups. Notably, alpha TF was significantly higher in younger subjects than in the three oldest groups [14+/-1 ms/mmHg compared with 9+/-1 (P<0.05), 8.1+/-1 (P<0.001) and 8.1+/-1 (P<0.05) ms/mmHg respectively]. BS(phen) showed a similar pattern [12+/-1 ms/mmHg compared with 8+/-0.5 (P<0.001), 6+/-0.5 (P<0.05) and 6+/-1 (P<0.05) ms/mmHg respectively]. No significant differences were found for cardiac baroreflex sensitivity among the three oldest groups. All alpha indexes were correlated inversely with age. The index yielding the closest correlation with BS(phen) was alpha TF (r=0.81, P<0.001). Cardiac baroreflex sensitivity in normotensive individuals declines with age. It falls predominantly in middle age (from approx. 48 years onwards) and remains substantially unchanged thereafter. The elderly subjects we selected for this study probably had greater resistance to cardiovascular disease that is manifested clinically, with preserved cardiac baroreceptor sensitivity.     

Attenuated cardiac baroreflex in men with presyncope evoked by lower body negative pressure

Mechanisms responsible for presyncope during lower body negative pressure (LBNP) in otherwise healthy subjects are poorly understood. Muscle sympathetic nerve activity (MSNA), blood pressure, heart rate (HR), HR power spectra, central venous pressure (CVP) and stroke volume were determined in 14 healthy men subjected to incremental LBNP. Of these, seven experienced presyncope at LBNP >-15 mmHg. Subjects who tolerated LBNP >-15 mmHg had significantly lower CVP (2.6+/-1.0 versus 7.2+/-1.2 mmHg; means+/-S.E.M., P<0.02), HR (59+/-2 versus 66+/-3 beats/min, P<0.05) and MSNA burst frequency (29.0+/-2.4 versus 39.0+/-3.5 bursts/min, P<0.05) during supine rest. LBNP at -15 mmHg had no effect on blood pressure, but caused similar and significant reductions in stroke volume and cardiac output in both groups. Subjects who tolerated LBNP had significant reflex increases in HR, MSNA burst frequency and burst amplitude with LBNP of -15 mmHg. These responses were absent in those who experienced presyncope. The gain of the cardiac baroreflex regulation of MSNA was markedly attenuated in pre-syncopal subjects (1.2+/-0.6 versus 8.8+/-1.4 bursts/100 heart beats per mmHg; P<0.001). Healthy subjects who experience presyncope in response to LBNP appear more dependent, when supine, upon MSNA to maintain preload, and less able to increase sympathetic vasoconstrictor discharge to skeletal muscle reflexively in response to orthostatic stimuli.     

Muscle afferent and central command contributions to the cardiovascular response to isometric exercise of postural muscle in patients with mild chronic heart failure

The roles of muscle afferent activity and central drive in controlling the compromised cardiovascular system of patients with mild chronic heart failure (CHF) during isometric exercise were examined. Blood pressure and heart rate responses were recorded in eight stable CHF patients (ejection fraction 20-40%; age 62+/-11 years) and in nine healthy age-matched controls during voluntary and electrically evoked isometric plantar flexion and subsequent post-exercise circulatory occlusion (PECO). During voluntary contraction, control subjects had a greater mean increase in systolic blood pressure than patients (42.4+/-19.2 and 23.0+/-10.9 mmHg respectively; P<0.01), but this was not the case during PECO. During electrically evoked contraction, but not during PECO, the CHF group had smaller (P<0.05) mean increases in both systolic and diastolic blood pressure than controls (13.0+/-5.3 compared with 25.4+/-14.0 mmHg and 7.6+/-3.0 compared with 12.9+/-7.2 mmHg respectively). Intra-group comparison between responses to voluntary and electrically evoked contractions revealed greater (P<0.05) mean increases in systolic and diastolic blood pressure during the voluntary contraction in both the patients and the control subjects. These data suggest that muscle afferent drive to the pressor response from the triceps surae is low in this age group, both in control subjects and in CHF patients. Additionally, the patients may have a relatively desensitized muscle mechanoreceptor reflex.     

Exercise training reduces the sympathetic component of the blood pressure-heart rate baroreflex in man.

1. Exercise training reduces resting sympathetic activity, but the effects on sympathetic activation or withdrawal during baroreflex responses to blood pressure perturbations are controversial. The purpose of this study was to investigate the effects of training on both the vagal and sympathetic reflex heart rate responses to blood pressure changes. 2. Using 10 healthy males in a randomized cross-over design, we examined the effects of three 30 min cycling sessions at 70% of maximal capacity for 4 weeks on the steady-state reflex heart rate responses to perturbations in mean arterial pressure induced with injections of nitroprusside and phenylephrine. The method provides a sigmoidal relationship between changes in heart rate and blood pressure. The upper plateau (maximum tachycardia in response to blood pressure reduction) and lower plateau (maximum bradycardia in response to blood pressure elevation) are mainly mediated by the cardiac sympathetics and vagus, respectively. The slope of the relationship is a measure of reflex gain. 3. Training, which increased maximal oxygen consumption by 13 +/- 2% (mean +/- standard error of the difference), reduced supine and standing blood pressures by 3 +/- 1/3 +/- 1 mmHg (P less than 0.05) and 4 +/- 1/2 +/- 2 mmHg (P less than 0.05 for systolic), respectively, whereas resting heart rate was lowered by 6 +/- 1 beats/min (P less than 0.05). Reflex sensitivity in the presence of functioning vagus and sympathetics was not altered with training, but the vagal component of sensitivity, as assessed after sympathetic blockade with propranolol, was significantly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)     

A "Dysautonomic" Head-Up Tilt Test Pattern in Elderly Patients with Neurocardiogenic Syncope

The characteristics of neurocardiogenic syncope (NCS) in elderly patients remain unclear. We compared the hemodynamic profiles of young and older patients with consecutive and positive head-up tilt tests (HUT). Continuous, noninvasive, and reliable monitoring of arterial pressure (AP) and heart rate (HR) was done throughout 46 consecutive positive HUTs of symptomatic patients. The population (12-82 years old) was divided into two groups: younger patients, Y (n = 25, < or = 65 years), and older patients, O (n = 21). Changes in AP and HR after the first minute of tilting, during the stable orthostatic phase and during syncope were compared. Except for systolic pressure, baseline hemodynamic parameters were similar in Y and O. No difference appeared in the mean time elapsed before syncope (19+/-9 vs 22+/-2 min). Asymptomatic hypotension was observed, only in O, 1 minute after tilting, followed by a progressive fall in the mean AP before syncope (0+/-0.9 vs -1+/-0.7 mmHg/min) without HR increase (0.7+/-1 vs 0+/-0.6 beats/min). This pressure slope was strongly related to age (r = 0.54, P < 0.001). Hemodynamic recording during HUT identifies a dysautonomic pattern in elderly patients with NCS and the abnormal AP/HR responses to orthostasis may be a feature specific to this population. Although the central mechanism of NCS is common to all ages, the age-related characteristics of the trigger event may indicate the need for specific management at different ages.     

Aging alters verapamil elimination and dynamics: single dose and steady-state responses

Verapamil elimination kinetics and pharmacodynamic effects were studied in 29 healthy individuals (23-81 years of age) after single i.v. doses (0.15-0.22 mg/kg) and during infusions to reach stable plasma verapamil concentrations of 28 +/- 11, 57 +/- 19 and 112 +/- 26 ng/ml (mean +/- S.D.). Aging prolonged verapamil elimination (P less than .008): elimination half-life of 218 +/- 91 min in young (ages 20-39), 280 +/- 78 min in middle-aged (40-59) and 288 +/- 73 min in elderly (greater than 60). After single verapamil doses. 1) heart rate increased with lesser increases in elderly subjects; 2) blood pressure decreased (P = .006) with greater decreases in elderly subjects; 3) spontaneous P-R intervals increased with lesser increases in elderly subjects but, 4) atrioventricular conduction times increased during transesophageal pacing without detectable age differences in responses. During steady-state infusions, 1) heart rate during sinus rhythm was unchanged but atrioventricular dissociation with junctional rhythms developed in elderly subjects (3/9); 2) blood pressure decreased with greater decreases in the elderly; 3) spontaneous P-R intervals increased with lesser increases in the elderly but no age differences in paced P-R interval changes were detected at equivalent verapamil concentrations; 4) heart rate variation (during sinus rhythm) decreased in an age-independent manner as measured by decreases in the S.D. of R-R intervals and decreased power spectral content with greatest changes seen in high frequency (respiratory) content; and 5) heart rate and blood pressure responses to cold pressor and handgrip testing were not attenuated by verapamil. In conclusion, aging prolongs verapamil elimination and alters dynamic responses to verapamil with greater sinus node depression and hypotensive effects in elderly vs. younger subjects. Although less spontaneous P-R interval prolongation was seen on ECG of the elderly vs. young, underlying atrioventricular conduction was prolonged by verapamil independent of age as shown by results when pacing was used to eliminate frequency-dependent effects caused by differing heart rate responses.