Bianca M. Cattaneo

Sympathetic Activation in Obese Normotensive Subjects

Human obesity is characterized by profound alterations in the hemodynamic and metabolic states. Whether these alterations involve sympathetic drive is controversial. In 10 young obese subjects (body mass index, 40.5 +/- 1.2 kg/m2, mean +/- SEM) with normal blood pressure and 8 age-matched lean normotensive control subjects, we measured beat-to-beat arterial blood pressure (Finapres technique), heart rate (electrocardiogram), postganglionic muscle sympathetic nerve activity (microneurography at the peroneal nerve), and venous plasma norepinephrine (high-performance liquid chromatography). The measurements were performed in baseline conditions and, with the exception of plasma norepinephrine, during baroreceptor stimulation and deactivation caused by increases and reductions of blood pressure via intravenous infusions of phenylephrine and nitroprusside. Baseline blood pressure and heart rate were similar in obese and control subjects. Plasma norepinephrine was also similar in the two groups. Muscle sympathetic nerve activity, however, was 38.6 +/- 5.1 bursts per minute in obese subjects and less than half that level in control subjects (18.7 +/- 1.3 bursts per minute), the difference being highly statistically significant (P < .02). Muscle sympathetic nerve activity and heart rate were reduced during phenylephrine infusion and increased during nitroprusside infusion, but the changes were about half as great in obese subjects as in control subjects. Thus, even in the absence of any blood pressure alteration, human obesity is characterized by a marked sympathetic activation, possibly because of an impairment of reflex sympathetic restraint. This may be involved in the high rate of hypertension and cardiovascular complications seen in obesity.

Baroreflex Control of Sympathetic Nerve Activity in Essential and Secondary Hypertension

Studies performed in experimental animals and in humans have documented that high blood pressure markedly impairs baroreceptor control of heart rate. Whether a similar impairment also characterizes baroreceptor control of sympathetic activity modulating peripheral vasomotor tone is still unknown. In 28 untreated essential hypertensive subjects [14 of moderate and 14 of more severe degree, age 51.6+/-2.4 and 52.6+/-2.1 years (mean+/-SEM)] and in 13 untreated secondary hypertensives (renovascular or pheochromocytoma, age 50.1+/-4.6 years), we measured beat-to-beat arterial blood pressure (finger photoplethysmographic device), heart rate (electrocardiogram), and efferent postganglionic muscle sympathetic nerve activity (microneurography) at rest and during baroreceptor stimulation and deactivation induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Data were compared with those obtained in 15 age-matched normotensive control subjects. Muscle sympathetic nerve activity (bursts per 100 heart beats) showed a progressive and significant (P<.01) increase from normotension (40.3+/-3.3) to moderate (55.6+/-4.1) and more severe essential hypertension (68.2+/-4.1), paralleling the progressive increase in blood pressure values. In contrast, muscle sympathetic nerve activity was not increased in secondary hypertensives (40.5+/-6.7) despite blood pressure values similar to or even greater than those of severe essential hypertensives. In both essential and secondary hypertensives, baroreceptor-heart rate control was displaced toward elevated blood pressure values and markedly impaired compared with normotensive subjects (average reduction, 38.5%). In contrast, the sympathoinhibitory and sympathoexcitatory responses to baroreceptor stimulation and deactivation were displaced toward elevated blood pressure values but similar in all groups. Thus, sympathetic activation characterizes essential but not secondary hypertension. Regardless of its nature, however, hypertension is not accompanied by an impairment of baroreceptor modulation of sympathetic activity.

Sympathetic Activation and Loss of Reflex Sympathetic Control in Mild Congestive Heart Failure

BACKGROUND Baroreflex control of sympathetic activity is impaired in severe congestive heart failure (CHF), probably causing the marked sympathetic activation typical of this condition. Little information exists, however, as to whether baroreflex impairment and related sympathetic activation also occur in mild CHF. METHODS AND RESULTS We studied 19 patients (age, 57.5 +/- 2.2 years, mean +/- SEM) with CHF in New York Heart Association (NYHA) class III or IV and with a marked reduction in left ventricular ejection fraction (LVEF, 30.1 +/- 1.5% from echocardiography) and 17 age-matched patients with CHF in NYHA class I or II and with an only slightly reduced LVEF (44.9 +/- 3.3%) that never was < 40%. Seventeen age-matched healthy subjects served as control subjects. Primary measurements included beat-to-beat arterial blood pressure (with the Finapres technique), heart rate (from ECG), and postganglionic muscle sympathetic nerve activity (MSNA, from microneurography at the peroneal nerve). Measurements were performed at baseline and during baroreceptor stimulation (intravenous phenylephrine infusion), baroreceptor deactivation (intravenous nitroprusside infusion), and cold-pressor test. Baseline blood pressure was similar in the three groups, whereas heart rate was progressively greater from control subjects to patients with mild and severe CHF, MSNA (bursts per 100 heart beats) increased significantly and markedly from control subjects to patients with mild and severe CHF (47.1 +/- 2.9 versus 64.4 +/- 6.2 and 82.1 +/- 3.4, P < .05 and P < .01, respectively). Heart rate and MSNA were progressively reduced by phenylephrine infusion and progressively increased by nitroprusside infusion. Compared with control subjects, the responses were strikingly impaired in severe CHF patients, but a marked impairment also was seen in mild CHF patients. On average, baroreflex sensitivity in mild CHF patients was reduced by 59.1 +/- 5.5% (MSNA) and 64.8 +/- 4.8% (heart rate). In contrast, reflex responses to the cold-pressor test were similar in the three groups. CONCLUSIONS These results demonstrate that in mild CHF patients the baroreceptor inhibitor influence on heart rate and MSNA is already markedly impaired. This impairment may be responsible for the early sympathetic activation that occurs in the course of CHF.

Body Weight Reduction, Sympathetic Nerve Traffic, and Arterial Baroreflex in Obese Normotensive Humans

BACKGROUND Previous studies have shown that sympathetic cardiovascular outflow is increased in obese normotensive subjects and that this increase is associated with a baroreflex impairment. The purpose of this study was to determine whether these abnormalities are irreversible or can be favorably affected by body weight reduction. METHODS AND RESULTS In 20 obese normotensive subjects (age, 31.3+/-1.7 years; body mass index, 37.6+/-0.9 kg/m2, mean+/-SEM), we measured beat-to-beat arterial blood pressure (Finapres technique), heart rate (ECG), postganglionic muscle sympathetic nerve activity (microneurography at a peroneal nerve), and venous plasma norepinephrine (high-performance liquid chromatography) at rest and during baroreceptor stimulation and deactivation induced by increases and reductions of blood pressure via stepwise intravenous infusions of phenylephrine and nitroprusside. Measurements were repeated in 10 subjects after a 16-week hypocaloric diet with normal sodium content (4600 to 5000 J and 210 mmol NaCl/d) and in the remaining 10 subjects after a 16-week observation period without any reduction in the caloric intake. The hypocaloric diet significantly reduced body mass index, slightly reduced blood pressure, and caused a significant and marked decrease in both muscle sympathetic nerve activity (from 50.0+/-5.1 to 32.9+/-4.6 bursts per 100 heart beats, P<.01) and plasma norepinephrine (from 356.2+/-43 to 258.4+/-29 pg/mL, P<.05). This was associated with a significant improvement in the sensitivity of the baroreceptor heart rate (+71.5 +/- 11%, P<.01) and muscle sympathetic nerve activity (+124.5 +/- 22%, P<.001) reflex. Total body glucose uptake also increased significantly (+60.8 +/- 12.0%, P<.05), indicating an increase in insulin sensitivity. All variables remained unchanged in subjects not undergoing caloric restriction. CONCLUSIONS In obese normotensive subjects, a reduction in body weight induced by a hypocaloric diet with normal sodium content exerts a marked reduction in sympathetic activity owing to central sympathoinhibition. This can be due to the consequences of an increased insulin sensitivity but also to a restoration of the baroreflex control of the cardiovascular system with weight loss.

Effects of chronic ACE inhibition on sympathetic nerve traffic and baroreflex control of circulation in heart failure

BACKGROUND In congestive heart failure ACE inhibitors chronically reduce plasma norepinephrine. No information exists, however, on whether and to what extent this reduction reflects a true chronic inhibition of sympathetic outflow and which mechanisms may be responsible. METHODS AND RESULTS In 24 patients aged 60.3+/-2.0 years (mean+/-SEM) affected by congestive heart failure (New York Heart Association class II) and treated with diuretics and digitalis, we measured mean arterial pressure (Finapres), plasma renin activity and angiotensin II levels (radioimmunoassay), plasma norepinephrine (high-performance liquid chromatography), and muscle sympathetic nerve activity (microneurography at a peroneal nerve) at rest and during baroreceptor stimulation and deactivation caused by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. In 12 patients measurements were repeated after a 2-month addition of the ACE inhibitor benazepril (10 mg/d P.O.), while in the remaining 12 patients they were performed again after 2 months without any treatment modifications. Benazepril did not alter mean arterial pressure, markedly increased plasma renin activity, reduced plasma angiotensin II, and caused a nonsignificant reduction in plasma norepinephrine. In contrast, muscle sympathetic nerve traffic was significantly reduced (-30.5+/-5.3%, P<.01). This reduction was accompanied by no change in the sympathoexcitatory responses to baroreceptor deactivation but by a marked enhancement of the sympathoinhibitory responses to baroreceptor stimulation (103.5+/-3.4%). CONCLUSIONS These results provide the first direct evidence that in congestive heart failure chronic ACE inhibitor treatment is accompanied by a marked reduction in central sympathetic outflow. This reduction may depend on a persistent restoration of baroreflex restraint on the sympathetic neural drive.

Baroreflex Impairment by Low Sodium Diet in Mild or Moderate Essential Hypertension

Low sodium intake is the most widely used nonpharmacological approach to the treatment of hypertension. Although nonpharmacological treatment is by definition regarded as safe, the suggestion has been made that low sodium intake is not totally devoid of inconveniences, and animal data have shown it to be accompanied by an impairment of reflex blood pressure control and homeostasis. However, no data exist on this issue in humans. In mild essential hypertensive patients (age, 34.1+/-3.3 years [mean+/-SEM]), we measured beat-to-beat arterial blood pressure (finger photoplethysmographic device), heart rate (electrocardiogram), and efferent postganglionic muscle sympathetic nerve activity (microneurography) at rest and during baroreceptor stimulation and deactivation, induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Measurements were performed at the end of three dietary periods, ie, after 8 days of regular sodium intake (210 mmol NaCl/d), low sodium intake (20 mmol NaCl/d) with unchanged potassium intake, and again regular sodium intake. Compared with the initial regular sodium diet, low sodium intake reduced urinary sodium excretion, whereas urinary potassium excretion was unchanged. Systolic blood pressure was significantly (P<.05), although slightly, reduced, whereas diastolic blood pressure was unaffected. Muscle sympathetic nerve activity was increased by 23.1+/-5.2% (P<.05). The increase was accompanied by a clear-cut impairment of the baroreceptor ability to modulate muscle sympathetic nerve activity, ie, by a 43.9+/-5.7% (P<.01) reduction in the sensitivity of the baroreceptor-muscle sympathetic nerve activity reflex compared with the control condition. Baroreceptor modulation of heart rate was also impaired, although to a smaller and less consistent extent. When regular sodium intake was restored, all the above-mentioned parameters and baroreflex responses returned to the values observed at the initial regular sodium diet. These data raise evidence that in humans sodium restriction may impair the arterial baroreflex. This may be responsible for the sympathetic activation occurring in this condition and for the impairment of blood pressure homeostasis.

Reflex cardiovascular control in congestive heart failure

This article reviews evidence that the reflex control of the cardiovascular system provided by negative feedback mechanisms is impaired in congestive heart failure (CHF). The impairment involves vagal and sympathetic modulation of the heart exerted by arterial baroreceptors. It also affects baroreceptor control of blood pressure and peripheral vascular resistance, as well as the cardiopulmonary receptors ability to modulate sympathetic activity. The degree of such impairment is most marked in severe CHF but is also apparent, to a minor degree, in mild heart failure. Reflex impairment is due to a reduction in the receptor signal, but other factor under investigation are probably also involved. Digoxin and other pharmacologic treatments of CHF improve reflex function, thereby facilitating a reduction in the elevated sympathetic activity and a stepping up of the reduced vagal activity typical of CHF. This may be relevant to a patients prognosis.

Cardiac and vascular structural changes in normotensive subjects with parental hypertension

Objective To evaluate whether a predisposition to hypertension is associated with early cardiac and vascular alterations. Subjects Twenty-five normotensive subjects with both parents hypertensive (group 1) and 28 age- and sex-matched control subjects with both parents normotensive (group 2). Methods In the two groups the measurements included: clinic blood pressure; left ventricular end-diastolic diameter, septal wall thickness and posterior wall thickness (by echocardiography); minimal forearm and calf vascular resistances (i.e. resistance assessed immediately after prolonged ischaemia, which depends on arteriolar wall thickness); and baseline and postischaemic radial artery compliance-pressure curves over the systolodiastolic pressure range (by echotracking device and finger blood pressure). Results Group 1 had a slightly higher clinic blood pressure, and septal and posterior wall thickness, than group 2. Minimal forearm vascular resistance was clearly greater in group 1 than in group 2, whereas minimal calf vascular resistance was not significantly different in the two groups. Radial artery compliance was also similar in the two groups. Conclusions Parental predisposition to hypertension is accompanied by cardiac and arteriolar structural changes qualitatively similar to those found in hypertensive patients, although arteriolar structural changes do not involve all vascular beds. Arterial compliance is not altered in this condition. Vascular changes may be determined by mechanisms other than blood pressure elevation.

Sympathomoderating influence of benazepril in essential hypertension

Objective: In essential hypertension, captopril attenuates forearm vasoconstriction reflexly induced by deactivation of cardiopulmonary and arterial baroreceptors, thus exerting a sympathomoderating effect. We investigated whether this is a common effect of angiotensin converting enzyme (ACE) inhibitors. Methods and design: Cardiopulmonary and arterial baroreceptors were deactivated by progressively reducing central venous pressure (CVP) through progressively greater lower body negative pressures in eight untreated mild essential hypertensives on a moderately low-sodium diet (50mmol/l per day). This deactivation was performed after oral administration of the non-sulphidrylic ACE inhibitor benazepril (10 mg) and placebo according to a double-blind randomized crossover experimental design. Results: After placebo, the reduction in CVP increased forearm vascular resistance (FVR; mean arterial pressure: plethysmographic forearm blood flow ratio). After benazepril, baseline blood pressure (beat-to-beat finger pressure) and FVR were significantly reduced whilst plasma angiotensin II was suppressed and PRA increased (both measured by radioimmunoassay). The FVR increases induced by progressive CVP reduction were less than after placebo administration, and the overall difference was statistically significant. Benazepril did not affect the reflex FVR reduction observed by increasing CVP through leg raising, nor the reflex changes in plasma norepinephrine measured by high-performance liquid chromatography accompanying the changes in FVR. Conclusions: Benazepril attenuates sympathetic vasoconstriction as does captopril. This effect (which is mainly operative during an increased sympathetic drive and exerted through a reduction of adrenoceptor responsiveness) is thus likely to be a class- rather than a compound-related feature.

Reflex vasopressin and renin modulation by cardiac receptors in humans.

Animal studies have shown that vasopressin secretion is modulated by arterial baroreceptors and cardiopulmonary volume receptors. Whether this is the case also in humans is controversial, however. To determine whether vasopressin is reflexly modulated by cardiac volume receptors, we studied the effect on plasma vasopressin (venous blood, radioimmunoassay) of reducing venous return and left ventricular end-diastolic diameter (echocardiography) by producing a 20-minute lower body negative pressure in 14 healthy subjects (aged 49.3 +/- 3.8 years, mean +/- SEM). The data were compared with those of 14 age-matched heart-transplant recipients, i.e., subjects with cardiac denervation. In healthy subjects, lower body negative pressure at -15 mm Hg caused a modest reduction in left ventricular end-diastolic diameter (-5 +/- 3.4%) and no change in vasopressin, whereas lower body negative pressure at -37.5 mm Hg caused a more marked reduction in left ventricular end-diastolic diameter (-12 +/- 2.5%) and a small, variable, but overall statistically significant (p < 0.05) increase in vasopressin (+145 +/- 46%, p < 0.01). The left ventricular end-diastolic diameter changes induced by the two lower body negative pressure stimuli were similar in heart-transplant recipients, but the vasopressin increase seen with the lower body negative pressure at -37.5 mm Hg was abolished. The marked increase in plasma renin activity and forearm vascular resistance induced by lower body negative pressure in healthy subjects was also abolished or drastically attenuated in heart-transplant recipients.(ABSTRACT TRUNCATED AT 250 WORDS)