G. Bolla

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.

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.

Mechanisms responsible for sympathetic activation by cigarette smoking in humans.

The pressor and tachycardic effects of cigarette smoking are associated with an increase in plasma catecholamines, suggesting the dependence of these effects on adrenergic stimulation. Whether the stimulation occurs at a central or a peripheral level and whether reflex mechanisms are involved is unknown. Methods and ResultsIn nine normotensive healthy subjects (age, 33.0±3.5 years, mean±SEM), we measured blood pressure (Finapres device), heart rate (ECG), calf blood flow and vascular resistance (venous occlusion plethysmography), plasma norepinephrine and epinephrine (high-performance liquid chromatography assay), and postganglionic muscle sympathetic nerve activity (microneurography from the peroneal nerve) while subjects were smoking a filter cigarette (nicotine content, 1.1 mg) or were in control condition. Cigarette smoking (which raised plasma nicotine measured by highperformance liquid chromatography from 1.0±0.9 to 44.2±7.1 ng/mL) markedly and significantly increased mean arterial pressure (+13.2±2.3%), heart rate (+30.3±4.7%), calf vascular resistance (+ 12.1±4.9%), plasma norepinephrine (+34.8±7.0%), and plasma epinephrine (+90.5±39.0%). In contrast, muscle sympathetic nerve activity showed a marked reduction (integrated activity −31.8±5.1%, P < .01). The reduction was inversely related to the increase in mean arterial pressure (r= −.67, P < .05), but the slope of the relation was markedly less (−54.1±7.5%, P < .05) than that obtained by intravenous infusion of phenylephrine in absence of smoking. The hemodynamic and neurohumoral changes were still visible 30 minutes after smoking and occurred again on smoking a second cigarette. Sham smoking was devoid of any hemodynamic and neurohumoral effect. ConclusionsThese data support the hypothesis that in humans the sympathetic activation induced by smoking depends on an increased release and/or a reduced clearance of catecholamines at the neuroeffector junctions. Central sympathetic activity is inhibited by smoking, presumably via a baroreceptor stimulation triggered by the smoking-related pressor response. The baroreflex is impaired by smoking, however, indicating that partial inability to reflexly counteract the effect of sympathetic activation is also responsible for the pressor response.

Adrenergic and Reflex Abnormalities in Obesity-Related Hypertension

Previous studies have shown that essential hypertension and obesity are both characterized by sympathetic activation coupled with a baroreflex impairment. The present study was aimed at determining the effects of the concomitant presence of the 2 above-mentioned conditions on sympathetic activity as well as on baroreflex cardiovascular control. In 14 normotensive lean subjects (aged 33.5±2.2 years, body mass index 22.8±0.7 kg/m2 [mean±SEM]), 16 normotensive obese subjects (body mass index 37.2±1.3 kg/m2), 13 lean hypertensive subjects (body mass index 24.0±0.8 kg/m2), and 16 obese hypertensive subjects (body mass index 37.5±1.3 kg/m2), all age-matched, we measured beat-to-beat arterial blood pressure (by Finapres device), heart rate (HR, by ECG), and postganglionic muscle sympathetic nerve activity (MSNA, by microneurography) at rest and during baroreceptor stimulation and deactivation induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Blood pressure values were higher in lean hypertensive and obese hypertensive subjects than in normotensive lean and obese subjects. MSNA was significantly (P <0.01) greater in obese normotensive subjects (49.1±3.0 bursts per 100 heart beats) and in lean hypertensive subjects (44.5±3.3 bursts per 100 heart beats) than in lean normotensive control subjects (32.2±2.5 bursts per 100 heart beats); a further increase was detectable in individuals with the concomitant presence of obesity and hypertension (62.1±3.4 bursts per 100 heart beats). Furthermore, whereas in lean hypertensive subjects, only baroreflex control of HR was impaired, in obese normotensive subjects, both HR and MSNA baroreflex changes were attenuated, with a further attenuation being observed in obese hypertensive patients. Thus, the association between obesity and hypertension triggers a sympathetic activation and an impairment in baroreflex cardiovascular control that are greater in magnitude than those found in either of the above-mentioned abnormal conditions alone.

Effect of central and peripheral body fat distribution on sympathetic and baroreflex function in obese normotensives

Background Previous studies have shown that obesity is characterized by a sympathetic overactivity coupled with an insulin resistance state and a baroreflex impairment. The present study was set out to compare the effects of peripheral versus central obesity on sympathetic, metabolic and reflex function. Methods In 36 lean subjects (age 35.8 ± 1.4 years, mean ± SEM), 20 subjects with peripheral obesity (PO) and 26 subjects with central obesity (CO), all age-matched and with normal blood pressure values, we measured beat-to-beat arterial blood pressure (Finapres), heart rate (HR, ECG), homeostasis model assessment (HOMA) index, plasma norepinephrine (NE, high-performance liquid chromatography) and postganglionic muscle sympathetic nerve traffic (MSNA, microneurography) at rest and during baroreceptor stimulation and deactivation induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Results Both HOMA index, NE and MSNA values were significantly increased (P < 0.01) in obese as compared with lean individuals. Subjects with CO displayed MSNA and HOMA values significantly greater than those found in individuals with PO (65.4 ± 2.0 versus 47.9 ± 1.9 bs/100hb and 2.85 ± 0.10 versus 2.43 ± 0.11 a.u., respectively, P < 0.05 for both). Both in male and female subjects with CO or PO, MSNA, HOMA index and waist-to-hip ratio were significantly related to each other. Baroreceptor-HR and -MSNA control was significantly (P < 0.01) impaired in obese as compared with lean subjects, the degree of impairment being similar in CO and PO. Conclusions These data suggest that CO is characterized by a sympathetic activation greater for magnitude than that detectable in PO. This appears not to be related to gender or to baroreflex mechanisms but rather to metabolic factors, i.e. to the greater insulin resistance characterizing CO.

Cardiopulmonary reflex before and after regression of left ventricular hypertrophy in essential hypertension.

Studies that have examined the cardiopulmonary receptor control of circulation in hypertension have produced conflicting results. In 10 normotensive subjects and in age-matched essential hypertensive subjects without (n = 10) or with left ventricular hypertrophy (n = 12), as well as in seven subjects of the latter group restudied after 1 year of treatment that induced regression of cardiac hypertrophy, we examined the cardiopulmonary reflex by increasing central venous pressure and stimulating cardiopulmonary receptors through passive leg raising and by reducing central venous pressure and deactivating cardiopulmonary receptors through nonhypotensive lower body negative pressure. Reflex responses were measured as changes in forearm vascular resistance (mean blood pressure divided by plethysmographically measured blood flow), plasma norepinephrine concentration, and plasma renin activity. In hypertensive subjects without left ventricular hypertrophy, stimulation and deactivation of cardiopulmonary receptors caused changes in forearm vascular resistance, norepinephrine concentration, and plasma renin activity that were modestly reduced as compared with those in normotensive subjects. However, all these changes were markedly reduced in hypertensive subjects with left ventricular hypertrophy. Following regression of left ventricular hypertrophy, the changes in vascular resistance, plasma norepinephrine, and plasma renin activity induced by cardiopulmonary receptor manipulation all unproved markedly. These results demonstrate that cardiopulmonary receptor regulation of peripheral vascular resistance and of neurohumoral variables is impaired in essential hypertension and that the impairment is much more pronounced when this condition is associated with cardiac structural alterations. Therapeutic regression of these alterations, however, leads to a marked improvement of this reflex, with consequent favorable effects on circulatory homeostasis.

CIGARETTE SMOKING AND THE ADRENERGIC NERVOUS SYSTEM

The acute increase in blood pressure and heart rate that accompanies cigarette smoking is associated with a rise in plasma catecholamines and it is thus believed to result from stimulation of the adrenergic nervous system. We have employed direct recording of efferent post-ganglionic sympathetic nerve activity by the microneurographic technique from the peroneal nerve to determine whether this stimulation occurs centrally or peripherally. It was shown that during cigarette smoking blood pressure, heart rate, plasma norepinephrine and epinephrine do increase markedly. Sympathetic nerve activity, however, shows a concomitant specular reduction. Thus peripheral (adrenal gland stimulation, reduction in norepinephrine reuptake, reduction in catecholamine clearance, etc.) rather than central mechanisms explain the adrenergic involvement in the acute hemodynamic effect of smoking, the central sympathetic drive being inhibited rather than excited probably as a result of arterial baroreceptor stimulation.

Preservation of the Baroreceptor Heart Rate Reflex by Chemical Sympathectomy in Experimental Heart Failure

Background—The mechanisms underlying impaired baroreflex sensitivity in congestive heart failure (CHF) are incompletely understood. The purpose of the present study was to test the hypothesis that this alteration depends on the marked degree of sympathetic overactivity known to characterize the CHF syndrome. Methods and Results—Eight-week-old rats were subjected to induction of postmyocardial infarction CHF obtained by coronary ligation (Lig), chronic chemical sympathectomy by 6-hydroxydopamine (Sx), both interventions (Sx-Lig), or neither intervention (Veh-Sham, sham surgery, and vehicle administration). Four weeks after infarction, in conscious state, baroreflex sensitivity was assessed from the bradycardic responses to graded phenylephrine-induced elevations in blood pressure (BP). Left ventricular (LV) diameter was assessed by echocardiography, and plasma catecholamines were assayed to estimate sympathetic activity. Lungs were eventually excised and weighed (LW). CHF was associated with the following: (1) no changes in BP and heart rate; (2) sympathetic overactivity (norepinephrine, 320.2±53.8 pg/mL for Veh-Lig versus 173.4±20.5 pg/mL for Veh-Sham, P <0.01), prevented by Sx (181.2±35.5 pg/mL for Sx-Lig versus 159.8±33.1 pg/mL for Sx-Sham, P =NS); (3) LV enlargement (10.3±0.7 mm for Veh-Lig versus 6.8±0.6 mm for Veh-Sham, P <0.01), irrespective of Sx (9.7±0.7 mm for Sx-Lig versus 6.6±0.5 mm for Sx-Sham, P <0.01); (4) pulmonary congestion (LW, 7.55±0.40 mg per gram of body weight for Veh-Lig versus 5.21±0.44 mg per gram of body weight for Veh-Sham, P <0.01), marginally attenuated by Sx (6.54±0.28 mg per gram of body weight for Sx-Lig versus 4.98±0.22 mg per gram of body weight for Sx-Sham, P <0.05); (5) reduction in baroreflex sensitivity (0.443±0.032 ms/mm Hg for Veh-Lig versus 0.860±0.420 ms/mm Hg for Veh-Sham, P <0.01), entirely prevented by Sx (1.217±0.058 ms/mm Hg for Sx-Lig versus 1.345±0.093 ms/mm Hg for Sx-Sham, P =NS). Conclusions—In early post-MI CHF, sympathectomy only partially attenuated LV dysfunction and entirely prevented baroreflex sensitivity impairment that arises from enhanced sympathetic activity.

Early effects of total paracentesis and albumin infusion on muscle sympathetic nerve activity in cirrhotic patients with tense ascites

BACKGROUND/AIMS Cirrhotic patients with ascites are characterized by a marked activation of the sympathetic and the renin-angiotensin-aldosterone system. Total paracentesis is associated with a short-lived suppression of the renin-angiotensin-aldosterone system. Little information exists as to whether this favourable effect is parallelled by sympathoinhibition. METHODS In 16 Child C cirrhotic patients (age: 57.1+/-6.2 years, mean+/-SEM) with tense ascites we assessed the time course of the effects of total paracentesis followed by intravenous albumin (6-8 g/l of ascites) on beat-to-beat mean arterial pressure (Finapres), heart rate, plasma norepinephrine, epinephrine (high performance liquid chromatography) and muscle sympathetic nerve activity (microneurography, peroneal nerve). Measurements were obtained under baseline conditions, during staged removal of ascitic fluid (250 ml/min) and 24 h later. The patient remained supine throughout the study period. RESULTS Total paracentesis (10.6+/-1.3 l) induced a decrease in mean arterial pressure (from 95.0+/-2.6 mmHg to 88.2+/-3.2 mmHg, p<0.01), in heart rate (from 82.5+/-3.3 beats/min to 77.1+/-2.8 beats/min, p<0.01) and a reduction in plasma norepinephrine values (from 782+/-133 pg/ml to 624+/-103 pg/ml, p<0.01), which were substantially maintained 24 h later. In eight patients muscle sympathetic nerve activity did not change during paracentesis (from 65+/-7.1 bursts/min to 65+/-7.4 bursts/min, p=NS), but a marked reduction was observed 24 h later (48.4+/-5.6 bursts/min, p<0.01). CONCLUSIONS These data provide the first evidence that total paracentesis exerts an acute marked sympathoinhibitory effect. Whether this is a long-lasting phenomenon and to what extent plasma expansion with albumin contributes to this effects need to be further addressed.

Antihypertensive Effect of Barnidipine 10 mg or Amlodipine 5 to 10 mg Once Daily in Treatment-Naive Patients with Essential Hypertension : A 24-Week, Randomized, Open-Label, Pilot Study

BACKGROUND Dihydropyridine calcium antagonists are largely employed for the treatment of hypertension, coronary heart disease, and heart failure. OBJECTIVE The aim of our study was to compare the antihypertensive effect of the dihydropyridine calcium antagonists barnidipine and amlodipine. METHODS This was a 24-week, randomized, open-label, pilot study. Consecutive treatment-naive patients with grade I or II essential hypertension (office sitting systolic blood pressure [BP] of 140-179 mm Hg and diastolic BP of 90-109 mm Hg) were enrolled. The primary end points were the effect of treatment with either barnidipine 10 mg or amlodipine 5 mg once daily on office and ambulatory BP, left ventricular mass index (LVMI), and markers of cardiac damage, serum procollagen type I C-terminal propeptide, and plasma amino-terminal pro-B-type natriuretic peptide concentrations. Patients were assessed at enrollment, and 12 and 24 weeks. During each visit, the prevalence of adverse events (AEs) was also monitored using spontaneous reporting, patient interview, and physical examination, the relationship to study drug being determined by the investigators. Compliance with treatment was assessed at each study visit by counting returned tablets. RESULTS Thirty eligible patients (20 men, 10 women; mean [SD] age, 47 [12] years) were included in the study; all patients completed the 24 weeks of study treatment. Twelve weeks after randomization, 6 patients in the amlodipine group had their dose doubled to 10 mg due to inadequate BP control. Mean BP reductions at study end were not significantly different between the barnidipine and amlodipine groups (office BP, -10.3/-9.4 vs -16.6/-9.1 mm Hg; ambulatory BP, 9.4/6.4 vs 8.1/5.1 mm Hg). Reductions in LVMI and markers of cardiac damage were not significantly different between the 2 groups. Significantly more patients in the amlodipine group reported drug-related AEs compared with those in the barnidipine group (9 [60%] vs 2 [13%]; P < 0.05). CONCLUSION In this small sample of treatment-naive hypertensive patients, the antihypertensive effect of barnidipine 10 mg once daily was not significantly different from that of amlodipine 5 to 10 mg once daily.