Carlo Turri

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 chronic angiotensin converting enzyme inhibition on sympathetic nerve traffic and baroreflex control of the circulation in essential hypertension.

Background Human studies have shown that the blood pressure lowering effects of angiotensin converting enzyme inhibitors are accompanied by a reduction in plasma norepinephrine levels. Whether this is due to central or peripheral mechanisms is unknown, however. Objective To evaluate the effects of chronic interference with the renin–angiotensin system on sympathetic nerve traffic and baroreflex control of vagal and adrenergic cardiovascular drive. Patients and methods In 18 untreated mild to moderate essential hypertensive patients aged 48.5 ± 1.9 years (mean ± SEM), we measured mean arterial pressure (Finapres), heart rate (electrocardiogram), plasma renin activity (radioimmunoassay), plasma norepinephrine (high-performance liquid chromatography) and postganglionic muscle sympathetic nerve activity (microneurography at a peroneal nerve). In nine patients, measurements were performed before and after 2 months of oral administration of lisinopril (10 mg/day), while in the remaining nine patients they were performed before and after a 2 month observation period, without the drug administration. Measurements were performed at rest and during baroreflex stimulation and deactivation elicited by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Results Lisinopril induced a marked increase in plasma renin activity (from 1.1 ± 0.2 to 6.4 ± 1.3 ng/ml per h, P < 0.01) and a reduction in mean arterial pressure (from 109.6 ± 3.1 to 98.7 ± 2.9 mmHg, P < 0.01) without affecting the heart rate. Plasma norepinephrine and muscle sympathetic nerve activity values were not significantly different before and after lisinopril treatment (plasma norepinephrine values changed from 290.4 ± 39.2 to 308.1 ± 67.1 pg/ml; muscle sympathetic nerve activity changed from 56.4 ± 5.3 to 50.6 ± 6.6 bursts/100 heart beats). Neither the sympathoinhibitory nor the sympathoexcitatory responses to phenylephrine and nitroprusside were affected by lisinopril, nor the concomitant bradycardia and tachycardia. The curves relating mean arterial pressure to heart rate and muscle sympathetic nerve activity values during baroreceptor manipulation were shifted to the left, indicating a resetting of the baroreflex to the lower blood pressure values achieved during treatment. Conclusions In essential hypertension, sympathetic nerve traffic is not affected by chronic angiotensin converting enzyme inhibitor treatment that effectively interferes with the renin–angiotensin system and lowers the elevated blood pressure. The baroreflex ability to modulate heart rate and central sympathetic outflow is also unaffected. These data argue against the existence of a central sympathoexcitatory effect of angiotensin II in this condition. They also indicate that antihypertensive treatment with an angiotensin converting enzyme inhibitor preserves autonomic reflex control, with favorable consequences for cardiovascular homeostasis.

Sympathetic and reflex alterations in systo-diastolic and systolic hypertension of the elderly

Background Previous studies have shown that young and middle-aged essential hypertensives are characterized by a sympathetic activation coupled with an impaired baroreflex-heart rate control. The present study aimed to determine whether these neuroadrenergic and reflex alterations also characterize systo-diastolic and systolic hypertension of the elderly. Subjects and methods In 20 untreated elderly essential hypertensive subjects [10 with a systo-diastolic and 10 with an isolated systolic hypertension, aged 67.2 ± 1.5 years and 66.9 ± 1.7 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. Data were compared with those obtained in 11 age-matched normotensive control subjects. Results Compared to the elderly normotensive group, muscle sympathetic nerve activity was increased to a similar degree in the group of systo-diastolic and systolic hypertension (50.8 ± 4.2 versus 75.2 ± 5.2 and 70.4 ± 5.1 bursts per 100 heart beats, respectively, P <0.01 for both). In the control group, the stepwise increase in arterial pressure induced by phenylephrine caused progressive bradycardia and sympathoinhibition, while the stepwise decrease in arterial pressure had opposite effects. While baroreceptor-heart rate control was markedly impaired (average reduction 41.6%), in both systo-diastolic and systolic hypertensive patients, baroreceptor modulation of sympathetic nerve traffic was similar to that seen in normotensive individuals. Conclusions These data demonstrate that sympathetic activation is not only a feature of young and middle-aged, but also of elderly hypertensives, regardless of whether both systolic and diastolic or only systolic blood pressure is increased. They also show that hypertension of the elderly is not accompanied by an impaired baroreceptor modulation of sympathetic nerve traffic.

Impairment of Thermoregulatory Control of Skin Sympathetic Nerve Traffic in the Elderly

Background—Human aging is characterized by a marked increase in muscle sympathetic nerve traffic (MSNA). No information exists, however, on the effects of aging on skin sympathetic nerve traffic (SSNA) and on its reflex modulation by thermoregulatory mechanisms. Methods and Results—In 13 young, 11 middle-aged, and 12 elderly healthy subjects, we measured arterial blood pressure (Finapres), skin temperature (thermocouples), and resting MSNA and SSNA (microneurography). Measurements also included the SSNA responses to (1) an acute increase and reduction (±8°C) in room temperature, each lasting 45 minutes and (2) an acoustic stimulus capable to trigger an emotional arousal. Although resting MSNA was progressively and significantly (P <0.05) increased from young to middle-aged and elderly groups, SSNA was significantly (P <0.05) reduced in the latter compared with the former 2 groups. Cold exposure induced a SSNA increase that was significantly (P <0.01) smaller in the elderly than in young and middle-aged subjects. Conversely, heat exposure induced a SSNA reduction that was significantly (P <0.05) smaller in elderly than in young and middle-aged subjects. Compared with SSNA in young individuals, the SSNA change from cold to warm temperature was reduced by 61% in the elderly group. This was not the case, however, for the SSNA responses to the arousal stimulus, which were superimposable in the 3 groups. Conclusions—These data provide the first demonstration of a dichotomy in the MSNA and SSNA responses to aging. They also show that aging markedly impairs thermoregulatory control of SSNA and that this impairment might participate at the age-related SSNA decrease.

Baroreflex and non-baroreflex modulation of vagal cardiac control after myocardial infarction

Vagal control of sinus node exerted by arterial baroreceptors is markedly impaired 48 hours after acute myocardial infarction (AMI), but it recovers 10 days later. However, it is unknown whether this recovery is peculiar to baroreceptor vagal control or reflects normalization of the overall vagal modulation of heart rate. In 21 untreated patients (aged 51+/-3 years, mean +/- SEM) studied 10+/-1 and 21+/-1 days after an AMI and in 13 healthy controls (aged 47+/-2 years), we examined the increases in RR interval (electrocardiogram) induced by carotid baroreceptor stimulation via a neck chamber and by immersion of the face in iced water for 15 seconds (diving reflex). Both 10 and 21 days after AMI, baseline blood pressure and RR interval values were superimposable to those obtained in controls. Ten days after AMI, the bradycardic responses to carotid baroreceptor stimulation were similar to those seen in controls (maximal RR interval lengthenings: 248+/-34 vs 270+/-31 ms, respectively, p = NS) and remained virtually unchanged later. In contrast, the bradycardic response to diving was reduced in patients after AMI compared with controls (maximal RR interval lengthenings: 203+/-43 vs 325+/-52 ms, respectively, p <0.05) and did not improve later. Thus, in AMI recovery of the early impairment of baroreceptor-heart rate control does not reflect normalization of vagal cardiac control, which remains lower than normal values at a time when the baroreflex is restored.

Short-Versus Long-Term Effects of Different Dihydropyridines on Sympathetic and Baroreflex Function in Hypertension

Abstract—Antihypertensive treatment with dihydropyridines may be accompanied by sympathetic activation. Data on whether this is common to all compounds and similar in the various phases of treatment are not univocal, however. In 28 untreated essential hypertensives (age, 56.4±1.8 years; mean±SEM) finger blood pressure (BP, Finapres), heart rate (HR, ECG), plasma norepinephrine (NE, high-performance liquid chromatography), and muscle sympathetic nerve traffic (MSNA, microneurography) were measured at rest and during baroreceptor manipulation (vasoactive drugs) in the placebo run-in period and after randomization to double-blind acute and chronic (8 weeks) felodipine (10 mg/d, n=14) or lercanidipine (10 mg/d, n=14). Acute administration of both drugs induced pronounced BP reductions and marked increases in HR, NE, and MSNA. After 8 weeks of treatment, BP reductions were similar to those observed after acute administration, whereas HR, NE, and MSNA responses were markedly attenuated (−7%, −32%, and −14%, respectively;P <0.05). There was a small residual increase in sympathetic activity in the felodipine group, whereas in the lercanidipine group, all adrenergic markers returned to baseline values. Baroreflex control of HR and MSNA was markedly impaired (−42% and −48%, respectively) after acute drug administration, with a recovery and complete resetting during chronic treatment. Thus, the sympathoexcitation induced by 2 different dihydropyridines is largely limited to the acute administration. The 2 drugs have, nevertheless, a different chronic sympathetic effect, indicating that dihydropyridines do not homogeneously affect this function. The acute sympathoexcitation, but not the small between-drugs differential chronic adrenergic effect, is accounted for by baroreflex impairment.

Sympathetic Nerve Traffic Responses to Surgical Removal of Pheochromocytoma

Pheochromocytoma is usually characterized by a marked increase in peripheral catecholamine secretion. Whether this is accompanied by an alteration in central sympathetic drive has not been clarified. In 6 patients with adrenal pheochromocytoma (mean+/-SEM age, 49. 3+/-7.2 years), we measured systolic and diastolic blood pressure (photoplethysmographic device), heart rate (ECG), venous plasma catecholamines (high-performance liquid chromatography), and postganglionic muscle sympathetic nerve activity (microneurography) before and 78.3+/-13 days after surgical removal of the tumor. In each experimental session, measurements were performed during (1) a 60-minute resting period to compare several values of sympathetic nerve traffic at similar blood pressures before and after surgery and (2) voluntary end-expiratory apnea, ie, a maneuver inducing sympathetic activation. Tumor removal significantly (P<0.05 at least) reduced plasma catecholamines, blood pressure, and heart rate. In contrast, muscle sympathetic nerve activity was significantly (P<0.01) increased, both when quantified as bursts per minute (from 28.1+/-5.7 to 54.3+/-7.5) and as bursts per 100 heartbeats (from 33. 4+/-5.6 to 65.1+/-6.5). This was also the case when data were evaluated in periods of 2 experimental sessions characterized by similar diastolic blood pressure values. The apnea maneuver induced sympathetic nerve traffic responses that were significantly (P<0.05) greater after surgery than before surgery. These data provide the first direct evidence that in pheochromocytoma central sympathetic outflow is markedly reduced and that this reduction cannot be ascribed to a reflex inhibitory response to elevated blood pressures. It is likely that this sympathoinhibition is rather due to a central depression of sympathetic outflow induced by high circulating catecholamines.

Effects of Chronic Clonidine Administration on Sympathetic Nerve Traffic and Baroreflex Function in Heart Failure

Abstract—Congestive heart failure is characterized by a sympathetic activation that is coupled with a baroreflex impairment. Whether these alterations are affected by clonidine is unknown. In 26 normotensive patients age 58.0±1.1 years (mean±SEM) affected by congestive heart failure (New York Heart Association functional class II or III) and treated with furosemide and enalapril, we measured mean arterial pressure, heart rate, venous plasma norepinephrine, and muscle sympathetic nerve traffic (microneurography) at rest and during baroreceptor stimulation and deactivation caused by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Measurements were repeated after a 2-month administration of transdermal clonidine patch (14 patients) or placebo (12 patients) according to a double-blind, randomized sequence. Clonidine caused a slight, nonsignificant reduction in mean arterial pressure and heart rate without affecting exercise capacity and echocardiographically determined left ventricular ejection fraction. In contrast, both plasma norepinephrine and sympathetic nerve traffic were significantly reduced (−46.8% and −26.7%, respectively;P <0.01 for both). This reduction was coupled with no change in cardiac and sympathetic baroreflex responses. Transdermal placebo administration for a 2-month period did not affect any of the above-mentioned variables. Thus, in congestive heart failure patients who are undergoing conventional drug treatment, chronic clonidine administration exerts marked sympathoinhibitory effects without adversely affecting cardiac functions and clinical state. Whether this leads to further therapeutic benefits remains to be tested.

Sympathetic Response to Ventricular Extrasystolic Beats in Hypertension and Heart Failure

Provoked premature ventricular contractions (PVCs) evoke, in concomitance with an early and late blood pressure fall and overshoot, an early sympathoexcitation and a later period of sympathoinhibition, respectively. The present study was designed to examine whether in healthy subjects this is the case for spontaneous PVCs. Because of their pathophysiological relevance for arrhythmogenesis, it was also designed to determine whether the sympathetic responses are different from those seen in essential hypertension and congestive heart failure. In 14 untreated mild essential hypertensives (EH; age, 53.8±2.6 years; mean±SEM), 20 untreated congestive heart failure patients (CHF; age, 56.7±2.5 years; New York Heart Association class, II or III), and 16 age-matched healthy subjects (control) in Lown class <II, we evaluated the blood pressure (Finapres), heart rate (ECG), and muscle sympathetic nerve traffic (MSNA; by microneurography) responses to isolated monofocal PVCs. MSNA, quantified as bursts/100 heart beats, was significantly increased in EH (57.8±3.8, P <0.05) and CHF patients (77.7±4.0, P <0.01) compared with controls (44.6±4.4). In controls, the PVC-induced blood pressure fall and overshoot were accompanied by a sympathoexcitation (144.2±14%), followed by a period of sympathoinhibition (average duration, 12043±985 ms). The responses were similar in EH but not in CHF, in whom the magnitude of the sympathoexcitation and particularly the duration of the subsequent sympathoinhibition were strikingly reduced (average reduction, −46.1 and −72.8%, respectively). The most important factor accounting for this reduction appeared to be an altered baroreflex response to the PVC-induced BP changes. These data demonstrate that the MSNA responses to spontaneous PVCs are similar in controls and EH but markedly impaired in CHF, presumably because of the baroreflex alteration. This may represent an important factor for the genesis of the life-threatening ventricular arrhythmias that characterize CHF.

Comparison of angiotensin II receptor blockers: impact of missed doses of candesartan cilexetil and losartan in systemic hypertension.

Blood pressure remains poorly controlled in the hypertensive population due in large part to low or unsatisfactory patient compliance. Clinical studies that incorporate an intentionally missed dose have been designed to evaluate the impact of poor patient compliance on the effectiveness of antihypertensive medications. In these studies, ambulatory blood pressure monitoring is continued throughout the dosing interval and beyond in order to determine when systolic and diastolic blood pressure increase into the hypertensive range. In an 8-week, randomized, double-blind, placebo-controlled trial in patients with mild-to-moderate hypertension, the antihypertensive effects of candesartan cilexetil 16 mg were maintained after a missed dose, whereas systolic and diastolic blood pressure increased toward baseline levels after a missed dose of losartan 100 mg. Candesartan cilexetil provided a significantly greater reduction in sitting systolic (p = 0.004) and diastolic blood pressure (p = 0.008) than losartan when measured 48 hours after the last dose. Moreover, the homogeneity of antihypertensive effects was greater after candesartan cilexetil than losartan based on calculation of the smoothness index from ambulatory systolic and diastolic measurements during the first 24-hour period after dosing and during the 12-hour period after the missed dose. These results demonstrate that missing or delaying a dose of candesartan cilexetil has less impact on antihypertensive efficacy than missing or delaying a dose of losartan.