Effects of amlodipine on sympathetic nerve traffic and baroreflex control of circulation in heart failure

Short-acting calcium antagonists exert a sympathoexcitation that in heart failure further enhances an already elevated sympathetic activity. Whether this is also the case for long-acting formulations is not yet established, despite the prognostic importance of sympathetic activation in heart failure. It is also undetermined whether in this condition long-acting calcium antagonists favorably affect a mechanism potentially responsible for the sympathetic activation, ie, the baroreflex impairment. In 28 heart failure patients (NYHA functional class II) under conventional treatment we measured plasma norepinephrine and efferent postganglionic muscle sympathetic nerve activity (microneurography) at rest and during arterial baroreceptor stimulation and deactivation induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Measurements were performed at baseline and after 8 weeks of daily oral amlodipine administration (10 mg/d, 14 patients) or before and after an 8-week period without calcium antagonist administration (14 patients). Amlodipine caused a small and insignificant blood pressure reduction. Heart rate, left ventricular ejection fraction, and plasma renin and aldosterone concentrations were not affected. This was the case also for plasma norepinephrine (from 2.43+/-0.41 to 2.50+/-0.34 nmol/L, mean+/-SEM), muscle sympathetic nerve activity (from 54.4+/-5.9 to 51.0+/-4.3 bursts/min), and arterial baroreflex responses. No change in the above-mentioned variables was seen in the control group. Thus, in mild heart failure amlodipine treatment does not adversely affect sympathetic activity and baroreflex control of the heart and sympathetic tone. This implies that in this condition long-acting calcium antagonists can be administered without untoward neurohumoral effects anytime conventional treatment needs to be complemented by drugs causing additional vasodilatation.     

Enalaprilat augments arterial and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with heart failure

Objectives. This study sought to determine the effects of enalaprilat on reflex control of sympathetic nerve activity.Background. Angiotensin-converting enzyme inhibitors decrease mortality in patients with congestive heart failure. Their efficacy appears to be related importantly to antiadrenergic effects, the mechanism for which has not been determined. Because baroreflexes tonically inhibit sympathetic outflow, and baroreflexes are blunted in heart failure, we hypothesized that these agents reduce sympathetic activity by augmenting baroreflexes.Methods. We assessed baroreflex control sympathetic nerve activity and heart rate in patients with congestive heart failure and in control subjects before and after enalaprilat (0.02 mg/kg body weight intravenously). Arterial baroreflexes were perturbed by bolus administration of sodium nitroprusside and phenylephrine. Cardiopulmonary baroreflexes were perturbed by lower body negative pressure and head-down tilt. Muscle sympathetic nerve activity was recorded by microneurography.Results. Enalaprilat decreased systolic blood pressure in patients with heart failure and control subjects. Sympathetic nerve activity increased in control subjects but decreased in patients with heart failure after enalaprilat despite reductions in central venous pressure in this group. Baroreflex control of sympathetic nerve activity was unchanged by enalaprilat in control subjects. In patients with heart failure, both arterial and cardiopulmonary baroreflex control of sympathetic nerve activity was enhanced by enalaprilat. Baroreflex control of heart rate was unchanged by enalaprilat in either group.Conclusions. Enalaprilat augments both arterial and cardiopulmonary baroreflex control of sympathetic activity in heart failure. These augmented inhibitory influences are associated with a reduction in sympathetic outflow and may contribute to the beneficial effects of angiotensin-converting enzyme inhibitors in heart failure.     

依那普利对心力衰竭患者血压及交感活性的影响

目的 研究不同剂量依那普利治疗后,在不同血压水平对充血性心力衰竭患者交感神经活性的影响.方法 选取2012年1月至2013年4月在江苏省泰兴市人民医院住院的心力衰竭患者,在未服降压药物的情况下,血压110/70 mm Hg（1 mm Hg=0.133 kPa）以上,纽约心脏协会心功能Ⅲ级或不必卧床的Ⅳ级.所有患者在入院时进行病史资料采集,并检测血浆肾上腺素、去甲肾上腺素、肾素、血管紧张素Ⅱ、醛固酮浓度.入选后予依那普利口服,起始剂量5 mg/d,根据血压情况,逐渐加量至10 mg/d.三周后按平均收缩压≥100 mm Hg和＜100 mm Hg分为A组和B组.对于A组患者,从第4周开始,增加药物剂量,至平均收缩压＜100 mmHg,并维持至第6周.B组患者继续原治疗方案至第6周.在第3周和第6周分别进行上述神经内分泌因子活性检测,比较不同时间段两组神经内分泌因子的活性.结果 48例患者入选,其中A组26例,B组22例.两组治疗前临床特点、交感活性及治疗后左心室射血分数比较,差异无统计学意义（P＞0.05）.治疗6周后,A组血管紧张素转换酶抑制剂（ACEI）剂量较B组大,差异有统计学意义[（14.3±4.5） mg vs.（7.5±2.4） mg,P＜0.05].两组肾上腺素、去甲肾上腺素浓度比治疗前显著降低,差异有统计学意义[A组肾上腺素：（256.1±77.3） pg/mL vs.（168.7±53.3）,P＜0.05;A组去甲肾上腺素：（1 734±534） pg/mL vs.（844±399） pg/mL,P＜0.05;B组肾上腺素：（248.7±62.3） pg/mL vs.（218.1±60.3） pg/mL,P＜0.05;B组去甲肾上腺素（1 645±619）pg/mL vs.（1 084±431） pg/mL,P＜0.05],且A组下降更明显.两组治疗前后血浆肾素、血管紧张素、醛固酮变化不明显,差异无统计学意义（P＞0.05）.结论 血管紧张素转换酶抑制剂治疗后,达到相同目标血压时,较大治疗剂量患者交感活性下降明显,而治疗剂量较小者交感活性虽有下降,但下降幅度小,提示对于后者应当采取各种措施进一步降低交感活性.     

Effects of chronic clonidine administration on sympathetic nerve traffic and baroreflex function in heart failure

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.     

Reflex control of renal sympathetic nervous activity in heart failure

It is not completely clear if the renal sympathetic nerves are essential for normal renal function, however, it has been reasonably well established that the renal nerves can influence renal function under experimental conditions. These influences are manifested as changes in sodium excretion, urine flow, renin release, renal blood flow and glomerular filtration rate. Under conditions of stress the renal nerves can have powerful influences on renal function and, as a result, on systemic hemodynamics. Because renal sympathetic outflow is under central control, the reflex modulation of renal nerve activity is an extremely important factor in the control of salt and water balance. We have shown that cardiac and arterial baroreflex control of renal nerve activity is abnormal in chronic congestive heart failure. The mechanisms for this abnormality can reside in any arm of the reflex arc. The evidence from this and other laboratories has clearly implicated the afferent limb of these reflexes as being abnormal. Experiments done in anesthetized dogs with pacing induced heart failure have indicated that the central component of these reflexes are probably normal. The experiments described above cannot differentiate between abnormal afferent mechanisms and abnormal end organ responses to renal nerve stimulation. Several humoral mechanisms may be operative in heart failure to modulate renal nerve activity. These include bradykinin, prostaglandins and the renin-angiotensin aldosterone axis. Future work should be directed towards a further understanding of the role played by these and other humoral factors in the control of renal sympathetic outflow in heart failure.     

Effects of orthotopic heart transplantation on sympathetic control mechanisms in congestive heart failure

Abnormal sympathetic nervous system activity in severe congestive heart failure (CHF) was studied in 14 patients before and 3 to 6 months after orthotopic heart transplantation. Before transplantation plasma norepinephrine (NE) levels at rest were elevated (909 +/- 429 pg/ml, p less than 0.01 compared with normal, 185 +/- 60 pg/ml). No reflex activation of the sympathetic nervous system was seen with infusion of sodium nitroprusside despite a significant decrease in arterial pressure. The response to orthostatic tilt also was blunted in the patients before transplantation. Exercise capacity was reduced in these patients and plasma NE increased promptly at low exercise loads. After cardiac transplantation plasma NE levels returned to normal (319 +/- 188 pg/ml) and the sympathetic response to the stresses of orthostatic tilt (320 +/- 196 to 419 +/- 197, p less than 0.002) and nitroprusside infusion (255 +/- 94 to 555 +/- 130, p less than 0.001) normalized within 6 months after transplantation. Exercise capacity increased and the increase in plasma NE levels at various exercise loads was reduced for any given workload. Therefore, abnormal adrenergic activity in patients with severe CHF results mostly from the reduction in left ventricular pump function and is reversible if adequate pump function is restored.     

Differential effects of captopril and nicardipine on baroreflex control of sympathetic nerve activity and heart rate in renal hypertension.

OBJECTIVE: To test the hypothesis that an angiotensin I converting enzyme inhibitor and a calcium channel blocker have different effects on the arterial baroreflex in renal hypertension. DESIGN AND METHODS: We examined the baroreflex control of renal sympathetic nerve activity and heart rate before and after blood pressure was reduced by a similar magnitude (11 +/- 1 mmHg) with intravenous captopril or nicardipine in two-kidney, one clip hypertensive (mean arterial pressure 92 +/- 2 mmHg, n = 12) and normotensive rabbits (mean arterial pressure 75 +/- 1 mmHg, n = 9) in the conscious state. Data obtained during activation and deactivation of baroreceptors were analysed with logistic function curves, and the maximum slope of the curve was taken as the sensitivity of the baroreflex. RESULTS: The maximum slopes of the curves relating mean arterial pressure to renal sympathetic nerve activity and to the heart rate in hypertensive rabbits were significantly smaller than the maximum slopes in normotensive rabbits. In renal hypertensive rabbits, the maximum slope of the mean arterial pressure-renal sympathetic nerve activity curve was increased with captopril compared with that with vehicle. In contrast, the maximum slope of the mean arterial pressure-heart rate curve was increased with nicardipine compared with that with vehicle. CONCLUSIONS: Our data indicating that the baroreflex control of renal sympathetic nerve activity was improved by captopril and that baroreflex control of the heart rate was potentiated by nicardipine suggest that these classes of antihypertensive agents had differential effects in conscious hypertensive rabbits.     

Brain-selective overexpression of angiotensin-converting enzyme 2 attenuates sympathetic nerve activity and enhances baroreflex function in chronic heart failure

Angiotensin-converting enzyme 2 (ACE2) has been suggested to be involved in the central regulation of autonomic function. During chronic heart failure (CHF), elevated central angiotensin II signaling contributes to the sustained increase of sympathetic outflow. This is accompanied by a downregulation of ACE2 in the brain. We hypothesized that central overexpression of ACE2 decreases sympathetic outflow and enhances baroreflex function in CHF. Transgenic mice overexpressing human ACE2 selectively in the brain (SYN-hACE2 [SA]) and wild-type littermates (WT) were used. CHF was induced by permanent coronary artery ligation. Four weeks after coronary artery ligation, both WT and SA mice exhibited a significant decrease in left ventricular ejection fraction (<40%). A slight decrease in mean arterial pressure was found only in SA mice. Compared with WT mice with CHF, brain-selective ACE2 overexpression attenuated left ventricular end-diastolic pressure; decreased urinary norepinephrine excretion; baseline renal sympathetic nerve activity (WT CHF: 71.6±7.6% max versus SA CHF: 49.3±6.1% max); and enhanced baroreflex sensitivity (maximum slope: WT sham: 1.61±0.16%/mm Hg versus SA CHF: 1.51±0.17%/mm Hg). Chronic subcutaneous blockade of mas receptor increased renal sympathetic nerve activity in SA mice with CHF (A779: 67.3±5.8% versus vehicle: 46.4±3.6% of max). An upregulation in angiotensin II type 1 receptor expression was detected in medullary nuclei in WT CHF mice, which was significantly attenuated in SA mice with CHF. These data suggest that central ACE2 overexpression exerts a potential protective effect in CHF through attenuating sympathetic outflow. The mechanism for this effect involves angiotensin (1-7) mas signaling, as well as a decrease in angiotensin II type 1 receptor signaling in the medulla.     

Insulin in the brain increases gain of baroreflex control of heart rate and lumbar sympathetic nerve activity

Chronic central administration of insulin increases the gain of baroreflex control of heart rate, but whether baroreflex control of the sympathetic nervous system is similarly affected is unknown. The sites and mechanisms by which brain insulin influences the baroreflex are also unclear. Therefore, the present study tested the hypothesis that acute infusion of insulin into the brain ventricles of urethane-anesthetized rats increases gain of baroreflex control of heart rate and lumbar sympathetic nerve activity and that this action is gender specific. Furthermore, to identify the location within the brain that mediates these effects, insulin was infused into either the lateral ventricle or the fourth ventricle. Lateral ventricular insulin infusion increased the gain of baroreflex control of heart rate (2.1+/-0.3 to 4.0+/-0.6 bpm/mm Hg; P<0.05) and sympathetic activity (2.3+/-0.3% to 4.8+/-1.1% control/mm Hg; P<0.05) within 60 to 90 minutes; however, the increase in heart rate gain was similar in males and females. Increases in the maximum of baroreflex control of heart rate (395+/-10 to 452+/-13 bpm; P<0.05) and of sympathetic activity (156+/-13% to 253+/-22% control; P<0.05) were also observed. In contrast, fourth ventricular insulin infusion failed to alter baroreflex function. In conclusion, increases in brain insulin act acutely in the forebrain to enhance gain of baroreflex control of heart rate and lumbar sympathetic nerve activity.     

Augmented input from cardiac sympathetic afferents inhibits baroreflex in rats with heart failure

It has been established that the baroreflex is markedly decreased in chronic heart failure (CHF). Our recent study has indicated that activation of the cardiac sympathetic afferent reflex (CSAR) inhibits the baroreflex in normal rats, and in the rats with CHF the CSAR is significantly enhanced, which is related to augmented central angiotensin II (Ang II) mechanism. Therefore, the hypothesis is that the augmented CSAR in the CHF state tonically inhibits the baroreflex via central AT1 receptor. To test the hypothesis, the rats with myocardial infarction-induced CHF or sham surgery were anesthetized with alpha-chloralose and urethane, vagotomized, and recordings were made of the mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). We found: (1) left ventricular epicardial application of capsaicin or electrical stimulation of the central end of the left cardiac sympathetic nerve blunted the baroreflex in both sham and CHF rats; (2) left ventricular epicardial application of lidocaine had no significant effects on the baroreflex in sham rats but improved the baroreflex in CHF rats (maximum slope, 1.7+/-0.3 to 2.9+/-0.2%/mm Hg; P<0.01); and (3) intracerebral ventricular injection of losartan had no significant effect on baroreflex in sham rats but improved the baroreflex in CHF rats (maximum slope 1.9+/-0.2 to 3.1+/-0.2%/mm Hg; P<0.01). These results suggest that tonic cardiac sympathetic afferent input plays an important role in the blunted baroreflex associated with CHF, which is mediated by central AT1 receptors.     

Effects of amlodipine on baroreflex and sympathetic nervous system activity in mild-to-moderate hypertension

To investigate the effect of amlodipine on baroreflex sensitivity and sympathetic system activity, 36 patients with essential hypertension were randomized to once-daily, double-blind treatment with amlodipine 5 mg or placebo 5 mg for 60 days. Measurements with a Finapres device allowed calculation of baroreflex sensitivity and blood pressure (BP) variability. Adrenergic activity was assessed via measurements of lymphocyte β₂-adrenoceptors and plasma catecholamine concentrations. Compared with placebo, amlodipine significantly decreased BP, but did not significantly alter baroreflex sensitivity. Spectral analysis of Finapres data showed that, compared with placebo, amlodipine decreased the variability of systolic blood pressure, diastolic blood pressure, and RR interval in the low frequency band. There were no simultaneous changes in adrenergic function, however, suggesting that these effects of amlodipine were not mediated via sympathetic nervous system activation.     

Effects of hypoxia on sympathetic neural control in humans

This special issue is principally focused on the time domain of the adaptive mechanisms of ventilatory responses to short-term, long-term and intermittent hypoxia. The purpose of this review is to summarize the limited literature on the sympathetic neural responses to sustained or intermittent hypoxia in humans and attempt to discern the time domain of these responses and potential adaptive processes that are evoked during short and long-term exposures to hypoxia.     

Analysis of baroreflex control of heart rate in conscious dogs with pacing-induced heart failure

The autonomic components of the baroreflex control of heart rate were evaluated in conscious mongrel dogs before and after 4-6 weeks of ventricular pacing (250 beats/min). Arterial baroreflex sensitivity (BRS) was determined by the slopes of linear regression of pulse interval versus the preceding systolic arterial pressure in response to bolus injections of either phenylephrine or nitroglycerin. BRS was significantly depressed in the heart failure state [nitroglycerin slope, 5.0 +/- 2.7 (mean +/- SD) versus 16.6 +/- 5.1 msec/mm Hg, p less than 0.005; phenylephrine slope, 15.0 +/- 14.8 versus 32.0 +/- 26.7 msec/mm Hg, p less than 0.005]. There was no depression in BRS in dogs that were used as time controls or were acutely paced for 30 minutes. After beta 1-adrenergic blockade with metoprolol, the resting heart rate in the heart failure state was depressed more than in the normal state (-17.0 +/- 5.0% versus -3.2 +/- 3.4%, p less than 0.001). Atropine significantly increased resting heart rate more in the normal state than in the heart failure state (115.8 +/- 36.7% versus 25.4 +/- 14.5%, p less than 0.005). Thus, dogs in the heart failure state appear to have high resting cardiac sympathetic tone and low resting vagal tone. For nitroglycerin administration, metoprolol depressed BRS by 47.6 +/- 26.3% in the normal state and by 63.6 +/- 58.5% in the heart failure state. Atropine decreased the BRS by 86.7 +/- 7.8% in the normal state and by 39.5 +/- 30.2% in the heart failure state.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical, hemodynamic and sympathetic neural correlates of heart rate variability in congestive heart failure.

Heart rate (HR) variability has long been recognized as a sign of cardiac health. In the presence of heart disease, HR variability decreases, an observation that has been associated with poor prognosis in a number of recent studies. HR variability is particularly altered in congestive heart failure (CHF), a condition associated with a number of typical functional hemodynamic and neurohumoral alterations. The relation of measurements of HR variability to these abnormalities in patients with heart failure has not been carefully examined. Twenty-three patients (19 men, 4 women, mean age 49 years) with New York Heart Association class II to IV CHF were studied prospectively without cardiac medications; radionuclide ventriculography, right-sided heart catheterization, peroneal microneurography, plasma norepinephrine and 24- to 48-hour ambulatory electrocardiography were performed. Average RR interval and its standard deviation, and HR power spectrum (0 to 0.5, 0.05 to 0.15 and 0.2 to 0.5 Hz) were derived from the ambulatory electrocardiographic recordings and compared with left ventricular ejection fraction, thermodilution cardiac output, pulmonary arterial wedge pressure, New York Heart Association class, age, muscle sympathetic nerve activity (peroneal nerve) and norepinephrine level by linear regression. None of the measures of HR variability were significantly related to age, left ventricular ejection fraction, cardiac output or functional classification, whereas the 0.05 to 0.15 and 0.20 to 0.50 Hz components were weakly but significantly related to cardiac output (r = 0.49 and 0.42, p = 0.02 and 0.045, respectively). In contrast, a generally stronger and negative relation was demonstrated between spectral and nonspectral measurements of HR variability, and indicators of sympathoexcitation, muscle sympathetic nerve activity and plasma norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Naloxone potentiates cardiopulmonary baroreflex sympathetic control in normal humans.

Naloxone, an opioid antagonist, augments baroreflex mechanisms in animals; this occurrence suggests that endogenous opioids blunt baroreflex responses. Limited human studies suggest an inhibitory action of endogenous opioids on baroreflex-mediated vagal responses during arterial baroreceptor deactivation. To evaluate the potential effect of endogenous opioids on cardiopulmonary baroreflex mechanisms in humans, we measured arterial and central venous pressures, heart rate, and efferent muscle sympathetic nerve activity (MSNA, by peroneal microneurography) during unloading of cardiopulmonary baroreceptors with incremental lower body negative pressure (LBNP, from 0 to -15 mm Hg) and during the cold pressor test in 21 normal subjects (aged 24 +/- 1 [mean +/- SEM] years). In 14 subjects, we performed LBNP before and after naloxone (0.15 mg/kg i.v.) and placebo (n = 11) on separate days. In six of these 14 subjects and an additional seven subjects (n = 13), studies were also performed before and after administration of a lower dose of naloxone (0.075 mg/kg i.v.) on separate days. Neither dose of naloxone significantly altered control arterial or central venous pressures or heart rate. Control MSNA was reduced after the higher but not after the lower dose of naloxone. Comparable reductions in central venous pressure were produced by LBNP in all groups before and after naloxone or placebo, whereas LBNP did not alter arterial pressure. Cardiopulmonary baroreflex sympathetic sensitivity, which was derived as the slope of the linear regression relation between percent change in total MSNA (units) per absolute change in central venous pressure (mm Hg) during incremental LBNP, was significantly augmented after both the high dose (from 18.6 +/- 4.7%/mm Hg to 39.3 +/- 8.1%/mm Hg, p = 0.001) and low dose of naloxone, whereas placebo had no effect. MSNA responses to the cold pressor test were not altered by either dose of naloxone. Thus, naloxone selectively potentiates cardiopulmonary baroreflex regulation of sympathetic neural activity in normal humans. These findings suggest that endogenous opioids exert a tonic inhibitory effect on sympathetic responses to orthostatic stress in normal humans.