Essential hypertension: neural considerations

Current evidence suggests that the sympathetic nervous system plays a predominant role in some fraction of essential hypertension. Patients in whom such mechanisms are likely to be operative are young people with mild or labile hypertension. These mechanisms are expressed clinically through orthostatic hypertension, rapid heart rate, modestly elevated cardiac output, and normal or slightly elevated peripheral vascular resistance. The vascular resistance is inappropriately high for the level of cardiac output, and this is reflected in a mildly elevated blood pressure. This evidence carries therapeutic implications and suggests that sympatholytic drugs should be the first line of therapy. An additional pressor mechanism may arise from increased sympathetic activity along renal efferent nerves that impairs sodium excretion and another possible mechanism is stimulation of brain centers through impulses from the kidneys carried in renal afferent nerves.     

Renal sympathetic denervation for treatment of patients with heart failure: summary of the available evidence

Heart failure syndrome results from compensatory mechanisms that operate to restore – back to normal – the systemic perfusion pressure. Sympathetic overactivity plays a pivotal role in heart failure; norepinephrine contributes to maintenance of the systemic blood pressure and increasing preload. Cardiac norepinephrine spillover increases in patients with heart failure; norepinephrine exerts direct toxicity on cardiac myocytes resulting in a decrease of synthetic activity and/or viability. Importantly, cardiac norepinephrine spillover is a powerful predictor of mortality in patients with moderate to severe HF. This provided the rationale for trials that demonstrated survival benefit associated with the use of beta adrenergic blockers in heart failure with reduced ejection fraction. Nevertheless, the MOXCON trial demonstrated that rapid uptitration of moxonidine (inhibitor of central sympathetic outflow) in patients with heart failure was associated with excess mortality and morbidity, despite reduction of plasma norepinephrine. Interestingly, renal norepinephrine spillover was the only independent predictor of adverse outcome in patients with heart failure, in multivariable analysis. Recently, renal sympathetic denervation has emerged as a novel approach for control of blood pressure in patients with treatment-resistant hypertension. This article summarizes the available evidence for the effect of renal sympathetic denervation in the setting of heart failure.

• Key messages

• Experimental studies supported a beneficial effect of renal sympathetic denervation in heart failure with reduced ejection fraction.

• Clinical studies demonstrated improvement of symptoms, and left ventricular function.

• In heart failure and preserved ejection fraction, renal sympathetic denervation is associated with improvement of surrogate endpoints.

     

Endovascular denervation (EDN): From Hypertension to Non-Hypertension Diseases

Recently, the use of endovascular denervation (EDN) to treat resistant hypertension has gained significant attention. In addition to reducing sympathetic activity, EDN might also have beneficial effects on pulmonary arterial hypertension, insulin resistance, chronic kidney disease, atrial fibrillation, heart failure, obstructive sleep apnea syndrome, loin pain hematuria syndrome, cancer pain and so on. In this article we will summarize the progress of EDN in clinical research.     

Autonomic nervous dysfunction in essential hypertension

Borderline hypertension, a condition in which the blood pressure oscillates between normal and high values, is a predictor of future more severe hypertension. Pathophysiologically, borderline hypertension is different from established hypertension. A large proportion of such patients have elevated cardiac output and a normal vascular resistance. In established hypertension, the output is normal and resistance is elevated. The elevation of cardiac output in borderline hypertension is neurogenic; it can be abolished by an autonomic blockade of the heart. In addition to an increased cardiac sympathetic drive, increased sympathetic tone to the kidney, arterioles, and veins has also been found. In parallel with the hypersympathetic state, patients with borderline hypertension also show decreased parasympathetic tone. The enhanced sympathetic tone leads to a decreased cardiac responsiveness, and eventually, the cardiac output returns to the normal range. High blood pressure causes vascular hypertrophy, and hypertrophic vessels are hyperresponsive to vasoconstriction. These secondary changes in the responsiveness of the heart and blood vessels are the basis of transition from a high cardiac output to high-resistance hypertension. These hemodynamic changes are associated with a downregulation of the sympathetic tone. A picture of an apparently nonneurogenic high-resistance hypertension emerges. Nevertheless, when assessed in regard to the enhanced pressor responsiveness, the sympathetic drive in such patients is still excessive. Despite the apparently normal tone, the sympathetic nervous system continues to play an important pathophysiological role in established hypertension. Borderline hypertension is associated with numerous metabolic abnormalities including obesity and insulin resistance. It is tempting to view all these abnormalities as a common expression of the increased sympathetic drive in hypertension. Explanation of the basis of the association of hypertension and metabolic abnormalities promises to bring new insights into the pathophysiology of two common diseases of civilization: hypertension and diabetes mellitus.     

Role of renal sympathetic nerves in mediating hypoperfusion of renal cortical microcirculation in experimental congestive heart failure and acute extracellular fluid volume depletion.

To evaluate the pathophysiologic importance of renal nerves in regulating the renal vasomotor tone, we measured several parameters of renal cortical microcirculation before and after acute renal denervation (DNx) in the following three groups of anesthetized Munich-Wistar rats: (group 1) congestive heart failure after surgically induced myocardial infarction (n = 10), (group 2) acute extracellular fluid volume depletion after deprivation of drinking water for 48 h (n = 8), and (group 3) sham or nontreated controls (n = 6). In the myocardial-infarcted rats, DNx led to a uniform increase in glomerular plasma flow rate of, on average, 36%. Single nephron glomerular filtration rate of myocardial-infarcted rats also increased despite a reduction in glomerular capillary hydraulic pressure. These changes were associated with a fall in arteriolar resistances, particularly in the efferent arteriole. The glomerular capillary ultrafiltration coefficient rose in all but one myocardial-infarcted animal. A similar hemodynamic pattern was seen after DNx in water-deprived animals. In every water-deprived animal, glomerular plasma flow rate and single nephron GFR increased on average by 28 and 14%, respectively. Again, afferent and efferent arteriolar resistances decreased significantly. Furthermore, the ultrafiltration coefficient increased uniformly and substantially with DNx. To ascertain the potential importance of the interaction between the renal nerves and angiotensin II in these circumstances, we compared the renal cortical hemodynamics in additional groups of water-deprived rats (group 4) after DNx (n = 15), (group 5) during inhibition of angiotensin II with saralasin (n = 15), and (group 6) during treatment with both saralasin and DNx (n = 15). No appreciable difference was detected between group 4 vs. 6. In contrast, substantial differences were noted between group 5 vs. 6: on average, the glomerular plasma flow rate was 26% higher and the afferent and efferent arteriolar resistances 25% and 27% lower, respectively, in group 6. These observations provide direct evidence to indicate pathophysiologic importance of renal nerves in the profound intrarenal circulatory adjustments in prerenal circulatory impairment. The vasoconstrictive effects of renal nerves appear to be mediated in part by their stimulatory influence on angiotensin II release and their direct constrictor actions on pre- and post-glomerular vessels as well.     

脊髓损伤后膀胱功能障碍的药物治疗

对影响膀胱尿道功能神经递质及其药理作用 ,从4个方面进行了介绍 :中枢神经系统 ,交感、副交感神经节 ,外周传出纤维和传入神经。对目前常用的神经药物 ,从影响膀胱贮尿和排尿功能两方面进行了讨论 ,并介绍了最新研究进展。     

心肾综合征新视角

近年来,心肾疾病之间的关系引起了广泛关注.随着心肾综合征(CRS)概念的提出,流行病学提示CRS临床较常见且与患者的不良预后密切相关.最新的研究认为,CRS的病理生理机制涉及中心静脉充血、神经激素作用、贫血、氧化应激和肾交感神经兴奋等.为更好的了解CRS,本文就CRS的流行病学、病理生理机制及治疗措施进行综述.     

Acute decompensated heart failure: the cardiorenal syndrome

The cardiorenal syndrome is not well understood, and a uniform definition is lacking. Worsening renal function as determined by a decline in creatinine clearance in patients with decompensated heart failure is an identifier of patients with this syndrome. Treatment is a challenge. Diuretic therapy is valuable in treating congestion but may worsen renal function. Patients with decompensated heart failure are often refractory to diuretics, in which case higher doses must be used or alternate methods explored to reduce salt and water.     

肾功能不全对心力衰竭预后的影响

目的探讨肾功能不全对心力衰竭预后的影响。方法根据肾功能将心力衰竭患者分为心肾综合征组70例和单纯心力衰竭组131例，观察其治疗和预后情况。结果心肾综合征组与单纯心力衰竭组相比，年龄、血肌酐、水肿发生率，糖尿病和高血压患病率及住院天数显著增高（P〈0．05或0．01），血红蛋白浓度显著降低（P〈0．01）；而2组间性别、心力衰竭时间、心功能、冠心病及高脂血症的患病率差异无显著性。随访心肾综合征组生存率明显低于单纯心力衰竭组（P〈0．001），在成功应用血管紧张素转换酶抑制剂的患者中也有类似关联。Cox回归模型分析显示，心功能分级、射血分数、血肌酐水平和血红蛋白浓度与心力衰竭死亡独立相关。结论肾功能不全明显增加心力衰竭病死率。     

Role of the Renal Sympathetic Nerves in the Development and Maintenance of Hypertension in the Spontaneously Hypertensive Rat

Neurogenic factors and, in particular, enhanced renal sympathetic tone, have been implicated in the pathogenesis of hypertension in the spontaneously hypertensive rat of the Okamoto strain. To examine the hypothesis that the renal sympathetic nerves contribute to the development and maintenance of hypertension by causing urinary sodium retention, 7-wk-old (early hypertensive) and 18-wk-old (established hypertensive) male spontaneously hypertensive rats were subjected to bilateral renal denervation and compared with sham-operated controls. In 7-wk-old animals renal denervation delayed the onset and slowed the rate of development of hypertension. These alterations were associated with a significantly greater fractional excretion of sodium (percentage of sodium intake excreted) during the first 3 wk after denervation. Blood pressure 2 wk after surgery was 169±3.5 (sham) vs. 150±2.4 mm Hg (denervated) (P < 0.001), corresponding to fractional sodium excretions of 65±1.3% (sham) vs. 80±2.3% (denervated) (P < 0.001). By the 5th wk after surgery, at which time an increase in renal norepinephrine content of denervated animals suggested reinnervation, blood pressures in the two groups converged (sham, 199±6.5 mm Hg vs. denervated 180±3.5 mm Hg, NS) and there was no difference in sodium excretion (sham, 77±2.5% vs. denervated 79±2.3%). Plasma and kidney renin activity of denervated animals did not differ significantly from that of sham-operated controls. In 18-wk-old rats renal denervation did not alter blood pressure or urinary sodium excretion. These data indicate that the renal sympathetic nerves contribute to the development of hypertension in the spontaneously hypertensive rat in part by causing enhanced sodium retention. Once hypertension is established the renal nerves do not play a significant role in the maintenance of increased blood pressure.     

The glucocorticoid in acute decompensated heart failure: Dr Jekyll or Mr Hyde?

Glucocorticoid administration is not recommended in patients with heart failure because of its related sodium and fluid retention. However, previous experimental and clinical studies have demonstrated that glucocorticoids can also induce a diuretic effect and improve renal function in patients with acute decompensated heart failure (ADHF) with refractory diuretic resistance. We report the case of a 65-year-old man with a known diagnosis of aortic stenosis, systolic ventricular dysfunction, and chronic obstructive pulmonary disease who was admitted for ADHF. After 3 days, during which resistance to conventional therapy was observed, intravenous methylprednisolone (60 mg/d) was added to ongoing medical treatment. Three days after the onset of glucocorticoid therapy, daily urine volume progressively increased (up to 5.8 L/d). Concurrently, signs and symptoms of congestion improved, the weight and brain natriuretic peptide plasma levels decreased (?7 kg and ?46%, respectively) and glomerular filtration rate increased (+26%). Bioimpedance vector analysis showed a net reduction of fluid content (from 88.4% to 73.6% of hydration at discharge). In conclusion, this case report suggests that in a patient with ADHF and congestion resistant to diuretic therapy, glucocorticoid administration is safe and associated with improvement in congestion, neurohormonal status, and renal function. These data support the possible usefulness of glucocorticoids in this setting.     

Renal denervation: effects on atrial electrophysiology and arrhythmias

Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with significant morbidity and mortality. Currently, atrial endocardial catheter ablation, mainly targeting focal discharges in the pulmonary veins, is the most widely used interventional treatment of drug-refractory AF. Despite technical improvements, results are not yet optimal. There is ongoing search for alternative and/or complementary interventional targets. Conditions associated with increased sympathetic activation such as hypertension, heart failure and sleep apnea lead to structural, neural and electrophysiological changes in the atrium thereby contributing to the progression from paroxysmal to persistent AF and increasing recurrence rate of AF after PVI. Until now, interventional modulation of autonomic nervous system was limited by highly invasive techniques. Catheter-based renal denervation (RDN) was introduced as a minimally invasive approach to reduce renal and whole body sympathetic activation with accompanying blood pressure control and left-ventricular morphological and functional changes in resistant hypertension. This review focuses on the potential atrial antiarrhythmic and antiremodeling effects of RDN in AF patients with hypertension, heart failure, and sleep apnea and discusses the possible role of RDN in the treatment of AF.     

Obesity hypertension

Obesity and hypertension are two major risk factors for the cardiovascular system. Whereas arterial hypertension increases afterload to the left ventricle, obesity produces an increase in stroke volume and increases preload. As a result of this double burden, the heart adapts with eccentric left ventricular hypertrophy. Contractility becomes impaired early in the course of obesity hypertension, and ventricular ectopy is observed. As a consequence, the obese hypertensive patient is at a high risk for congestive heart failure and sudden death. Despite the synergistic effects of obesity and hypertension on the heart, patients appear to be relatively protected from nephrosclerosis and coronary artery disease. These epidemiologic observations are supported by the pathophysiologic changes that take place in obesity hypertension. At any given level of arterial pressure, cardiac output and renal blood flow are elevated in obese hypertensive patients, whereas systemic and renal vascular resistance are decreased when compared to lean hypertensive patients. Because total peripheral resistance is considered the hemodynamic hallmark of arterial hypertension, systemic vascular complications may be less pronounced in obesity hypertension. Weight loss decreases preload, afterload to the left ventricle, and the sympathetic drive to the heart. Protecting the heart from these hypertrophic stimuli should be a major goal of preventive cardiology.     

Interaction of Cardiopulmonary and Somatic Reflexes in Humans

Activation of cardiopulmonary receptors with vagal afferents results predominantly in reflex inhibition of efferent sympathetic activity, whereas activation of somatic receptors reflexly increases sympathetic activity to the heart and circulation. Previous studies in experimental animals indicate that there is an important interaction between these excitatory and inhibitory reflexes in the control of the renal circulation.     

Renal blood flow during acute ischaemic heart failure in dogs: effects of dopamine and high doses of insulin

The effects of acute ischaemic heart failure on renal blood flow and the influence of dopamine at low dose range and high doses of insulin were examined. Acute left ventricular (LV) failure was induced in dogs by injection of 50-micron plastic microspheres into the left main coronary artery. The dogs showed signs of severely depressed LV function. Cardiac output was decreased to a significantly greater extent than renal blood flow, and while total peripheral resistance was significantly increased, there were no significant changes in renal vascular resistance. The results indicate different sympathetic discharge to the various vascular beds during acute ischaemic heart failure. Dopamine at low dose range and high doses of insulin were found to improve myocardial contractility and to reduce renal vascular resistance and increase renal blood flow.     

Diuretic therapy in congestive heart failure--new views on spironolactone therapy

Cardiac pump failure leads to a reduction of the effective arterial volume. This is sensed by the kidney via afferent sympathetic fibres. The renal response to the perceived lack of volume is the retention of sodium and water. Although initially homeostatic, this renal counterregulation is maladaptive later on and may contribute to further cardiac compromise by increasing preload (volume retention) and afterload (hyperreninism). The renal sodium retention in congestive heart failure is a consequence of the activation of the sympathetic nervous system and of the renin-angiotensin-aldosterone system. The retention of osmotically free water is partly caused by the nonosmotic secretion of antidiuretic hormone from the posterior pituitary and partly by a diminished osmoregulatory capacity of the kidney due to diuretic therapy and/or (pre-)renal insufficiency. In the near future specific blocking drugs of vasopressin receptors should become available which could make a significant contribution to the management of hyponatremia in this setting. For the management of extracellular volume overload a negative sodium balance is the central objective. A moderate reduction of sodium intake is helpful to achieve this goal and has the additional benefit of reducing thirst and renal potassium loss. However, the majority of patients require (loop) diuretics in addition. Patients who are refractory to high and repeated doses of loop diuretics may respond to a combination of diuretics which act on different nephron segments. Diuretics increase the risk of hypokalemia which can trigger life-threatening tachyarrhythmia, particularly in patients with cardiac dysfunction. Hypokalemia is therefore an indicator of an adverse outcome. Secondary hyperaldosteronism--which can persist despite effective therapy with ACE-inhibitors--is the major cause of hypokalemia in this setting. The randomized aldactone evaluation study (RALES) has shown that spironolactone (25 mg/day) reduced the risk of hypokalemia and decreased morbidity, mortality and clinical symptoms in patients with heart failure. The recent encouraging results with vasopressin receptor antagonists and spironolactone point to the fact that the therapeutic modification of maladaptive homeostatic renal mechanisms plays an increasingly important role in the modern diuretic management of heart failure beyond symptomatic relief from volume overload.     

Acupuncture affects regional blood flow in various organs

In this review, our recent studies using anesthetized animals concerning the neural mechanisms of vasodilative effect of acupuncture-like stimulation in various organs are briefly summarized. Responses of cortical cerebral blood flow and uterine blood flow are characterized as non-segmental and segmental reflexes. Among acupuncture-like stimuli delivered to five different segmental areas of the body; afferent inputs to the brain stem (face) and to the spinal cord at the cervical (forepaw), thoracic (chest or abdomen), lumbar (hindpaw) and sacral (perineum) levels, cortical cerebral blood flow was increased by stimuli to face, forepaw and hindpaw. The afferent pathway of the responses is composed of somatic groups III and IV afferent nerves and whose efferent nerve pathway includes intrinsic cholinergic vasodilators originating in the basal forebrain. Uterine blood flow was increased by cutaneous stimulation of the hindpaw and perineal area, with perineal predominance. The afferent pathway of the response is composed of somatic group II, III and IV afferent nerves and the efferent nerve pathway includes the pelvic parasympathetic cholinergic vasodilator nerves. Furthermore, we briefly summarize vasodilative regulation of skeletal muscle blood flow via a calcitonin gene-related peptide (CGRP) induced by antidromic activation of group IV somatic afferent nerves. These findings in healthy but anesthetized animals may be applicable to understanding the neural mechanisms improving blood flow in various organs following clinical acupuncture.     

Profiling Antihypertensive Therapy

The objectives of treating hypertension are to achieve adequate control of blood pressure (BP) and maintain it under tight control. Maintenance of tight control of BP will most likely prevent stroke, heart attack, and heart failure, cause regression of left ventricular hypertrophy, and quite possibly preserve or improve renal function. The last two salutary effects combined will further reduce the morbidity and mortality in the treated hypertensive subjects. Choice of antihypertensive drugs is of significant importance so that our efforts to control hypertension do not grossly alter the quality of life. The cost of therapy is also an important consideration. Thus, thiazide diuretics, beta-blockers, and central inhibitors that are relatively inexpensive and adequately lower BP should be a common choice. However, if drowsiness interferes with work, or impotence becomes a threat for the marital partner or significant other, adjustment has to be made. The metabolic abnormalities consisting mainly of impaired glucose tolerance, hypercholesterolemia, and insulin resistance often induced by these relatively inexpensive drugs have put calcium channel blocker and ACE inhibitor group of drugs on the top of the list for antihypertensive therapy. They are far more expensive, yet offer no greater antihypertensive advantage than a diuretic or central inhibitor, except in special circumstances.     

Role of renal nerves in excretory responses to administration of kappa agonists in conscious spontaneously hypertensive rats

The present study examined whether the renal sympathetic nerves contribute to the renal excretory responses produced by kappa opioid receptor agonist administration in conscious spontaneously hypertensive rats (SHR). Intravenous infusion of the kappa opioid receptor agonists, ketocyclazocine (KC) and U-50488H, produced increases in urine flow rate. KC and U-50488H infusion also resulted in a marked and sustained antinatriuresis which was promptly reversed by low-dose naloxone (50 micrograms/kg i.v.), thus suggesting an opioid receptor-mediated action of both agonists. Although these kappa agonists did not produce changes in glomerular filtration rate or renal plasma flow, efferent renal sympathetic nerve activity increased with the same time course as the antinatriuretic response. To investigate whether the decrease in urinary sodium excretion was mediated via the increase in efferent renal sympathetic nerve activity, experiments were repeated in SHR with prior bilateral renal denervation. These studies demonstrated that similar renal excretory responses (diuresis and a naloxone reversible antiinatriuresis occurred during infusion of KC and U-50488H in renal denervated as were seen in intact SHR. These studies indicate that the renal excretory responses to the kappa opioid agonists KC and U-50488H are not mediated through changes in renal hemodynamics or via a pathway requiring intact renal innervation. Because an antinatriuretic response was observed in renal denervated SHR, this suggests that kappa opioid receptor agonists may influence the renal tubular reabsorption of sodium by additional naloxone-sensitive mechanisms independent of intact renal innervation.     

Effects of the diethylamino analog of ethmozin (ethacizin) upon sympathetic and parasympathetic efferent activity to the canine heart

This study examined the effects of the diethylamino analog of ethmozin (ethacizin) (1 mg/kg i.v.) on the spontaneous and reflexly elicited efferent activity in thoracic cardiac sympathetic and parasympathetic nerves. Nitroglycerin and phenylephrine (4 and 8 micrograms/kg i.v.) were administered to 15 anesthetized mongrel dogs while monitoring blood pressure and heart rate. In each dog two cardiac nerves were isolated and efferent neurograms were recorded simultaneously and analyzed by microprocessor. Ethacizin significantly attenuated the spontaneous sympathetic efferent activity in both left and right, preganglionic (n = 8) and postganglionic (n = 14) sympathetic nerves to the heart. In contrast, reflex changes in sympathetic activity elicited by baroreceptor challenges were not affected by ethacizin. Also, ethacizin did not significantly affect either spontaneous or baroreceptor reflex-induced parasympathetic efferent activities in eight preganglionic nerves. Thus, this new phenothiazine derivative may exert part of its antiarrhythmic action through a reduction of the spontaneous sympathetic tonic discharges to the heart. The fact that ethacizin reduced neither the reflex-induced changes in sympathetic or parasympathetic activities nor influenced the tonic vagal discharges further suggests that the compound is not likely to interfere with reflexly mediated cardiovascular adaptive changes.