Wenzel, René R.; Bruck, Heike; Noll, Georg*; Schäfers, Rafael F.; Daul, Anton E.; Philipp, Thomas
The sympathetic nervous system (SNS) is an important regulator of cardiovascular function. Its activity is determined by psychological, neuronal and humoral factors (1). Activation of neurohumoral systems as well as impairment of local regulatory mechanisms play a significant role in the pathogenesis and prognosis of cardiovascular diseases.
SNS activity increases with age, independent of disease state (2). Furthermore, in congestive heart failure, SNS activity is markedly elevated and strongly correlates with mortality (3). Elevated sympathetic activity not only plays a role in the induction of ischemia due to reflextachycardia and coronary vasoconstriction (4), but also correlates with hypertension, insulin resistance and coronary risk (5). Although its role in advanced hypertension is controversial, the SNS seems to contribute to the development of hypertension in early stages of the disease (6-8). Essential hypertension is thought to be associated with an enhanced sympathetic activity triggered at the level of the central nervous system in a complex manner (2,7,9). Therefore, in theory, it is likely that interference with neuronal centers and pathways involved in the regulation of sympathetic activation at the level of the central nervous system may reduce blood pressure and cardiovascular risk. Thus, antihypertensive pharmacotherapy and its influence on the SNS are of great importance and will be discussed in this paper.
REGULATION OF THE SYMPATHETIC NERVOUS SYSTEM
The efferent fibers arise from neuronal structures of the medulla oblongata, called the vasomotor center (Fig. 1). The effector organs are innervated with two neurons that are switched in the ganglia. From the cytosomes of the preganglionic neurons in thoracic and lumbar medulla, myelinated axons lead to the postganglionic neurons in the truncus sympathicus and the prevertebral ganglia. Acetylcholine is the neurotransmitter from the pre to the postsynaptic neuron and binds to nicotinic receptors. Adrenergic receptors with the transmitter norepinephrine mediate the transduction to the effector organ (Fig. 1).
The catecholamines epinephrine, norepinephrine and dopamine are released from the adrenal medulla, which, phylogenetically, is a ganglion. In peripheral vessels, sympathetic activation leads to vasoconstriction mediated by α1-adrenoceptors on smooth muscle cells, whereas effects on the heart are mediated by β-adrenoceptors (β1 > β2). Alpha2-adrenoceptors may be secondary in the sympathetic regulation of the cardiovascular system; however, experimental and first clinical data suggest that α2-adrenoceptors on the vascular endothelium modulate adrenergic vasoconstriction (10,11).
The SNS interacts with the renin-angiotensin system (RAS) and the vascular endothelium (Fig. 2). Angiotensin (Ang) II influences the release and re-uptake of norepinephrine through presynaptic receptors (12) and stimulates the SNS through a central mechanism (13,14). Furthermore, stimulation of β1-adrenoceptors of the juxtaglomerular apparatus leads to activation of the RAS via elevation of renin (15); this mechanism increases blood pressure as well as sodium and water retention.
Besides purines, histamine, dopamine and prostaglandines, norepinephrine itself inhibits norepinephrine release through presynaptic receptors, whereas epinephrine and Ang II stimulate norepinephrine-release presynaptically.
METHODS TO ASSESS SYMPATHETIC NERVOUS SYSTEM ACTIVITY
Assessment of sympathetic activity can occur through different approaches (Fig. 3). Effector-organ activities like blood pressure, blood flow and heart rate are well known indirect measures of SNS activity. As effector organs in part react slowly to variations of the sympathetic activity, and they also depend on local chemical, mechanical and hormonal influences, the interpretation of these parameters is complex. In clinical practice, sympathetic activity is assessed by measuring plasma norepinephrine. Plasma norepinephrine, however, is only an indirect measure of sympathetic nerve activity as only the overflow of the adrenergic neurotransmitter from the synaptic cleft is measured. Furthermore, plasma norepinephrine not only reflects the activity of adrenergic neurons, but also that of the adrenal medulla (Fig. 3). Finally, most methodologies to measure plasma catecholamines are prone to considerable variation (16), so the more specific measurement of norepinephrine spillover from the heart and other methods like blood pressure and heart rate variability have been introduced (17,18).
Microneurography allows assessment of skin sympathetic nerve activity or muscle sympathetic nerve activity (MSA) directly in a peripheral nerve (19,20) (Fig. 3). The signals can be obtained on-line and, hence, small and short-lasting changes during stimulatory maneuvers, as well as their time course, can be recorded (19-23). This methodology directly assesses electrical outflow of the SNS from the medulla oblongata. The latter property of microneurography allows one to characterize changes in sympathetic nerve activity during application of cardiovascular drugs and to analyze the importance of pharmacokinetic properties of a given preparation under these conditions (24) (see later).
Furthermore, the measurement of systolic time intervals, impedance cardiography, laser Doppler flowmetry and the measurement of muscle blood flow can be applied to assess the influence of the sympathetic nerve activity on effector organs (16,25-28) (Fig. 3).
EFFECTS OF DRUGS ON SYMPATHETIC NERVOUS SYSTEM
Beta-adrenoceptor antagonists inhibit β1-adrenoceptor-mediated positive inotropism and chronotropism of catecholamines on the heart and the β2-adrenoceptor-mediated relaxation of the vascular smooth muscle (29-32). Furthermore, blockade of β-adrenoceptors antagonizes the metabolic effects of catecholamines like lipolysis or glycogenolysis (31).
In the therapy of cardiovascular diseases, selective blockade of β1-adrenoceptors protects the heart from enhanced sympathetic tone reducing heart rate and inotropism, and thus cardiac oxygen consumption.
Beta-adrenoceptor antagonists are established in the therapy of hypertension and ischemic heart disease as they positively influence mortality, ischemic episodes, risk for myocardial (re)-infarction and sudden death (33-36).
In the past few years, β-adrenoceptor antagonists have been introduced in the therapy of congestive heart failure (37-39). The positive effects of β-blockade in congestive heart failure have been shown for bisoprolol (40), metoprolol (41) and carvedilol (42), and seem to result from a better efficiency of the SNS under β-blockade. They improve hemodynamics and symptoms, and have recently been shown to reduce mortality (42,43), although at the beginning of therapy, i.e. during dose titration, an increased mortality in severe chronic heart failure has been observed. Thus, β-adrenoceptor antagonists inhibit the downregulation of β-adrenoceptors and increase the sensitivity to β-adrenoceptor agonists (44). The effect of β-blockade on central sympathetic nerve activity is controversial and not extensively studied (45,46). While sympathetic nerve activity is enhanced after intravenous administration of the β1-selective β-blocker metoprolol to previously untreated hypertensive patients (45), it is reduced after long-term treatment of hypertension with this drug (46). Interestingly, the effects of nonselective β-blockers on sympathetic nerve activity may differ from those of β1-selective drugs, at least in healthy volunteers after first-time administration. In this situation, plasma catecholamines are significantly increased after administration of the β1-selective β-blocker bisoprolol, while there is no change in plasma norepinephrine after administration of the nonselective β-blocker propranolol (29,31).
Diuretics inhibit the salt and water reabsorption in the tubulus, and thus lead to a reduction of preload and after-load. The diuretic-induced loss of salt and water activates several hormonal systems such as vasopressin, the renin-angiotensin-aldosterone system or the SNS, which tend to compensate for the changes in sodium and water balance (47).
Nitrates are peripheral vasodilators that cause endothelium-independent relaxation of vascular smooth muscle. Reflex tachycardia is a known unwanted reaction to the application of several vasodilators. In a double-blind placebo-controlled study, isosorbide-dinitrate markedly increased both heart rate and MSA as assessed by microneurography (24), confirming earlier studies of intravenous administration of other vasodilatators (48-50). This effect can be explained by an arterial baroreceptor-mediated mechanism, a decrease in pulse pressure and an activation of low-pressure receptors caused by a possible decrease in central venous pressure (24).
Other vasodilators including peripheral alpha1-blockers
The pure vasodilators minoxidil (potassium channel opener) and hydralazin are effective antihypertensives that lower preload and afterload. However, they stimulate SNS activity and, with long-term treatment, compensatory activation of the sympathetic and the renin-angiotensin systems predominate (51).
Selective α1-adrenoceptor antagonists like prazosin also lower pre and afterload through inhibition of peripheral sympathetic vasocontraction, but do not influence the sympathetic activity to the heart, which is predominantly β-adrenoceptor mediated (52). This might explain, why the Veterans Administration Cooperative Study, using prazosin, could not show a better prognosis of patients with heart failure (53). Interestingly, the α1-adrenoceptor antagonist doxazosin induces significant sympathetic overactivation both at rest and under physical exercise, when compared with placebo (29,54).
Calcium antagonists (CA) lead to peripheral vasodilation and inhibit the effects of vasoconstrictor hormones at the level of vascular smooth muscle by reducing the calcium inflow through blockade of slow voltage-dependent L-type calcium channels. The lowered intracellular calcium concentration inhibits electromechanical coupling, and hence leads to vasodilation and lowering of blood pressure. Three groups of CA exist, dihydropyridine type (e.g. nifedipine), phenylalkylamine type (e.g. verapamil) and benzothiazepine type (e.g. diltiazem), which bind to different sites of the α1-subunit of the calcium channel. While dihydropyridine calcium antagonists are mainly peripheral vasodilators, verapamil-type calcium antagonists also have direct effects on the sinu-atrial (SA)-node and possibly reduce SNS activity.
CA are effective antihypertensive drugs and exert anti-ischemic effects (55). Furthermore, they exhibit vascular protective properties; they improve endothelial function in atherosclerosis and hypertension, both experimentally (56) and in human hypertension (57). They inhibit proliferation of human coronary artery smooth muscle cells (58) and slightly reduce the development of new atherosclerotic lesions (59).
In spite of these vascular protective effects, clinical trials with CA yielded disappointing results in patients with coronary artery disease and impaired left ventricular function and diabetes (60-67).
Activation of the SNS may not only depend on the class of CA used, but also on its pharmacokinetics. Indeed, CA of the dihydropyridine type (i.e. nifedipine, felodipine, amlodipine) lead to sympathetic activation with reflex-tachycardia (68,69). In contrast, verapamil leads to a reduction of heart rate and sympathetic activity as assessed by plasma norepinephrine (70). After acute administration in healthy volunteers, nifedipine markedly increased MSA as assessed by microneurography; interestingly, this occurred not only with short-acting nifedipine, but also with a very slow-release formulation of nifedipine, i.e. the GITS formulation. In contrast, heart rate increased only with short-acting and not with slow-release nifedipine (68). Therefore, nifedipine differently activates cardiac and peripheral sympathetic tone depending on pharmacokinetics. Thus, heart rate does not necessarily predict SNS activity, i.e. a lack in heart rate increase cannot be used as proof for a missing SNS activation (68).
Amlodipine, a newer, slow-acting dihydropyridine-type CA, seems to stimulate SNS to a lesser degree than other dihydropyridines. Nevertheless, heart rate and plasma norepinephrine increased significantly in hypertensives after acute application, but there was no long-term effect on heart rate (69).
Angiotensin converting enzyme-inhibitors
Through the blockade of the converting enzyme, angiotensin converting enzyme (ACE)-inhibitors inhibit the synthesis of Ang II, a strong vasoconstrictor that enhances the release of norepinephrine through stimulation of peripheral presynaptic receptors (71). Furthermore, Ang II stimulates central SNS activity (72). ACE-inhibitors also seem to prevent the breakdown of bradykinin, inducing further vasodilation via stimulation of nitric oxide and prostacyclin release. Bradykinin leads to release of nitric oxide and prostacyclin from the endothelium, which may contribute to the hemodynamic reaction to ACE-inhibition. On the other hand, bradykinin may also be responsible for the adverse reactions such as cough and angio-edema (73-77).
In contrast to pure vasodilators (i.e. nitrates or calcium antagonists) that activate the SNS, ACE-inhibitors induce no reflex tachycardia or increases in plasma norepinephrine (78). In a double-blind, placebo-controlled study, the ACE-inhibitor captopril, after acute administration in healthy volunteers, reduced MSA despite lowering blood pressure without influencing the responsiveness to mental or physical stress, whereas nitrates strongly activated MSA (3,24). This indicates that reduction of circulating Ang II, which stimulates SNS activity, lowers sympathetic tone (72). This might be one possible explanation for the beneficial effects of ACE-inhibitors on survival in patients with left ventricular dysfunction, in which activation of the SNS is strongly associated with morbidity and mortality (79). These positive effects of the ACE-inhibitors on morbidity and mortality of patients with heart failure and impaired left ventricular function, and patients after myocardial infarction, have been documented in numerous clinical studies (79-83).
However, with chronic administration, a number of mechanisms exist that may partially co-interact the beneficial effects of ACE-inhibition after acute dosing. Especially, Ang II may be synthesized by alternate non-ACE-dependent pathways (so called chymases), which may in part oppose the acute depressing effects on SNS activity (84-86). On the other hand, it has been shown that chronic ACE-inhibition did not change biosynthesis, storage or release of catecholamines (87). From the fact that bradykinin stimulated norepinephrine release dose dependently, almost during converting enzyme inhibition, it has been concluded that bradykinin may compensate for the lack of effect of converting enzyme inhibitors on catecholamine release (87). At least, in heart failure, chronic ACE-inhibitor treatment is accompanied by a marked reduction in central sympathetic outflow, which may depend on a persistent restoration of baroreflex restraint on the sympathetic neural drive (88). Furthermore, vagal activity seems not to be influenced as acute and chronic ACE inhibition did not blunt important cardiovascular reflexes (89).
Angiotensin receptor type 1-receptor antagonists
The blockade of the Ang II receptor is the most direct way to inhibit the RAS. In contrast to the ACE-inhibitors, which do not affect norepinephrine release because of the activation of compensatory mechanisms and inhibition of norepinephrine re-uptake and norepinephrine metabolism, angiotensin receptor type 1 (AT1)-receptor antagonists in vitro suppress the angiotensin-induced norepinephrine release and thus its proliferative effects (90,91).
The effects of AT1-receptor antagonists have not yet been studied extensively in humans in vivo. The Evaluation of Losartan in the Elderly Study showed that the effects of the AT1-antagonist losartan on mortality of patients with symptomatic heart failure older than 65 were more pronounced than with the ACE-inhibitor captopril (92). There was no significant difference between plasma levels of norepinephrine in the losartan compared with the captopril group.
Experimental data suggest that AT1-receptor antagonists lead to a more complete suppression of catecholamines than ACE-inhibitors (93). The newer nonpeptide AT1-receptor antagonist, eprosartan, has been shown to inhibit the pressor response induced by spinal cord stimulation in pithed rats, whereas equivalent doses of other nonpeptide AT1-receptor antagonists, such as losartan, valsartan and irbesartan, had no effect on sympathetic outflow; this has been interpreted as a more effective inhibition of prejunctional Ang II receptors (94).
Whether these effects on SNS activity play a role in vivo in humans, is not known. However, first clinical data from a double-blind, placebo-controlled study suggest that at least losartan does not reduce basal nor exercise-induced sympathetic activity when compared with placebo or enalapril (54).
Central sympatholytic agents
Clonidine, guanfacine, guanabenz and α-methyl-DOPA are well known centrally acting antihypertensive agents, which act on central α2-adrenoceptors (95). This leads to sympatho-inhibition and hence reduction in blood pressure, predominantly as a result of vasodilation and a consequent decrease in peripheral vascular resistance. Although these drugs are effective antihypertensives, they are no longer used as first-line drugs in the treatment of hypertension because of their unpleasant side-effects like dizziness, dry mouth, and sedation. In the case of clonidine, there were also concerns about rebound hypertension (96). These side-effects are to a major extent mediated by α2-adrenoceptors (97).
A new generation of centrally acting antihypertensive drugs with less adverse effects (i.e. moxonidine and rilmenidine) have been introduced into clinical treatment. It has been shown that they mainly act on central imidazoline1-receptors and less so on central α2-adrenoceptors (97-99). In contrast, other centrally acting antihypertensives, i.e. α-methyl-DOPA, guanfacine or guanabenz, mainly act on central α2-receptors (95). In animals, moxonidine led to a decreased sympathetic tone to resistance vessels, the heart and the kidney (97,100). A double-blind, placebo-controlled study with direct measurement of sympathetic outflow in humans using microneurography under in vivo conditions for the first time demonstrated that the imidazoline1-receptor agonist moxonidine reduces systolic and diastolic blood pressure in both healthy volunteers and untreated hypertensive subjects through a reduction in central sympathetic outflow (68). Moxonidine decreased MSA and plasma norepinephrine levels in both healthy volunteers and hypertensives, whereas epinephrine and renin levels did not change (68). Heart rate decreased after moxonidine in healthy subjects; in hypertensives, heart rate decreased only during the night hours (68) (Fig. 4).
The potential of moxonidine to control blood pressure is similar to other antihypertensive agents such as α- and β-blockers, calcium antagonists or ACE-inhibitors (Fig. 5); side-effects such as dizziness and dry mouth were less pronounced than with the older centrally acting antihypertensives, i.e. clonidine (30,101).
Rilmenidine is another imidazoline1-receptor agonist with a high affinity for the imidazoline receptors (102). Patient trials confirmed effective blood pressure lowering and less side-effects than with clonidine (103-105). Rilmenidine, in comparison with the β-adrenoceptor antagonist atenolol, was similarly well tolerated, and both drugs caused similar decreases in systolic and diastolic blood pressure. However, in contrast to atenolol, rilmenidine did not influence autonomic function such as heart rate during exercise and the Valsalva maneuver (106). Studies directly assessing effects of rilmenidine on central SNS activity in men are lacking.
INTERACTIONS OF THE SYMPATHETIC NERVOUS SYSTEM WITH THE VASCULAR ENDOTHELIUM
The vascular endothelium plays an important role in the regulation of vascular tone, and functional changes in the secretion of endothelium-derived mediators may be involved in the pathogenesis and progression of cardiovascular diseases, e.g. hypertension and atherosclerosis. Experimental data suggest various interactions between the SNS and the vascular endothelium (Fig. 2). Endothelin-1, which is released from endothelial cells, is the strongest vasoconstrictor; plasma levels of endothelin-1 are elevated in several cardiovascular diseases and predict cardiovascular mortality (107,108). Endothelin leads to peripheral vasoconstriction, and elevation of blood pressure; in rats, intrathekal injection of endothelin stimulates sympathetic activity (109). Furthermore, it is at least a comitogen of the proliferation of vascular smooth muscle cells (108).
Endothelin receptors on endothelial cells are linked to voltage-operated calcium channels via G-proteins (110). This may explain why calcium antagonists reduce endothelin-induced vasoconstriction in the human forearm circulation, i.e. intra-arterial application of verapamil or nifedipine prevent contractions to intra-arterially infused endothelin (28). On the other hand, drugs that stimulate SNS activity (i.e. nitrates, nifedipine) increased endothelin plasma levels in vivo in humans, whereas ACE-inhibitors and moxonidine decreased SNS activity and did not influence plasma endothelin (24,111).
Chronic therapy with calcium antagonists in experimental and human hypertension improved endothelium-dependent relaxation to acetylcholine (112). ACE-inhibitors stimulate endothelium-dependent relaxation indirectly through prevention of bradykinin breakdown, which leads to formation of nitric oxide and prostacyclin. In experimental approaches in the resistance circulation of spontaneously hypertensive rats, chronic blockade of the RAS with a nonpeptidic Ang II receptor antagonist, CGP 48369, the ACE-inhibitor benazepril HCl or the calcium antagonist nifedipine reduced blood pressure and improved endothelial dysfunction (56). Clinical studies showed that the ACE-inhibitors quinapril could reverse endothelial dysfunction and reduce the frequency of coronary ischemia (113-115). Administration of the ACE-inhibitors lisinopril to patients with essential hypertension has been shown to selectively increase vasodilatation in response to infusion of bradykinin (116).
Intrinsic differences exist between different ACE-inhibitors, i.e. quinaprilat and enalaprilat, that determine the ability to improve endothelium-mediated vasodilation, i.e. their different affinity to tissue ACE, because quinaprilat could improve flow-dependent dilation in patients with chronic congestive heart failure as the result of increased availability of nitric oxide, whereas enalaprilat could not (117).
Experimental and first clinical trials in the human skin microcirculation suggest that adrenoceptor agonists can stimulate endothelial α-adrenoceptors, leading to the release of nitric oxide (10,118). Indeed, α1-adrenoceptor-mediated constriction of vascular smooth muscle cells could be potentiated by nitric oxide inhibition both in vitro and in vivo in humans (10,118). This mechanism may be of pathophysiological importance in atherosclerosis and hypertension where endothelial function is impaired. No data are available regarding the effects of other antihypertensives on endothelial function or the endothelin system.
The effects of cardiovascular drugs on the SNS are important. However, most studies so far have only assessed SNS activity indirectly, i.e. measuring plasma catecholamines or heart rate variability. In contrast, microneurography directly records central sympathetic nerve traffic.
The complex effects of antihypertensive drugs on the pressor systems (SNS, RAS and endothelin system) seem to be relevant for clinical use, especially for the therapy of patients with cardiovascular diseases. A potential mediator of untoward effects of cardiovascular drugs is an activation of the SNS. Indeed, the fact that plasma norepinephrine levels are a very strong predictor of mortality in patients with heart failure (3,119,120) suggests that an activation of the SNS is detrimental at least in these patients, but possibly also in other patient groups, i.e. hypertensives (121). Overactivation of the SNS may also be detrimental in patients with diabetes and coronary artery disease, including acute coronary syndromes (122).
Whether the beneficial effects of some antihypertensive drugs on the SNS lead to a reduction in hard endpoints, i.e. cardiovascular and total mortality, needs to be investigated in interventional trials.
Acknowledgements: The studies mentioned in this paper were in part supported by grants of the German Research Association (DFG WE 1772/1-1) and the OERTEL Foundation.
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Proceedings of a Satellite Symposium to the 20th Congress of the European Society of Cardiology; Vienna, Austria; August 25, 1998
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