Central sympatholytic drugs for the treatment of hypertension

In this issue of the Journal, Esler et al. [1] present a remarkable study on the neurohumoral effects of the sympatholytic agent rilmenidine in hypertensive patients. The authors have treated hypertensive patients with the central sympatholytic agent rilmenidine and with placebo in a double-blind, randomized cross-over trial and measured blood pressure, heart rate and catecholamine spillover. They observed an average systodiastolic blood pressure decrease by 15/7 mmHg with rilmenidine and a reduction in norepinephrine spillover by 35% without affecting epinephrine release. The results are intriguing for several reasons. First, Esler et al. [1] obviously have studied hypertensive subjects with elevated sympathetic nerve activity. Although no control collective was included in the present study, the study population had substantially higher norepinephrine spillover than historic control collectives from the authors’ laboratory. In these hypertensive subjects with elevated cardiovascular drive, the reduction in blood pressure was accompanied by a substantial reduction in sympathetic activity. However, only norepinephrine spillover was reduced by rilmenidine, the epinephrine ‘net release’ being almost unaffected. This suggests that adrenomedullary function was preserved. Second, and most importantly, the neurohumoral responses to stress were preserved with rilmenidine. Baseline blood pressure and norepinephrine spillover being lower, the increases in these variables with mental stress were similar to those during placebo treatment. Furthermore, the increase in epinephrine spillover was preserved on rilmenidine treatment. With postural challenge (head-up tilting), the increase in norepinephrine spillover was also preserved and, most importantly, both systolic and diastolic blood pressure did not decrease but tended to increase. Third, in the studied patient population, rilmenidine was free of side-effects such as sedation and rebound effect after withdrawal, which are common to central sympatholytic agents. Sympathoinhibition as a target of antihypertensive treatment The neurohumoral responses to central sympatholytic agents have been studied in various populations. In humans, most studies have been performed with clonidine. In patients with heart failure, for example, clonidine caused substantial decreases in muscle sympathetic nerve activity and plasma norepinephrine without affecting blood pressure [2]. These effects were observed when patients were pretreated with angiotensin-converting enzyme (ACE) inhibitors also exerting profound sympathoinhibitory effects. Importantly, arterial baroreflex function was not affected by clonidine, suggesting that the effects of clonidine were centrally mediated and not caused by an interference with the arterial baroreflex [2]. By contrast, Tank et al. [3] demonstrated that clonidine is able to significantly augment baroreceptor activation when administered to healthy volunteers devoid of elevated baseline sympathetic drive. Although baroreflex function was not studied by Esler et al. [1], it may be hypothesized that rilmenidine has enhanced baroreflex function in the hypertensive patients, and this effect may have contributed to the absence of hypotension during head-up tilt. In the present study [1], the effects of rilmenidine were evaluated after 2 weeks of treatment. The effects of imidazol-binding agents on sympathetic nerve activity can be observed after only a single dose. Wenzel et al. [4] studied the effects of a single dose of moxonidine on muscle sympathetic nerve activity in hypertensive patients and also in normotensive healthy volunteers. In both groups, they observed a reduction in muscle sympathetic nerve activity compared to placebo, which is consistent with a decrease in plasma norepinephrine, and no significant change in plasma epinephrine levels. Consequences of adrenergic activation and effects of therapeutic sympathoinhibition Besides blood pressure elevation, a tonic increase in sympathetic outflow causes structural and functional alterations at the myocardium, large arteries and the kidneys. Sympathetic activation is an important factor related to cardiac hypertrophy [5]. Sympathetic activation causes structural alterations of large arteries such as intima–media-thickening [6] and, importantly, functional alterations, notably arterial stiffening [7–9]. At the level of the kidneys, increased sympathetic nerve activity has been related to the progression of renal disease [10]. Cardiac hypertrophy [11], structural alterations of large arteries [12], arterial stiffening [13] and chronic renal failure [14,15] are all factors determining cardiovascular morbidity and mortality. It is not surprising that many studies have shown that the level of sympathetic outflow is of prognostic relevance in various disease states associated with sympathetic overactivity, notably heart failure [16] and chronic renal disease [17]. In the last decade, a series of studies have convincingly shown that drugs that are able to decrease sympathetic activity, such as β-blockers, ACE inhibitors and angiotensin receptor blockers, improve prognosis in heart failure [18] and renal disease [19]. However, the same remains still to be unequivocally demonstrated for central sympatholytic agents. Koldas et al. [20] have shown that rilmenidine is able to reduce left ventricular hypertrophy as effectively as perindopril in hypertensive patients. Trimarco et al. [21] showed that treatment with rilmenidine, besides reducing left ventricular hypertrophy, also improves large artery elasticity in hypertensive patients. The same group also has shown that rilmenidine decreases albuminuria as effectively as captopril in type II diabetic patients. This observation is in line with a report on a reduction of microalbuminuria in type I diabetics by moxonidine independent of blood pressure reduction [22]. The latter studies suggest that imidazoline receptor agonists are able to decrease the progression of renal disease. This has been clearly demonstrated in a series of elegant animal experiments by Amann et al. [23] and was confirmed in preliminary clinical studies in patients with chronic renal failure [24]. However, a trial of slow-release moxonidine in patients with heart failure showed increased mortality with the imidazoline receptor agonist compared to placebo [25]. This result was unexpected and is in contrast to the above-mentioned beneficial actions of central sympatholytic agents in disease states associated with increased sympathetic drive. Potential explanations for the unfavourable outcome of moxonidine in the MOXCON trial include a too rapid dose titration and too high doses applied [25]. Further outcome trials establishing the value of central sympatholytic agents are warranted in disease states associated with increased sympathetic drive, notably hypertension, heart failure and chronic renal disease. The use of central sympatholytic agents is limited by side-effects such as sedation, dizziness, dry mouth, fluid and volume retention, and a rebound effect after discontinuation. However, these effects are more likely observed with agents that have α2-agonist properties besides imidazoline receptor-binding properties, the typical compound of this class being clonidine [26]. In clinical studies, rilmenidine, a new-generation selective imidazoline-1-receptor agonist, has shown excellent tolerability and efficacy. Because the substance is devoid of α2-adrenergic properties, common side- effects of clonidine such as sedation and mouth dryness are not observed [27]. Rilemenidine also acts on renal imidazoline receptors, resulting in an inhibition of the Na+/H+ antiport in the proximal convoluted tubule. The result is a lack of sodium and water retention, and many studies with follow-up periods of up to 1 year have demonstrated consistent weight in the patients. Adverse effects with rilmenidine at a low dose do not appear to occur more often than with placebo [28]. Rilmenidine is further characterized by neutrality of lipid and glucose metabolism. This is true in patients with uncomplicated hypertension, in the elderly, in patients with dyslipidemia and in diabetic patients, as outlined in a detailed review by Reid [27]. In patients with syndrome X, an improvement in insulin sensitivity could be observed, possibly as a result of reduced sympathetic drive [29]. The antihypertensive efficacy of rilmenidine has been demonstrated in a series of trials, with efficacy comparable to that displayed by established drugs for first-line therapy of hypertension, such as diuretics, β-blockers, ACE inhibitors and calcium antagonists [27]. Long-term studies demonstrated a sustained antihypertensive efficacy. Besides the already discussed beneficial effects on left ventricular hypertrophy and microalbuminuria, rilmenidine is characterized by preserved cardiovascular adaptation to posture and exercise, and it has been shown to be superior to β-blockers in this respect. For this reason, rilmenidine was also effective and well tolerated in diabetic hypertensive patients [30,31], and this feature of the drug was also confirmed in the study by Esler et al. [1]. In conclusion, rilmenidine, as an example of a new generation of selective imidazoline-binding agents with central sympatholytic properties, is an effective antihypertensive drug that decreases sympathetic outflow but preserves cardiovascular adaptation to stress. Clinical studies have demonstrated the efficacy of the drug with respect to antihypertensive action and surrogate parameters such as left ventricular hypertrophy, microalbuminuria and metabolic profile. However, long-term studies are warranted to demonstrate the efficacy of the new generation imidazoline-binding agents with respect to cardiovascular morbidity and mortality.