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Centrally Acting Antihypertensives: a Renaissance of Tinterest: Mechanisms and Haemodynamics Van Zwieten, P.A

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Centrally Acting Antihypertensives: a Renaissance of Tinterest: Mechanisms and Haemodynamics Van Zwieten, P.A UvA-DARE (Digital Academic Repository) Centrally acting antihypertensives: a renaissance of tinterest: mechanisms and haemodynamics van Zwieten, P.A. Publication date 1997 Published in Journal of hypertension Link to publication Citation for published version (APA): van Zwieten, P. A. (1997). Centrally acting antihypertensives: a renaissance of tinterest: mechanisms and haemodynamics. Journal of hypertension, 15(Suppl.1), S3-S8. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:24 Sep 2021 New centrally acting antihypertensives van ZwietenReview S3 Centrally acting antihypertensives: a renaissance of interest. Mechanisms and haemodynamics Pieter A. van Zwieten Background Classic centrally acting antihypertensives are receptors, located in the nucleus reticularis lateralis will trig- α known to stimulate 2-adrenoceptors located in the ponto- ger peripheral sympathoinhibition, following similar path- α medullary region, in the vicinity of the nucleus tractus solitarii, ways as involved in the effects of the classic 2-adrenoceptor vasomotor centre, vagal nucleus and the various intercon- stimulants. Moxonidine and rilmenidine are I1-imidazoline α α necting neurones. The stimulation of these central 2-adreno- receptor stimulants with little affinity for 2-adrenoceptors. ceptors induces peripheral sympathoinhibition and hence a Accordingly, such agents lower elevated blood pressure in a reduction in (elevated) blood pressure, predominantly as a similar manner as the aforementioned older drugs, but it result of vasodilation and a consequent decrease in periph- may be hoped that their side-effect profile is more favour- eral vascular resistance. able. Antihypertensives Clonidine, guanfacine, guanabenz and α- Conclusion Accordingly, it would now be possible to sepa- methyldopa (via its active metabolite α-methylnoradren- rate the attractive haemodynamic properties and the side- aline) are well-known examples of classic centrally acting effects of centrally acting antihypertensives. antihypertensives. They are effective antihypertensives with an attractive haemodynamic profile. However, these agents have lost much of their clinical interest because of their Journal of Hypertension 1997, 15 (suppl 1):S3–S8 subjectively unpleasant side-effects (sedation, dry mouth, α impotence). Since these side-effects are also mediated, to Keywords: centrally acting antihypertensives, 2-adrenoceptors, clonidine, I -imidazoline receptors, moxonidine, rilmenidine α 1 a major extent, by 2-adrenoceptors it is virtually impossible to separate the desired centrally induced antihypertensive From the Departments of Pharmacotherapy and Cardiology, Academic effect and the adverse reactions by designing new com- Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. pounds. Requests for reprints to Prof. P.A. van Zwieten, Departments of Pharmacother- apy and Cardiology, Academic Medical Centre, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Drug targets I1-Imidazoline receptors have recently been discovered as a new target of centrally acting antihyper- tensives. When stimulated with agonists the I1-imidazoline © Rapid Science Publishers ISSN 0952-1178 Introduction ing peripheral sympathoinhibition and a fall in blood pres- Centrally acting antihypertensives were introduced in the sure. A direct peripheral effect involving the ‘false trans- management of hypertensive disease in the 1960s. It was mitter hypothesis’ has also been submitted [8,9]. recognized that part of the antihypertensive activity of reserpine was triggered within the central nervous system In the 1960s and 1970s clonidine and α-methyldopa were [1], although this well-known alkaloid also lowers blood appreciated as effective anyihypertensives with an attrac- pressure as a result of peripheral mechanisms involving the tive haemodynamic profile. All important circulatory re- sympathetic nervous system [2]. Clonidine, a stimulant of flexes are left unimpaired during treatment with these α 2-adrenoceptors in the central nervous system was then agents. Furthermore, the concept of sympathoinhibition somewhat later introduced as the prototype of centrally act- seems attractive on theoretical grounds; a relationship be- ing antihypertensives. Its antihypertensive activity was as- tween essential hypertension and an activated sympathetic α sumed to be triggered by the stimulation of 2-adrenoceptors nervous system is widely accepted to exist [10–12], although in the ponto-medullary region, thus causing peripheral many details concerning this association remain to be elu- sympathoinhibition and a reduction of elevated blood pres- cidated. In addition, the centrally acting antihypertensives sure [3–6]. Guanfacine and guanabenz were found to re- are known to effectively suppress the left ventricular hyper- duce blood pressure via similar mechanisms [7]. Somewhat trophy, associated with hypertensive disease, probably as a later the central antihypertensive activity of α-methyldopa result of peripheral sympathoinhibition [13–15]. was discovered [8,9]: α-methyldopa, a prodrug, is converted in vivo into its active metabolite α-methylnoradrenaline, Despite these various favourable properties the centrally act- α which stimulates the same 2-adrenoceptors known to be ing antihypertensives have lost much of their importance be- activated by clonidine and related compounds, thus caus- cause of their side-effect profile. Sedation, dry mouth and S4 Journal of Hypertension 1997, Vol 15 (suppl 1) sexual impotence in men are frequently observed during treat- Fig. 1 ment with such agents, and these subjectively unpleasant adverse reactions are considered as virtually unacceptable when compared with currently used antihypertensives such as β-blockers, low-dose diuretics, angiotensin converting en- α zyme inhibitors, calcium antagonists and 1-adrenoceptor an- tagonists. Numerous attempts have been made to develop centrally α acting 2-adrenoceptor stimulants as antihypertensives with a better profile of side-effects than that of the classic com- pounds. These attempts have largely failed, because most α of the aforementioned side-effects are mediated by 2- adrenoceptors as well, although located in different ana- tomical regions than those mediating the central antihyper- tensive action [16]. New light has been shed upon this problem by the discov- ery of I1-imidazoline receptors in the brain, involved in the central regulation of blood pressure and recognized as tar- gets of a novel type of centrally acting antihypertensive drugs [17–20]. Part of the antihypertensive effect of clon- idine may be mediated by central I1-imidazoline receptors α (in addition to the 2-adrenoceptor mechanism), whereas Chemical structures of the I1-imidazoline receptor agonists moxonidine and moxonidine and rilmenidine (Fig. 1) are assumed to act rilmenidine. predominantly as I1-imidazoline receptor agonists. Similarly, central serotonergic receptors of the 5-hydroxy- the rostral ventromedial medulla. The pathway descend- tryptamine (5HT)1A subtype may be considered as a target ing from the rostral ventrolateral medulla contains adreno- of new, centrally acting antihypertensives, although this ceptors and is linked to the peripheral sympathetic system. mechanism has not been explored in great detail so far. The other pathway coincides with the B3-group of serotonin- The hybrid compound urapidil, an agonist of central 5HT1A- containing neurons [20,21]. Centrally acting antihyper- α α α receptors besides its peripheral 1-adrenoceptor antagonis- tensives of the classical type ( -methyldopa, via -methyl- α tic activity, is the first example of a centrally acting anti- noradrenaline; clonidine) are known to be 2-adrenoceptor hypertensive involving central serotonergic receptors. agonists that cause peripheral sympathoinhibition. How- ever, central serotonergic receptors lateral with respect to Receptors and neuronal pathways in the central the midline B3 serotonin cells in the raphe (the rostral nervous system as targets of antihypertensive ventrolateral medulla) are also involved in the central anti- drugs hypertensive effect of the aforementioned classical cen- α Numerous pathways, neurotransmitters and their associated trally acting antihypertensives [22]. The 2-adrenoceptors receptors are known to be involved in the central nervous appear to be located in the regions of the nucleus tractus regulation of the cardiovascular system, including that of solitarii, the hypothetical vasomotor centre and the vagal arterial blood pressure. In this connection (nor)adrenaline, centre [18,23,24]. acetylcholine, serotonine, angiotensin II, γ-amino-butyric
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