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Clinical Profile of Eprosartan: A Different Angiotensin II Receptor Blocker

Clinical Profile of Eprosartan: A Different Angiotensin II Receptor Blocker Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, 6, 253-257 253 1,* 2 P. J. Blankestijn and H. Rupp 1 2 Department of Nephrology, University Medical Center, Utrecht, The Netherlands; Philipps University of Marburg, Department of Internal Medicine and Cardiology, Molecular Cardiology Laboratory, Marburg, Germany Abstract: Rationale. The goal of antihypertensive treatment is to reduce risk of cardiovascular morbidity and mortality. Apart from blood pressure lowering per se, also reducing the activities of the renin-angiotensin system and sympathetic nervous system appears to be important. Angiotensin II receptor blocker drugs (ARBs) have provided a useful class of anti-hypertensive drugs. Eprosartan is a relatively new ARB which is chemically distinct (non-biphenyl, non-tetrazole) from all other ARBs (biphenyl tetrazoles). An analysis has been made on available experimental and clinical data on eprosartan which not only is an effective and well tolerated antihypertensive agent, but also lowers the activities of the renin-angiotensin system and sympathetic nervous system. Experimental and pharmacokinetic studies on eprosartan have shown differences with the other ARBs. The distinct properties of this non-biphenyl, non-tetrazole ARB might be relevant in the effort to reduce cardiovascular risk, also beyond its blood pressure lowering capacity. Key Words: Eprosartan, hypertension, sympathetic nervous system, renin angiotensin system. INTRODUCTION across sympathetic ganglia, potentiates at the presynaptic level noradrenaline release from sympathetic nerve terminals and ampli- The purpose of treating patients with increased cardiovascular fies the alpha-adrenoceptor mediated vasoconstrictor response to risk is to reduce that risk. It is well established that blood pressure endogenous noradrenaline Fig (2). Further, angiotensin II exerts lowering per se substantially reduces cardiovascular risk. Both the inhibitory effects on baroreflex modulation of the heart rate and renin-angiotensin system (RAS) and the sympathetic nervous sympathetic drive. The idea that AngII directly stimulates centrally system (SNS) play an important role in the pathogenesis of various originated sympathetic outflow in humans was tested in an elegant forms of hypertension. Independent of their effect on blood study. Intravenous infusion of AngII raised blood pressure and pressure, these systems also contribute to the pathophysiology of suppressed muscle sympathetic nerve activity. But during simul- both structural and functional cardiovascular abnormalities. As a taneously infusion of nitroprusside to control blood pressure rise, consequence, counteracting the mechanisms involved in the patho- MSNA increased. An identical experiment with phenylephrine genesis of cardiovascular organ damage is also important, indepen- infusion showed no effect on MSNA [2]. dent of any direct blood pressure lowering effect. Various pathological conditions are associated with hyper- There is conclusive evidence that the RAS and SNS systems do activity of both the RAS and SNS systems, including hypertension, not operate independently, but that there are multiple interactions heart failure, kidney disease, hypertension associated with obesity on different levels of the cardiovascular system. It is well estab- and obstructive sleep apnea syndrome amongst others. In the lished that angiotensin converting enzyme (ACE) inhibitors and majority of these conditions both the RAS and the SNS are angiotensin II receptor blockers (ARBs) reduce the effects of activated. Because circulating renin is (almost) exclusively produced angiotensin II Fig. (1). These therapies also appear to have by the kidneys, it is logical to question how the kidneys might sympatholytic properties, which may be particularly important in contribute to the increased activities of the two pressor systems in determining the efficacy of these agents in reducing cardiovascular the above-mentioned conditions. The precise role of a local i.e. risk, since there is abundant evidence that sympathetic hyperactivity tissue RAS is much more difficult to quantify and evaluate. is associated with poor clinical outcome. Experimental studies have shown several pathophysiological In this brief review, we outline the interactions between the mechanisms through which the diseased kidneys can be involved. RAS and the SNS. Because eprosartan is a relatively new ARB, Inappropriate renin secretion in relation to the state of sodium- chemically distinct from other ARBs, it seems appropriate to volume balance has long been recognized. In humans, intravenous summarize available evidence of eprosartan as sympatholytic agent, infusion of angiotensin II stimulates central sympathetic outflow. and briefly review data on experience with this compound in various hypertensive populations. Renal ischemia can lead to sympathetic activation. During renal ischemia, adenosine is released and adenosine evokes an increase in ANGIOTENSIN – SYMPATHETIC INTERACTIONS afferent renal nerve traffic, as can be shown during adenosine RAS/SNS interactions appear bi-directional and occur at infusion in the renal artery of uninephrectomized dogs. Even a different sites in the chain of events leading to angiotensin II and small injury in one kidney caused by intrarenal injection of phenol, noradrenaline release, the two major transmitters of these two which does not affect glomerular filtration rate, leads to hyper- systems [1]. There is clear experimental evidence that the sympa- tension in association with an increased central sympathetic activity. thetic outflow to the kidneys regulates renin release. Electrical In these animal models renal denervation results in a reduction or stimulation of the renal nerves, as well as of certain central nervous total prevention of hypertension. Additionally, in the phenol system areas, causes an increase in renin release. There is a large hypertension model nephrectomy of the injured kidney several body of evidence in various experimental settings indicating that weeks after the induction of renal damage results in normalisation angiotensin II facilitates the sympathetic nervous system on of blood pressure. Thus kidney injury in experimental conditions different levels. It has been shown that intra-cerebral infusion of can lead to sympathetic hyperactivity and hypertension and this angiotensin II causes a pressor response associated with an increase hyperactivity is associated with activation of renal afferent nerves. in vascular resistance. On a peripheral level, angiotensin II also The signal from the diseased kidneys travels via the afferent renal elicits stimulatory action, because it stimulates neural transmission nerves to the central nervous system Fig. (3). Some forms of essential hypertension, hypertension associated *Address correspondence to this author at the Department of Nephrology, with chronic kidney disease, renovascular hypertension, heart room F03.220, University Medical Center, Pobox 85500, 3508 GA Utrecht, failure, and obesity/metabolic syndrome are all associated with both The Netherlands; Tel: + 31-88-7557336, secretary + 31-88-7557329; an activated RAS and an activated SNS. Agents that interfere with Fax: + 31 30 2543492; Email: p.j.blankestijn@umcutrecht.nl 1871-5257/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. 254 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, Vol. 6, No. 4 Blankestijn and Rupp Fig. (1). Schematic representation of the renin-angiotensin system and the sites of action of angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers. the RAS are particularly effective in reducing sympathetic activity Angiotensin II may stimulate the SNS on various levels Fig (2). when the RAS is activated. The apparent marked parallelism in the Consequently, ARBs can block this stimulatory effect of angio- activities of these two systems may be interpreted as indicating a tensin II at these different levels. The effects of eprosartan on cause and effect relation or a common origin, i.e. kidney ischemia sympathetic activity have been studied in experimental conditions. Fig. (3). Given the importance of sympathetic activity in determining Eprosartan induces dual blockade of angiotensin II receptors both cardiovascular morbidity and mortality, it is important to quantity pre- and post-synaptically Fig. (2). Importantly, it has been shown the ability of agents that affect the RAS to reduce sympathetic that eprosartan crosses the blood-brain barrier, which pro-bably activity. contributes to its antihypertensive efficacy [6]. The question whether ARBs have sympatholytic effects is addressed in experi- EPROSARTAN: EFFECTS ON THE RENIN-ANGIOTENSIN mental studies. For instance, Balt et al. [7] compared in the pithed AND THE SYMPATHETIC NERVOUS SYSTEM. rat model the efficacy of valsartan, candesartan, embusartan, telmi- Eprosartan is chemically-distinct from the other ARBs in its sartan, eprosartan, losartan and irbesartan on pre- and postjuncional class [3, 4]. It is the only ARB that belongs to the non-biphenyl, AngII receptors. Eprosartan appeared the most effective agent with non-tetrazole class of compounds and does not contain a biphenyl, respect to prejunctional effects. Ohlstein et al. [8] studied activation tetrazole moiety Fig. (4). The antagonistic properties of eprosartan of sympathetic outflow through spinal cord stimulation in the pithed on the angiotensin II receptor type 1 (AT1) have been extensively rat. Eprosartan inhibited sympathetic outflow – but not losartan, documented [5]. Unlike most other ARBs, which show noncom- valsartan or irbesartan. This difference might mean that eprosartan petitive kinetics, eprosartan is a pure competitive antagonist. Based is a more effective antagonist of prejunctional AngII receptors that on the absence of a direct comparison of eprosartan with other augment noradrenaline release. Shetty and Delgrande [9] found that ARBs, the clinical relevance of the difference in chemical structure eprosartan inhibited neuronal noradrenaline release in a rat atria and kinetics has to be judged as unclear. model by AngII enhancement of electrical stimulation, which might Fig. (2). Schematic representation of the central nervous system (CNS) and a neuro-effector junction. Levels are indicated where angiotensin II (Ang II) can enhance (+) sympathetic activity and where angiotensin II receptor blocker (Ang II blocker) can reduce (-) sympathetic activity. Nor = noradrenaline,  = alpha-adrenoceptor, AT = angiotensin receptor Clinical Profile of Eprosartan Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, Vol. 6, No. 4 255 Fig. (3). Schematic representation of the kidney involvement in the pathogenesis of sympathetic hyperactivity. Already minimal kidney damage, not necessarily affecting kidney function, results in area(s) of ischemia. Increased plasma levels of angiotensin II and/or increased afferent renal nerve activity stimulates the central nervous system to increase central sympathetic outflow, which results in sodium retention and vasoconstriction which are meant to restore kidney perfusion. be interpreted as an effect on prejunctional AngII receptors. but the response rate at 12 weeks for eprosartan (200-300 mg bid) Criscione et al. [10] found valsartan had no effect on stimulation was greater than with enalapril (5-20 mg od) (70% vs 63%, p<0.05) induced activation of the sympathetic nervous system in pithed rats. [15]. In severely hypertensive patients, eprosartan (200-400 mg bid) Nap and colleagues [11] showed in isolated rabbit thoraric aorta more effectively reduced systolic blood pressure with no difference that the AngII enhanced electrical field stimulation evoked sympa- in diastolic blood pressure reduction as compared to enalapril (10- thetic transmission was more effectively inhibited by candesartan 40 mg od) after 8 weeks [16]. In a study of mainly elderly patients than eprosartan. It is important to emphasize that studies are once daily 600-800 mg eprosartan or once daily enalapril 5-20 mg difficult to compare because protocol, experimental design, dosage for 12 weeks reduced blood pressure to a similar extent, with and methodology vary substantially between studies. However, they similar proportions of patients in both treatment arms achieving a seem to indicate that ARBs have a clear action on both pre- and response [17]. In yet another study in essential hypertensives, once postjunctional AngII receptors, and that there might be differences daily eprosartan (400-800 mg) resulted in significantly greater in this respect between the various compounds. Importantly, also in decrease in blood pressure than placebo [18]. humans, there is some indication of different efficacy. For instance, A recent study in essential hypertensive patients, assessing both in hypertensive patients Arosio et al. [12] reported that 15 days of brachial and central blood pressures (pulse wave analysis, Sphygmo eprosartan (600 mg od) blocks noradrenergic effects during stress Cor System) presented similar reductions during eprosartan (600 more effectively than valsartan (160 mg od). These data suggest mg od) and atenolol (50 mg od) in peripheral blood pressure after 6 that in hypertensive humans there could be a difference between weeks. Both agents reduced central systolic pressure, albeit epro- ARBs in their efficacy to block the noradrenergic system and any sartan more so than atenolol, but only eprosartan reduced wave such difference might be meaningful [13]. reflections. Central pressures more closely relate to clinical outcome than peripheral pressures, suggesting an advantage of eprosartan EPROSARTAN IN CLINICAL PRACTICE over atenolol [19]. These findings confirm earlier studies indicating Essential Hypertension differential effects of various antihypertensive agents on central The clinical efficacy of eprosartan has been established in a pressures (for instance the CAFE Study [20, 21]) and suggest a number of trials, both against placebo and other compounds. This mechanism to support the meta-analyses that have challenged the agent clearly has a 24-hour blood pressure lowering effect during recommendation to use a beta-blocker in uncomplicated hyperten- chronic treatment at the standard dose of 600 mg/day [14]. Epro- sion [22-24]. However, superiority can only be really proven by sartan showed similar or greater antihypertensive effect compared direct comparison in properly designed studies with relevant with enalapril. For instance, both agents reduced blood pressure, clinical endpoints. Fig. (4). Eprosartan (left) is a non-biphenyl, non-tetrazole angiotensin II receptor blocker (ARB), other ARBs are biphenyl tetrazoles (right). 256 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, Vol. 6, No. 4 Blankestijn and Rupp In patients with mild hypertension and type 2 diabetes once Antihypertensive efficacy of eprosartan and enalapril did not differ. daily eprosartan (600 mg od) and telmisartan (40 mg od) were In an equal percentage of patients, the diuretic was added. equally effective in reducing blood pressure during a 12 months In the ETAPA (Estudio de la Efectividad del Tratamiento study [25]. Obesity is often associated with a raised sympathetic antihipertensivo sobre la Presion de Pulso en adultos) study from activity leading not only to hypertension, but also insulin resistance Spain involving approximately 4,000 hypertensive patients (mean [26]. Essential hypertension is a heterogenous condition. Some age 67 y), eprosartan (600 mg) alone (87%) or in combination with forms are associated with increased sympathetic activity whilst a diuretic decreased systolic, diastolic and mean (resp. 26 mmHg, others are not. Krum et al. showed that in mild to moderate 13 mmHg and 17 mmHg, all p<0.01) blood pressure in hyper- essential hypertension ARB treatment (eprosartan 600 mg and tensive patients and was associated with a reduction in pulse losartan 50 mg, both od during 4 weeks) did not affect muscle pressure / mean blood pressure ratio (62 => 58%, p<0.05) [42]. sympathetic nerve activity, which is the centrally originated Also in the Robles et al. study, eprosartan (600 mg od for 16 postganglionic sympathetic activity [27]. weeks) in the primary care setting was well tolerated and effective Renal Disease in over 600 patients (mean age 63 y) in reducing blood pressure (systolic, diastolic and mean blood pressure resp: 26, 13 and 17 There is clear evidence that chronic renal disease is often mmHg, all p<0.001) as well as pulse pressure (13 mmHg, p<0.001). characterised by the presence of sympathetic hyperactivity and that Also the pulse pressure / mean arterial pressure ratio decreased (62 sympathetic activity is associated with poor cardiovascular out- => 59%, p< 0.001) [43]. comes in chronic renal failure patients [28-30]. It is important to realize that already minor kidney injury, not necessarily affecting Other High Risk Populations kidney function, may cause sympathetic hyperactivity. This increase The MOSES study (MOrbidity and mortality after Stroke, in sympathetic activity is thought to both initiate and sustain the Eprosartan compared with nitrendipe for Secondary prevention) is a elevated blood pressure that contributes to organ damage and large, prospective, randomised outcome study comparing the adverse cardiovascular events [31]. It may also affect the pro- addition of 600 mg eprosartan or 10 mg nitrendipine to existing gression of renal failure [30]. therapy in patients with a history of proven stroke or transient Current evidence suggests there is no accumulation of ischaemic attack [44]. Background therapy did not differ between eprosartan at the recommended dose of 600 mg, regardless of renal the two groups. In MOSES, 1405 patients were followed up for 2.5 function. Chronic treatment (> 6 weeks) with enalapril (20 mg od) years with eprosartan or nitrendipine. The primary outcomes were and losartan (100 mg od) significantly reduced but do not total mortality and cardiovascular and cerebrovascular disease and normalized muscle sympathetic nerve activity in patients with the secondary outcomes were mental status, neurological status and hypertensive chronic renal failure [32, 33]. Eprosartan (600 mg od) ambulatory blood pressure. Blood pressure did not differ between reduced muscle sympathetic nerve activity, blood pressure and also the treatment arms. There was a significant reduction of 21% in the heart rate (all p<0.05), suggesting that not only the sympathetic primary endpoint (all-cause mortality and the number of cardio- activity towards the resistance vasculature but also the cardiac vascular and cerebrovascular events, including all recurrent events) sympathetic activity is decreased with eprosartan. Combining epro- and of 25% (p=0.026) in the recurrence of stroke, and of 30% in sartan with the centrally-acting sympatholytic agent moxonidine first time cardiovascular events. This important study indicates that normalised both blood pressure and muscle sympathetic nerve meaningful prevention, beyond an effect on blood pressure, can be activity in hypertensive normovolemic patients with chronic renal obtained in a high risk population. Although there has been some failure [32]. Studies directly comparing effects on muscle sympa- concern on the reliability and relevance of the study [45], it extends thetic nerve activity, which is considered one of the gold standards the existing information on the effects of ARBs in high risk for quantifying sympathetic activity in humans, of eprosartan and patients. Some, but not all, other studies with ARBs suggest that other agents in disease states with high sympathetic activity are these agents especially reduce strokes. For instance in the LIFE presently not available. study in hypertensive patients with left ventricular hypertrophy losartan based therapy reduced stroke better than beta-blocker Experimental studies with eprosartan suggest that it might have based therapy [46]. In contrast, in the VALUE study, valsartan was a benefit in the prevention or delay of renal damage in hypertensive nonsignificantly worse than amlodipine in stroke prevention, but patients with renal impairment [34, 35]. Frank et al. [36] showed post hoc analyses suggested that this may have been attributable to that eprosartan (600 mg od for 7 days) preserves renal circulation less effective blood pressure control during valsartan during the during states of neurohumoral activation, suggesting an important first 6 months [47]. In ACCESS, candesartan (or placebo) was renoprotective effect of this compound. Osei et al. [37] noted an given after 7 days after onset of stroke. Neurological outcome after enhancement of the renal vasodilator effect of eprosartan (600 mg) 1 year in the ARB treated group was better than in the placebo during hyperglycemia consistent with activation of the intrarenal group [48]. The mechanism of this possible beneficial effect may RAS. lie in the selective blocking by ARBs of the deleterious effects The Elderly mediated through the AT1 receptor, whereas the effects on the AT2 receptor are unaffected or even enhanced [49]. AT2 receptor seem Isolated systolic hypertension is the most common form of to mediate beneficial effects on endothelium through decreased hypertension in the elderly [38, 39]. Eprosartan has been shown to coagulation and inflammation and these receptors also protect brain be an effective agent in the elderly. In a double-blind study versus tissue from ischemia in experimental models [50, 51]. placebo in 283 elderly patients with a mean age of 70 years eprosartan once-daily at doses of 600-1200mg during 3 months Ongoing Studies produced a significant reduction in systolic blood pressure (epro- Although different in terms of structure and mode of action, sartan vs. placebo: 16 and 8 mmHg, p<0.0001) [40]. For patients eprosartan has, to date, been seen as one of many sartans. Ongoing who did not respond to eprosartan alone, the addition of studies are now focusing in other areas where reduction of hydrochlorothiazide provided additive reduction in systolic blood sympathetic activity might be expected to show benefit. pressure (eprosartan vs. placebo: 22 and 14 mmHg, p<0.002). In a 26-week comparative study with enalapril (5 – 20 mg od), The STARLET study (Stress-induced Hypertension at the eprosartan at doses of 200-300mg twice daily, alone or in combi- Workplace) will examine the prevalence of ‘job-strain’ hyperten- nation with hydrochlorothiazide once daily, was shown to be safe sion and cardiovascular outcomes. Job-strain hypertension is and effective in hypertensive patients over 65 years of age [41]. defined as a difference of at least 5mm diastolic blood pressure Clinical Profile of Eprosartan Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, Vol. 6, No. 4 257 [19] Dhakam, Z.; McEniery, C.M.; Yasmin, P.; Cockcroft, J.R.; Brown, M.J.; and/or 8mm Hg systolic blood pressure between work and weekend Wilkinson, I.B. Am. J. Hypertens., 2006, 19, 214. mean daytime ambulatory blood pressure. First results show that [20] CAFE investigators. Circulation, 2006, 113, 1213. eprosartan effectively reduced blood pressure [51]. 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Dial. Transplant., 2004, 19, 1354. [29] Zoccali, C.; Mallamaci, F.; Parlongo, S.; Cutrupi, S.; Benedetto, A.; Tripepi, and mortality. It is important not only to quantify the blood pressure G. Cirulation, 2002, 105, 1354. lowering effect of antihypertensive compounds, but also to assess [30] Neumann, J.; Ligtenberg, G.; Klein, I.I.; Koomans, H.A.; Blankestijn, P.J. their ability to counteract mechanisms involved in the pathogenesis Kidney Int., 2004, 65, 1568. of cardiovascular morbidity and mortality, such as the hyper- [31] Koomans, H.A.; Blankestijn, P.J.; Joles, J.A. J. Am. Soc. Nephrol., 2004, 15, activities of the renin-angiotensin system and the sympathetic [32] Neumann, J.; Ligtenberg, G., Oey, P.L.; Koomans, H.A.; Blankestijn, P.J. J. nervous system. Eprosartan is an effective antihypertensive agent Am. Soc. 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Opin., 2007, 23(suppl. 5), S13. Study Group. J. Hypertens., 1999, 17, 129. Received: 21 September, 2007 Revised: 28 January, 2008 Accepted: 05 February, 2008 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cardiovascular & Hematological Agents in Medicinal Chemistry Pubmed Central

Clinical Profile of Eprosartan: A Different Angiotensin II Receptor Blocker

Cardiovascular & Hematological Agents in Medicinal Chemistry , Volume 6 (4) – Oct 1, 2008

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© 2008 Bentham Science Publishers Ltd.
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Abstract

Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, 6, 253-257 253 1,* 2 P. J. Blankestijn and H. Rupp 1 2 Department of Nephrology, University Medical Center, Utrecht, The Netherlands; Philipps University of Marburg, Department of Internal Medicine and Cardiology, Molecular Cardiology Laboratory, Marburg, Germany Abstract: Rationale. The goal of antihypertensive treatment is to reduce risk of cardiovascular morbidity and mortality. Apart from blood pressure lowering per se, also reducing the activities of the renin-angiotensin system and sympathetic nervous system appears to be important. Angiotensin II receptor blocker drugs (ARBs) have provided a useful class of anti-hypertensive drugs. Eprosartan is a relatively new ARB which is chemically distinct (non-biphenyl, non-tetrazole) from all other ARBs (biphenyl tetrazoles). An analysis has been made on available experimental and clinical data on eprosartan which not only is an effective and well tolerated antihypertensive agent, but also lowers the activities of the renin-angiotensin system and sympathetic nervous system. Experimental and pharmacokinetic studies on eprosartan have shown differences with the other ARBs. The distinct properties of this non-biphenyl, non-tetrazole ARB might be relevant in the effort to reduce cardiovascular risk, also beyond its blood pressure lowering capacity. Key Words: Eprosartan, hypertension, sympathetic nervous system, renin angiotensin system. INTRODUCTION across sympathetic ganglia, potentiates at the presynaptic level noradrenaline release from sympathetic nerve terminals and ampli- The purpose of treating patients with increased cardiovascular fies the alpha-adrenoceptor mediated vasoconstrictor response to risk is to reduce that risk. It is well established that blood pressure endogenous noradrenaline Fig (2). Further, angiotensin II exerts lowering per se substantially reduces cardiovascular risk. Both the inhibitory effects on baroreflex modulation of the heart rate and renin-angiotensin system (RAS) and the sympathetic nervous sympathetic drive. The idea that AngII directly stimulates centrally system (SNS) play an important role in the pathogenesis of various originated sympathetic outflow in humans was tested in an elegant forms of hypertension. Independent of their effect on blood study. Intravenous infusion of AngII raised blood pressure and pressure, these systems also contribute to the pathophysiology of suppressed muscle sympathetic nerve activity. But during simul- both structural and functional cardiovascular abnormalities. As a taneously infusion of nitroprusside to control blood pressure rise, consequence, counteracting the mechanisms involved in the patho- MSNA increased. An identical experiment with phenylephrine genesis of cardiovascular organ damage is also important, indepen- infusion showed no effect on MSNA [2]. dent of any direct blood pressure lowering effect. Various pathological conditions are associated with hyper- There is conclusive evidence that the RAS and SNS systems do activity of both the RAS and SNS systems, including hypertension, not operate independently, but that there are multiple interactions heart failure, kidney disease, hypertension associated with obesity on different levels of the cardiovascular system. It is well estab- and obstructive sleep apnea syndrome amongst others. In the lished that angiotensin converting enzyme (ACE) inhibitors and majority of these conditions both the RAS and the SNS are angiotensin II receptor blockers (ARBs) reduce the effects of activated. Because circulating renin is (almost) exclusively produced angiotensin II Fig. (1). These therapies also appear to have by the kidneys, it is logical to question how the kidneys might sympatholytic properties, which may be particularly important in contribute to the increased activities of the two pressor systems in determining the efficacy of these agents in reducing cardiovascular the above-mentioned conditions. The precise role of a local i.e. risk, since there is abundant evidence that sympathetic hyperactivity tissue RAS is much more difficult to quantify and evaluate. is associated with poor clinical outcome. Experimental studies have shown several pathophysiological In this brief review, we outline the interactions between the mechanisms through which the diseased kidneys can be involved. RAS and the SNS. Because eprosartan is a relatively new ARB, Inappropriate renin secretion in relation to the state of sodium- chemically distinct from other ARBs, it seems appropriate to volume balance has long been recognized. In humans, intravenous summarize available evidence of eprosartan as sympatholytic agent, infusion of angiotensin II stimulates central sympathetic outflow. and briefly review data on experience with this compound in various hypertensive populations. Renal ischemia can lead to sympathetic activation. During renal ischemia, adenosine is released and adenosine evokes an increase in ANGIOTENSIN – SYMPATHETIC INTERACTIONS afferent renal nerve traffic, as can be shown during adenosine RAS/SNS interactions appear bi-directional and occur at infusion in the renal artery of uninephrectomized dogs. Even a different sites in the chain of events leading to angiotensin II and small injury in one kidney caused by intrarenal injection of phenol, noradrenaline release, the two major transmitters of these two which does not affect glomerular filtration rate, leads to hyper- systems [1]. There is clear experimental evidence that the sympa- tension in association with an increased central sympathetic activity. thetic outflow to the kidneys regulates renin release. Electrical In these animal models renal denervation results in a reduction or stimulation of the renal nerves, as well as of certain central nervous total prevention of hypertension. Additionally, in the phenol system areas, causes an increase in renin release. There is a large hypertension model nephrectomy of the injured kidney several body of evidence in various experimental settings indicating that weeks after the induction of renal damage results in normalisation angiotensin II facilitates the sympathetic nervous system on of blood pressure. Thus kidney injury in experimental conditions different levels. It has been shown that intra-cerebral infusion of can lead to sympathetic hyperactivity and hypertension and this angiotensin II causes a pressor response associated with an increase hyperactivity is associated with activation of renal afferent nerves. in vascular resistance. On a peripheral level, angiotensin II also The signal from the diseased kidneys travels via the afferent renal elicits stimulatory action, because it stimulates neural transmission nerves to the central nervous system Fig. (3). Some forms of essential hypertension, hypertension associated *Address correspondence to this author at the Department of Nephrology, with chronic kidney disease, renovascular hypertension, heart room F03.220, University Medical Center, Pobox 85500, 3508 GA Utrecht, failure, and obesity/metabolic syndrome are all associated with both The Netherlands; Tel: + 31-88-7557336, secretary + 31-88-7557329; an activated RAS and an activated SNS. Agents that interfere with Fax: + 31 30 2543492; Email: p.j.blankestijn@umcutrecht.nl 1871-5257/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. 254 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, Vol. 6, No. 4 Blankestijn and Rupp Fig. (1). Schematic representation of the renin-angiotensin system and the sites of action of angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers. the RAS are particularly effective in reducing sympathetic activity Angiotensin II may stimulate the SNS on various levels Fig (2). when the RAS is activated. The apparent marked parallelism in the Consequently, ARBs can block this stimulatory effect of angio- activities of these two systems may be interpreted as indicating a tensin II at these different levels. The effects of eprosartan on cause and effect relation or a common origin, i.e. kidney ischemia sympathetic activity have been studied in experimental conditions. Fig. (3). Given the importance of sympathetic activity in determining Eprosartan induces dual blockade of angiotensin II receptors both cardiovascular morbidity and mortality, it is important to quantity pre- and post-synaptically Fig. (2). Importantly, it has been shown the ability of agents that affect the RAS to reduce sympathetic that eprosartan crosses the blood-brain barrier, which pro-bably activity. contributes to its antihypertensive efficacy [6]. The question whether ARBs have sympatholytic effects is addressed in experi- EPROSARTAN: EFFECTS ON THE RENIN-ANGIOTENSIN mental studies. For instance, Balt et al. [7] compared in the pithed AND THE SYMPATHETIC NERVOUS SYSTEM. rat model the efficacy of valsartan, candesartan, embusartan, telmi- Eprosartan is chemically-distinct from the other ARBs in its sartan, eprosartan, losartan and irbesartan on pre- and postjuncional class [3, 4]. It is the only ARB that belongs to the non-biphenyl, AngII receptors. Eprosartan appeared the most effective agent with non-tetrazole class of compounds and does not contain a biphenyl, respect to prejunctional effects. Ohlstein et al. [8] studied activation tetrazole moiety Fig. (4). The antagonistic properties of eprosartan of sympathetic outflow through spinal cord stimulation in the pithed on the angiotensin II receptor type 1 (AT1) have been extensively rat. Eprosartan inhibited sympathetic outflow – but not losartan, documented [5]. Unlike most other ARBs, which show noncom- valsartan or irbesartan. This difference might mean that eprosartan petitive kinetics, eprosartan is a pure competitive antagonist. Based is a more effective antagonist of prejunctional AngII receptors that on the absence of a direct comparison of eprosartan with other augment noradrenaline release. Shetty and Delgrande [9] found that ARBs, the clinical relevance of the difference in chemical structure eprosartan inhibited neuronal noradrenaline release in a rat atria and kinetics has to be judged as unclear. model by AngII enhancement of electrical stimulation, which might Fig. (2). Schematic representation of the central nervous system (CNS) and a neuro-effector junction. Levels are indicated where angiotensin II (Ang II) can enhance (+) sympathetic activity and where angiotensin II receptor blocker (Ang II blocker) can reduce (-) sympathetic activity. Nor = noradrenaline,  = alpha-adrenoceptor, AT = angiotensin receptor Clinical Profile of Eprosartan Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, Vol. 6, No. 4 255 Fig. (3). Schematic representation of the kidney involvement in the pathogenesis of sympathetic hyperactivity. Already minimal kidney damage, not necessarily affecting kidney function, results in area(s) of ischemia. Increased plasma levels of angiotensin II and/or increased afferent renal nerve activity stimulates the central nervous system to increase central sympathetic outflow, which results in sodium retention and vasoconstriction which are meant to restore kidney perfusion. be interpreted as an effect on prejunctional AngII receptors. but the response rate at 12 weeks for eprosartan (200-300 mg bid) Criscione et al. [10] found valsartan had no effect on stimulation was greater than with enalapril (5-20 mg od) (70% vs 63%, p<0.05) induced activation of the sympathetic nervous system in pithed rats. [15]. In severely hypertensive patients, eprosartan (200-400 mg bid) Nap and colleagues [11] showed in isolated rabbit thoraric aorta more effectively reduced systolic blood pressure with no difference that the AngII enhanced electrical field stimulation evoked sympa- in diastolic blood pressure reduction as compared to enalapril (10- thetic transmission was more effectively inhibited by candesartan 40 mg od) after 8 weeks [16]. In a study of mainly elderly patients than eprosartan. It is important to emphasize that studies are once daily 600-800 mg eprosartan or once daily enalapril 5-20 mg difficult to compare because protocol, experimental design, dosage for 12 weeks reduced blood pressure to a similar extent, with and methodology vary substantially between studies. However, they similar proportions of patients in both treatment arms achieving a seem to indicate that ARBs have a clear action on both pre- and response [17]. In yet another study in essential hypertensives, once postjunctional AngII receptors, and that there might be differences daily eprosartan (400-800 mg) resulted in significantly greater in this respect between the various compounds. Importantly, also in decrease in blood pressure than placebo [18]. humans, there is some indication of different efficacy. For instance, A recent study in essential hypertensive patients, assessing both in hypertensive patients Arosio et al. [12] reported that 15 days of brachial and central blood pressures (pulse wave analysis, Sphygmo eprosartan (600 mg od) blocks noradrenergic effects during stress Cor System) presented similar reductions during eprosartan (600 more effectively than valsartan (160 mg od). These data suggest mg od) and atenolol (50 mg od) in peripheral blood pressure after 6 that in hypertensive humans there could be a difference between weeks. Both agents reduced central systolic pressure, albeit epro- ARBs in their efficacy to block the noradrenergic system and any sartan more so than atenolol, but only eprosartan reduced wave such difference might be meaningful [13]. reflections. Central pressures more closely relate to clinical outcome than peripheral pressures, suggesting an advantage of eprosartan EPROSARTAN IN CLINICAL PRACTICE over atenolol [19]. These findings confirm earlier studies indicating Essential Hypertension differential effects of various antihypertensive agents on central The clinical efficacy of eprosartan has been established in a pressures (for instance the CAFE Study [20, 21]) and suggest a number of trials, both against placebo and other compounds. This mechanism to support the meta-analyses that have challenged the agent clearly has a 24-hour blood pressure lowering effect during recommendation to use a beta-blocker in uncomplicated hyperten- chronic treatment at the standard dose of 600 mg/day [14]. Epro- sion [22-24]. However, superiority can only be really proven by sartan showed similar or greater antihypertensive effect compared direct comparison in properly designed studies with relevant with enalapril. For instance, both agents reduced blood pressure, clinical endpoints. Fig. (4). Eprosartan (left) is a non-biphenyl, non-tetrazole angiotensin II receptor blocker (ARB), other ARBs are biphenyl tetrazoles (right). 256 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, Vol. 6, No. 4 Blankestijn and Rupp In patients with mild hypertension and type 2 diabetes once Antihypertensive efficacy of eprosartan and enalapril did not differ. daily eprosartan (600 mg od) and telmisartan (40 mg od) were In an equal percentage of patients, the diuretic was added. equally effective in reducing blood pressure during a 12 months In the ETAPA (Estudio de la Efectividad del Tratamiento study [25]. Obesity is often associated with a raised sympathetic antihipertensivo sobre la Presion de Pulso en adultos) study from activity leading not only to hypertension, but also insulin resistance Spain involving approximately 4,000 hypertensive patients (mean [26]. Essential hypertension is a heterogenous condition. Some age 67 y), eprosartan (600 mg) alone (87%) or in combination with forms are associated with increased sympathetic activity whilst a diuretic decreased systolic, diastolic and mean (resp. 26 mmHg, others are not. Krum et al. showed that in mild to moderate 13 mmHg and 17 mmHg, all p<0.01) blood pressure in hyper- essential hypertension ARB treatment (eprosartan 600 mg and tensive patients and was associated with a reduction in pulse losartan 50 mg, both od during 4 weeks) did not affect muscle pressure / mean blood pressure ratio (62 => 58%, p<0.05) [42]. sympathetic nerve activity, which is the centrally originated Also in the Robles et al. study, eprosartan (600 mg od for 16 postganglionic sympathetic activity [27]. weeks) in the primary care setting was well tolerated and effective Renal Disease in over 600 patients (mean age 63 y) in reducing blood pressure (systolic, diastolic and mean blood pressure resp: 26, 13 and 17 There is clear evidence that chronic renal disease is often mmHg, all p<0.001) as well as pulse pressure (13 mmHg, p<0.001). characterised by the presence of sympathetic hyperactivity and that Also the pulse pressure / mean arterial pressure ratio decreased (62 sympathetic activity is associated with poor cardiovascular out- => 59%, p< 0.001) [43]. comes in chronic renal failure patients [28-30]. It is important to realize that already minor kidney injury, not necessarily affecting Other High Risk Populations kidney function, may cause sympathetic hyperactivity. This increase The MOSES study (MOrbidity and mortality after Stroke, in sympathetic activity is thought to both initiate and sustain the Eprosartan compared with nitrendipe for Secondary prevention) is a elevated blood pressure that contributes to organ damage and large, prospective, randomised outcome study comparing the adverse cardiovascular events [31]. It may also affect the pro- addition of 600 mg eprosartan or 10 mg nitrendipine to existing gression of renal failure [30]. therapy in patients with a history of proven stroke or transient Current evidence suggests there is no accumulation of ischaemic attack [44]. Background therapy did not differ between eprosartan at the recommended dose of 600 mg, regardless of renal the two groups. In MOSES, 1405 patients were followed up for 2.5 function. Chronic treatment (> 6 weeks) with enalapril (20 mg od) years with eprosartan or nitrendipine. The primary outcomes were and losartan (100 mg od) significantly reduced but do not total mortality and cardiovascular and cerebrovascular disease and normalized muscle sympathetic nerve activity in patients with the secondary outcomes were mental status, neurological status and hypertensive chronic renal failure [32, 33]. Eprosartan (600 mg od) ambulatory blood pressure. Blood pressure did not differ between reduced muscle sympathetic nerve activity, blood pressure and also the treatment arms. There was a significant reduction of 21% in the heart rate (all p<0.05), suggesting that not only the sympathetic primary endpoint (all-cause mortality and the number of cardio- activity towards the resistance vasculature but also the cardiac vascular and cerebrovascular events, including all recurrent events) sympathetic activity is decreased with eprosartan. Combining epro- and of 25% (p=0.026) in the recurrence of stroke, and of 30% in sartan with the centrally-acting sympatholytic agent moxonidine first time cardiovascular events. This important study indicates that normalised both blood pressure and muscle sympathetic nerve meaningful prevention, beyond an effect on blood pressure, can be activity in hypertensive normovolemic patients with chronic renal obtained in a high risk population. Although there has been some failure [32]. Studies directly comparing effects on muscle sympa- concern on the reliability and relevance of the study [45], it extends thetic nerve activity, which is considered one of the gold standards the existing information on the effects of ARBs in high risk for quantifying sympathetic activity in humans, of eprosartan and patients. Some, but not all, other studies with ARBs suggest that other agents in disease states with high sympathetic activity are these agents especially reduce strokes. For instance in the LIFE presently not available. study in hypertensive patients with left ventricular hypertrophy losartan based therapy reduced stroke better than beta-blocker Experimental studies with eprosartan suggest that it might have based therapy [46]. In contrast, in the VALUE study, valsartan was a benefit in the prevention or delay of renal damage in hypertensive nonsignificantly worse than amlodipine in stroke prevention, but patients with renal impairment [34, 35]. Frank et al. [36] showed post hoc analyses suggested that this may have been attributable to that eprosartan (600 mg od for 7 days) preserves renal circulation less effective blood pressure control during valsartan during the during states of neurohumoral activation, suggesting an important first 6 months [47]. In ACCESS, candesartan (or placebo) was renoprotective effect of this compound. Osei et al. [37] noted an given after 7 days after onset of stroke. Neurological outcome after enhancement of the renal vasodilator effect of eprosartan (600 mg) 1 year in the ARB treated group was better than in the placebo during hyperglycemia consistent with activation of the intrarenal group [48]. The mechanism of this possible beneficial effect may RAS. lie in the selective blocking by ARBs of the deleterious effects The Elderly mediated through the AT1 receptor, whereas the effects on the AT2 receptor are unaffected or even enhanced [49]. AT2 receptor seem Isolated systolic hypertension is the most common form of to mediate beneficial effects on endothelium through decreased hypertension in the elderly [38, 39]. Eprosartan has been shown to coagulation and inflammation and these receptors also protect brain be an effective agent in the elderly. In a double-blind study versus tissue from ischemia in experimental models [50, 51]. placebo in 283 elderly patients with a mean age of 70 years eprosartan once-daily at doses of 600-1200mg during 3 months Ongoing Studies produced a significant reduction in systolic blood pressure (epro- Although different in terms of structure and mode of action, sartan vs. placebo: 16 and 8 mmHg, p<0.0001) [40]. For patients eprosartan has, to date, been seen as one of many sartans. Ongoing who did not respond to eprosartan alone, the addition of studies are now focusing in other areas where reduction of hydrochlorothiazide provided additive reduction in systolic blood sympathetic activity might be expected to show benefit. pressure (eprosartan vs. placebo: 22 and 14 mmHg, p<0.002). In a 26-week comparative study with enalapril (5 – 20 mg od), The STARLET study (Stress-induced Hypertension at the eprosartan at doses of 200-300mg twice daily, alone or in combi- Workplace) will examine the prevalence of ‘job-strain’ hyperten- nation with hydrochlorothiazide once daily, was shown to be safe sion and cardiovascular outcomes. Job-strain hypertension is and effective in hypertensive patients over 65 years of age [41]. defined as a difference of at least 5mm diastolic blood pressure Clinical Profile of Eprosartan Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, Vol. 6, No. 4 257 [19] Dhakam, Z.; McEniery, C.M.; Yasmin, P.; Cockcroft, J.R.; Brown, M.J.; and/or 8mm Hg systolic blood pressure between work and weekend Wilkinson, I.B. Am. J. Hypertens., 2006, 19, 214. mean daytime ambulatory blood pressure. First results show that [20] CAFE investigators. Circulation, 2006, 113, 1213. eprosartan effectively reduced blood pressure [51]. 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Opin., 2007, 23(suppl. 5), S13. Study Group. J. Hypertens., 1999, 17, 129. Received: 21 September, 2007 Revised: 28 January, 2008 Accepted: 05 February, 2008

Journal

Cardiovascular & Hematological Agents in Medicinal ChemistryPubmed Central

Published: Oct 1, 2008

References