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00004872-201111000-0001500004872_2011_29_2156_palma_contribution_11article< 138_0_24_10 >Journal of Hypertension© 2011 Lippincott Williams & Wilkins, Inc.Volume 29(11)November 2011p 2156–2166Renin–angiotensin and sympathetic nervous system contribution to high blood pressure in Schlager mice[Original papers: Sympathetic system]Palma-Rigo, Kesiaa,b,c; Jackson, Kristy L.a; Davern, Pamela J.a; Nguyen-Huu, Thu-Phuca; Elghozi, Jean-Lucb,c; Head, Geoffrey A.a,daNeuropharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, AustraliabINSERM U 970, Centre de Recherche CardiovasculairecUniversité Paris Descartes, Paris, FrancedDepartment of Pharmacology, Monash University, Clayton, Victoria, AustraliaCorrespondence to Geoffrey A. Head, Neuropharmacology Laboratory, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC 8008, AustraliaTel: +61 3 8532 1330; fax: +61 3 8532 1100; e-mail: geoff.head@baker.edu.auAbbreviations: ACE, angiotensin-converting enzyme; Ang, angiotensin; BP, blood pressure; BPH/2J, Schlager hypertensive mouse; BPN/3J, Schlager normotensive mouse; HR, heart rate; MAP, mean arterial pressure; RAS, reninangiotensin system; SHRs, spontaneously hypertensive rats; SNS, sympathetic nervous systemReceived 24 January, 2011Revised 26 July, 2011Accepted 8 August, 2011AbstractObjective: Schlager hypertensive (BPH/2J) mice have been suggested to have high blood pressure (BP) due to an overactive sympathetic nervous system (SNS), but the contribution of the renin–angiotensin system (RAS) is unclear. In the present study, we examined the cardiovascular effects of chronically blocking the RAS in BPH/2J mice.Methods: Schlager normotensive (BPN/3J, n = 6) and BPH/2J mice (n = 8) received the angiotensin AT1A-receptor antagonist losartan (150 mg/kg per day) in drinking water for 2 weeks. Pre-implanted telemetry devices were used to record mean arterial pressure (MAP), heart rate (HR) and locomotor activity.Results: MAP was reduced by losartan treatment in BPN/3J (−23 mmHg, P < 0.01) and in BPH/2J mice (−25 mmHg, P < 0.001), whereas HR was increased. Losartan had little effect on initial pressor responses to feeding or to stress, but did attenuate the sustained pressor response to cage-switch stress. During the active period, the hypotension to sympathetic blockade with pentolinium was greater in BPH/2J than BPN/3J (suggesting neurogenic hypertension), but was not affected by losartan. During the inactive period, a greater depressor response to pentolinium was observed in losartan-treated animals.Conclusion: The hypotensive actions of losartan suggest that although the RAS provides an important contribution to BP, it contributes little, if at all, to the hypertension-induced or the greater stress-induced pressor responses in Schlager mice. The effects of pentolinium suggest that the SNS is mainly responsible for hypertension in BPH/2J mice. However, the RAS inhibits sympathetic vasomotor tone during inactivity and prolongs sympathetic activation during periods of adverse stress, indicating an important sympatho-modulatory role.IntroductionThe ‘neurogenic hypothesis of hypertension’ inherently implies that excessive sympathetic vasomotor activity plays a key pathogenic role in triggering and sustaining the hypertensive state [1,2]. Recently, we reported that Schlager inbred hypertensive (BPH/2J) mice have high blood pressure (BP) due to an overactive sympathetic nervous system (SNS). This conclusion was based on the findings that the ganglion blocker pentolinium completely abolished the BP difference between BPH/2J and Schlager normotensive (BPN/3J) mice [3]. Importantly, the hypertension was most evident during the awake (night) period when the SNS is most active and results in an exaggerated day–night difference in BP [3]. Further, these mice display an exaggerated response to aversive stress that was associated with greater neuronal activation of hypothalamic and limbic nuclei critical for cardiovascular autonomic (sympathetic) regulation [3,4].The hypertensive pattern observed in the BPH/2J mice is unusual, as hypertension more often involves abnormalities in the renin–angiotensin (Ang) system (RAS) which is recognized as the major determinant of long-term BP through its renal actions to regulate salt and fluid balance [5]. Indeed, the most effective and widely used antihypertensive agents are Ang antagonists, Ang-converting enzyme (ACE) inhibitors and renin inhibitors. Importantly, there is a well described interaction between SNS and the RAS that occurs within the CNS and kidney. Centrally, Ang acts via AT1-receptors in circumventricular organs that lack the blood–brain barrier [6–8]. Within the kidney, activation of renal nerves is a potent stimulus for renin release [9]. Thus, to support the hypothesis of a neurogenic mechanism for hypertension in the BPH/2J mice, it is necessary to consider whether there is a contribution or interaction, or not, from the RAS.Earlier studies investigating the levels of renin in plasma, kidney and the submaxillary gland by enzymatic assay and by direct radioimmunoassay in BPN/3J and BPH/2J mice showed no difference between groups [10]. More recently, a greater decrease in BP in BPH/2J compared with BPN/3J mice was observed following the ACE inhibitor, captopril, given in drinking water [11]. These findings, based on tail-cuff measurements of BP, suggest that the hypertension in BPH/2J mice may involve a contribution from the RAS. However, this conclusion can be questioned, given the stressful and inaccurate method of BP assessment. To resolve the contribution of the RAS and its possible interaction with the SNS to neurogenic hypertension observed in the BPH/2J mice, we used radiotelemetry to examine the effect of the AT1-receptor antagonist, losartan, on 24-h BP and cardiovascular responses to stressful stimuli. Further, the effect of the ganglionic blocker pentolinium combined with losartan was examined to see whether the greater contribution of the SNS in these animals was partly driven by the RAS.MethodsExperiments were performed on six normotensive (BPN/3J) and eight hypertensive (BPH/2J) 18-week-old male mice. The experiments were approved by the Alfred Medical Research Education Precinct Animal Ethics Committee and conducted in accordance with the Australian Code of Practice for Scientific Use of Animals.BP telemetry transmitters (Model TA11PA-C10, Data Sciences International, St Paul, Minnesota, USA) were implanted under isoflurane open circuit anaesthesia (5% induction and 1.5–2% maintenance). The catheter of the telemetry device was inserted into the carotid artery and the transmitter probe was positioned subcutaneously along the right flank [12]. The mice were housed individually in a room with 12 : 12-h light–dark cycle (0100–1300 h light) with access ad libitum to water and mouse chow (19% protein, 5% fat, 5% fibre and 0.2% sodium; Specialty Feeds, Glen Forrest, Western Australia, Australia).Protocol for chronic losartan treatmentAt the end of the recovery period, 10 days after surgery, a 48-h recording of cardiovascular and locomotor activity was made. Continuous recordings of systolic (SAP), diastolic (DAP) and calculated mean arterial pressure (MAP), heart rate (HR) and locomotor activity were measured in freely moving mice in their home cage. The recordings were sampled at 1000 Hz using an analogue-to-digital data acquisition card (NI PCI-6024E, National Instruments, Austin, Texas, USA) as described previously [13]. The beat-to-beat arterial pressure and HR were detected online and analyzed later using a program written in Labview [14].The mice were then subject to treatment with losartan (30 or 150 mg/kg per day) based on previous studies in mice by Billet et al. [15]. Losartan (Sigma-Aldrich, St Louis, Missouri, USA) was added to the drinking water or no drug in a random order cross-over design [15]. Losartan doses were adjusted according to the volume ingested during the previous period every 3 days during the 2-week treatment. After 7 days of treatment, cardiovascular parameters and locomotor activity were recorded for another 48 h. As the 30 mg/kg per day dose was shown to be ineffective, the detailed cardiovascular assessment (response to stress, baroreflex assessment and cardiovascular variability) was only assessed at the higher dose.Relationship between locomotor activity and mean arterial pressure (days 7–9)The relationship between MAP and locomotor activity (arbitrary units) was calculated from the 1-min average values over 48 h, as described previously [16]. The activity score was logarithmically transformed to correct for positive skew.Cardiovascular variability and the cardiac baroreceptor sensitivity (days 7–9)Beat-to-beat data were analysed separately to calculate power spectra using a program written in Labview [14]. The autopower and cross-power spectra were calculated for multiple overlapping (by 50%) segments of MAP and HR using a fast Fourier transform as adapted for conscious mice [16]. The cardiac baroreflex sensitivity was estimated as the average value of the transfer gain in the frequency band between 0.3 and 0.5 Hz [16]. Baroreflex slope was considered significant if the coherence between MAP and HR across several overlapping segments in the analysed frequency band was more than 0.4. Data periods with low locomotor activity were chosen (usually two from each circadian period) from 48-h recordings, minimizing the influence of physical activity.Assessment of cardiovascular reactivity in response to behavioural tests (days 10–11)During the second week of losartan treatment or water alone, the animals were exposed to a series of behavioural stimuli (aversive and appetitive) performed on separate days during the light period when the animals were inactive, as described previously [17,18]. Restraint stress involved guiding the mouse into a cylindrical plexiglass restrainer with a sliding back plate to confine the animal for 5 min. Dirty cage-switch stress involved removing the mouse from its home cage and placing it for 1 h in a preoccupied cage of another male mouse. A feeding response involved giving a treat of an almond for 5 min. MAP responses were analysed as percentage changes, as described previously [17].Pharmacological test: sympathetic blockade (days 13–14)Following 1 day of recovery from the behavioural tests, BP and HR were recorded 30 min before and after intraperitoneal administration of the ganglion blocker pentolinium (5.0 mg/kg, Sigma-Aldrich) in BPN/3J and BPH/2J mice that drank either losartan or water alone. This pharmacological test was performed during the active and inactive periods of the circadian rhythm on two separate days.Statistical analysisCardiovascular data were expressed as mean ± SEM. The data were analysed by multifactor, nested split-plot analysis of variance which allowed for within and between animal contrasts [19]. The between groups sums of squares was partitioned into main effects of treatment (losartan/water), strain (BPH/BPN) and their interaction (treatment × strain). A combined residual was used that pooled the between and within animal variance, as described previously [20]. A probability of P value less than 0.05 was considered significant.ResultsEffect of 30 and 150 mg/kg per day losartan on cardiovascular and locomotor measurementsBPH/2J mice had greater 24-h average MAP, HR and locomotor activity than BPN/3J mice (P < 0.01 for all, Tables 1 and 2, Fig. 1). MAP, HR and activity were higher throughout the active (night) phase than the inactive (day) period, as expected for mice (Fig. 1). BPH/2J had greater MAP, HR and activity day–night differences compared with BPN/3J mice (P < 0.05 for all, Tables 1 and 2, Fig. 1).Table 1 Average mean arterial pressure, heart rate and activity over 24-h period and differences between day and night periodTable 2 Average mean arterial pressure, heart rate and activity over 24-h period and differences between day and night periodFig. 1. No captions available.After 7 days chronic treatment with 30 mg/kg per day losartan, there were no observed changes to MAP, HR or activity (Table 1). This dose did not affect the day–night differences in either strain (Table 1). However, the higher dose of 150 mg/kg per day induced a similar reduction in 24-h MAP in both groups when calculated as delta (BPN/3J = −23 mmHg and BPH/2J = −25 mmHg, Ptreatment < 0.001) or as percentage change (BPN/3J = −23% and BPH/2J = −21%, Pstrain × treatment = 0.7, Fig. 1). Losartan 150 also increased HR to a similar degree in both groups (BPN/3J = +107 beats/min and BPH/2J = +68 beats/min, standard error of the difference = 21 beats/min, P < 0.001, Pstrain × treatment = 0.2). MAP day–night difference was reduced by losartan 150 mg/kg per day (Ptreatment < 0.001) and more so in BPH/2J (Pstrain × treatment = 0.013, Table 2). This was due to a greater effect of losartan 150 during the active period in BPH/2J compared with the inactive period (Pperiod in BPH/2J = 0.018). By contrast, no differences were observed in BPN/3J mice (Pperiod in BPN/3J = 0.7). This was accompanied by, and possibly related to, a lesser increase in activity in BPH/2J mice during the active period under losartan treatment (Fig. 1). Day–night differences in HR or activity were not affected by losartan 150 mg/kg per day (Table 2).Time course of the effect of losartan 150 mg/kg per dayThe time course of the changes to cardiovascular parameters following losartan 150 were examined and shown in Fig. 2. Hypotension was just evident within the 24 h of administration (average −9.6 ± 3.7 mmHg, P = 0.08) but continued to fall over the next two days to reach a maximum hypotension by day 4 (−27.4 mmHg). Stable hypotension was observed for the rest of the observation period. The hypotension was accompanied by a tachycardia evident by 12 h after commencing treatment, but gradually declined over the week's treatment. There were no observed changes in activity (Fig. 2).Fig. 2. No captions available.Relationship between locomotor activity and mean arterial pressureThe slope of the linear relationship between log activity and MAP was 34% greater in BPH/2J compared with BPN/3J mice (F1,24 strain = 6.6, P = 0.02) but was not affected by losartan 150 mg/kg per day in either group (F1,24 treatment = 0.5, P = 0.5). However, the elevation of the line, which was higher in BPH/2J compared with BPN/3J mice (Pstrain < 0.01), was reduced similarly by losartan 150 mg/kg per day in both strains (Ptreatment < 0.001, Ptreatment × strain > 0.05, Fig. 3).Fig. 3. No captions available.Cardiovascular variability and cardiac baroreflex sensitivityDuring the inactive and active periods, the MAP midfrequency power and also the total power was greater in BPH/2J compared with BPN/3J mice (inactive F1 132 strain > 2.5, P < 0.05 for all, Fig. 4). Losartan 150 mg/kg per day treatment reduced MAP midfrequency power in both strains during both periods (inactive F1 132 treatment = 12, P < 0.001; active F1 144 treatment = 6.3, P < 0.05; Fig. 4), but had no effect on total power (inactive Ptreatment = 0.1, active Ptreatment = 0.4, Fig. 4). There were no strain × treatment interactions in MAP power during either period.Fig. 4. No captions available.During the active period, BPH/2J mice had lower baroreflex gain compared with BPN/3J mice (active Pstrain < 0.05, Fig. 4), but there was no difference between strains in the inactive period (inactive Pstrain = 0.1, Fig. 4). This was due to suppression of BPH/2J mice baroreflex gain during arousal in contrast to BPN/3J mice that showed no effect of changing between day and night. Losartan 150 mg/kg per day treatment improved baroreflex gain in both strains during both periods (inactive F1144 treatment = 23, P < 0.001; active F1 144 treatment = 11, P < 0.001; Fig. 4).Cardiovascular response to behavioural testsFeedingMice had a rapid pressor and tachycardic response when they commenced eating a piece of almond (Fig. 5). The pressor response to feeding was greater in BPH/2J mice compared with BPN/3J mice expressed as change (F1 130 strain = 29, P < 0.001) or percentage change (Pstrain < 0.001), but there was no effect of losartan 150 mg/kg per day on the percentage difference (Ptreatment = 0.9) nor was there any treatment × strain interaction (Ptreatment × strain = 0.3, Fig. 4). The tachycardic response to feeding was not different between strains and was not affected by losartan 150 mg/kg per day treatment. There was a significant treatment × strain interaction for the HR response to feeding (Ptreatment × strain < 0.001). Activity in response to feeding was greater in BPH/2J mice compared with BPN/3J mice (Pstrain < 0.001) and this response was not affected by losartan 150 mg/kg per day (Ptreatment = 0.21). There was a treatment × strain interaction for the activity response to feeding (Ptreatment × strain < 0.01).Fig. 5. No captions available.RestraintA 5-min restraint stress elicited sustained pressor and tachycardic responses in all groups (Fig. 6). The percentage increase in MAP in response to restraint was much greater in BPH/2J mice than in BPN/3J mice (F1120 strain = 14, P < 0.001). Responses were also greater after losartan 150 mg/kg per day in both strains (F1120 treatment = 13, P < 0.001, strain × treatment was not significant). Conversely, the similar tachycardic response to restraint in both strains was reduced by losartan 150 mg/kg per day across groups (Ptreatment < 0.001), presumably due to the higher baseline in losartan-treated animals. The losartan effect was greater in BPN/3J mice presumably due to the greater effect on basal HR (Ptreatment × strain < 0.001).Fig. 6. No captions available.Dirty cage-switchPressor, tachycardic and activity responses to 1 h in a preoccupied cage reached their maximum in the first 20 min, decreased thereafter, but remained higher than baseline levels at the end of the 60-min period (Fig. 7). The pressor response when expressed as a percentage increase was greater in BPH/2J mice compared with BPN/3J mice (F1 162 strain = 14, P < 0.001) and lesser in losartan 150 mg/kg per day-treated mice (F1 162 treatment = 7, P < 0.008, Fig. 7). Although the effect of losartan was more evident in the BPN/3J mice, the treatment × strain interaction was not significant. Interestingly, the effect of losartan 150 mg/kg per day was not evident in the first 10 min (+4.1% in BPN/3J mice, +1.8% in BPH/2J mice) with the inhibition of the response occurring during the remaining 50 min (−12.4% in BPN/3J mice; −2.3% in BPH/2J mice). Losartan 150 mg/kg per day markedly attenuated the tachycardia response in BPN/3J mice but not in BPH/2J mice (Ptreatment < 0.001, Ptreatment × strain < 0.001). The locomotor response to stress was greater in BPH/2J mice compared with BPN/3J mice (Pstrain < 0.001) and was reduced by losartan treatment (Ptreatment < 0.001) (Fig. 7). The effect of losartan on locomotion was not dependent on strain.Fig. 7. No captions available.Blood pressure response to sympathetic blockadeSympathetic blockade by pentolinium during the active (night) phase reduced MAP in the two groups to comparable levels between 10 and 20 min after the injection (Fig. 8a). At this time, the change in MAP was greater in BPH/2J mice compared with BPN/3J mice across both treatments (F1,78 strain = 92, P < 0.001, Fig. 8a). Losartan 150 mg/kg per day did not affect the depressor effect of pentolinium in both groups during the night time (Ptreatment < 0.5).Fig. 8. No captions available.During the inactive (day) phase, there was no difference in the hypotensive effect of pentolinium measured at 20–30 min in BPH/2J mice compared with BPN/3J mice (F1,75 strain = 2.3, P = 0.1). Note that an extra 10 min was allowed during the inactive period before measurement to allow the animals to settle. Losartan treatment increased the depressor effect of pentolinium similarly in both strains (F1,75 treatment = 5.4, P < 0.02, Fig. 8b).DiscussionThe present study shows that a 2-week blockade of AT1A-receptors by losartan (150 mg/kg/day) induced a similar degree of hypotension in BPH/2J and BPN/3J mice, but that acute inhibition of the SNS (with pentolinium) induced a markedly greater fall in MAP in the hypertensive mice. Taken together, these findings suggest that although the RAS is essential to maintain normal BP, the SNS is largely responsible for the hypertension in BPH/2J mice which supports the view that the hypertension is neurogenic [3]. One of the difficulties in comparing effects of losartan in hypertensive and normotensive animals is the difference in BP which in itself may influence the degree of hypotension and, therefore, the interpretation of the study. In this regard, the percentage change in MAP was also analysed which has been suggested as a way of countering this confounding effect [21]. Nevertheless, losartan-induced hypotension was similar in both strains, whether expressed as change or percentage change. Previous studies have shown that the depressor effect of RAS antagonists increases with the dose increase [15,22]. In the present study, we observed substantial falls in BP with the dose of 150 mg/kg per day, but little effect at a dose of 30 mg/kg per day. This agrees with earlier studies in mice expressing gain-of-function AT1A-receptors [15,23]. The treatment did not affect fluid intake, body weight or activity, suggesting that the dose was well tolerated by the mice. The slow onset of the hypotension taking 4 days to reach a maximum is consistent with known renal dependent hypotensive mechanisms of losartan [24]. Together with the dose being only five times higher than a threshold dose suggests that the effects we are observing are due to a specific inhibition of AT1-receptors.These findings contrast with other genetic models of hypertension, such as the Lyon hypertensive rat, in which the hypertension is completely dependent on the RAS [25]. It has long been established that ACE inhibition, during early life as hypertension develops, produces a permanent reduction in BP in spontaneously hypertensive rats (SHRs) [26]. Furthermore, chronic treatment of adult SHRs with the ACE inhibitor perindopril induced a two-fold greater reduction in BP in SHRs than normotensive Wistar–Kyoto (WKY) [27]. This starkly differs from the Schlager mouse strain in which losartan was equi-effective in the BPH/2J and BPN/3J groups. The conclusion from this finding, that hypertension in BPH/2J mice is not dependent on the RAS, is consistent with earlier studies by Iwao et al. [10], showing no difference in levels of renin in plasma, kidney and the submaxillary gland by enzymatic assay and by direct radioimmunoassay in Schlager BPN/3J and BPH/2J mice. However, a later study by Uddin et al.[28,29] showed somewhat elevated levels of renin activity, and a kallikrein-like pro-renin-converting enzyme but lower levels of Ang I in BPH/2J submandibular gland compared with BPN/3J. These paradoxical findings (high renin – low Ang I) may suggest a disturbance to tissue processing of Ang peptides, as suggested by the authors. They also suggest plasma renin activity is elevated in BPH/2J mice which contrasts the earlier findings by Iwao et al., but did not publish these findings. One explanation for the higher renin levels may be that the samples were taken in the morning when the BP had fallen to its lowest point and the animals were decapitated. Renin increases during the inactive period and the larger fall in BP may have caused a greater increase in plasma renin levels that may have reduced the available Ang I by its rapid conversion. Also Uddin et al. decapitated the animals one by one in the laboratory which may have stressed the BPH/2J mice and caused a release of renin through sympathetic activation. Acute stress and decapitation markedly alters renin levels compared with anaesthesia [30]. By contrast, Iwao et al. used pentobarbitone and quickly removed blood from the vena cava. Differences in techniques and stress reactivity of the BPH/2J mice compared with the BPN/3J mice may explain these differences. Thus, there is no convincing evidence of activation of the RAS in BPH/2J mice.A previous study by Leckie [11] has reported that treatment with captopril given in the drinking water for 1 week produced a slightly greater decrease in BP in BPH/2J mice compared with BPN/3J mice. Although this might suggest a contribution from the RAS to the hypertension, SBP was measured using the tail-cuff technique which involves restraining mice in a plastic tube similar to that used to evoke a restraint stress response. Thus, although mice are generally trained and acclimatized to the restrainer, a component of stress arousal is well recognized as contributing to the BP measured. Given the markedly greater response to stress that we have previously reported in BPH/2J mice [31] and confirmed in the current study, it is likely that the interpretation of the effects of ACE inhibition as reported by Leckie are somewhat confounded. Indeed, early studies in mice showed that the tail-cuff technique underestimates the hypotensive effect of the ACE inhibitor enalapril in mice by about one third [32].Previous studies using losartan administered systemically suggest that this nonpeptide AngII antagonist and/or its active metabolite can readily cross the blood–brain barrier and selectively inhibit AT1A-receptors located in brain nuclei which are known to influence BP regulation and the pressor responses to aversive stimuli [33,34]. Furthermore, it has been reported that a lesion in the area postrema attenuated the losartan decrease in BP after 7 days of treatment compared with sham rats [35]. This suggests that the interaction between AT1-receptor blockade and central effects involving changes to the SNS would likely have occurred within the current time frame. In the current study, a range of behavioural tests which activate the SNS, as well as indirect measures of sympathetic activity, have been performed after 7 days of losartan treatment to determine whether there was such an interaction between the SNS and RAS in these mice. Indeed, the pressor responses to cage-switch stress were reduced, consistent with blockade of central AT1-receptors involved in the hypothalamic/brainstem pathways mediating stress responses [36] and with the lesser pressor responses observed in AT1-receptor null mice compared with normal mice [18]. Although this may have been an effect of losartan on vascular reactivity perhaps due to the hypotension, there was no effect on acute pressor response to feeding, suggesting there has not been a global change to vascular reactivity. Importantly, the response to feeding does not involve activation of central AT1-receptors in mice [18] or in rabbits [37,38]. Further evidence of a central effect of losartan comes from the power spectral analysis that showed a reduction in midfrequency MAP power in BPH/2J and BPN/3J mice that occurs during the arousal (night) period and that has been previously shown to be related to sympathetic activity [39]. Importantly, the MAP total power was not affected, suggesting that the decrease in the MAP midfrequency power was not a generalized change in BP variability of AT1A-receptor blockade. Thus, these findings suggest that losartan may have acted centrally to inhibit AT1-receptors, causing a sympathetic inhibition during arousal.Interestingly, the early response to dirty cage-switch stress (up to 10 min) was not attenuated in losartan-treated animals and indeed, the 5-min restraint stress pressor response was greater following losartan. These findings suggest that the central AT1A-receptor plays a limited role or possibly an inhibitory role in the onset of the pressor response to aversive stress. This is not entirely unexpected as AT1-receptor null mice show exactly the same pattern [18]. Furthermore, Mayorov and Head [37] have shown that microinjection of losartan into the rostral ventrolateral medulla reduced the late but not the early pressor responses to air-jet stress. The initial response can be attenuated by the ionotropic glutamate receptor antagonist kynurenate [40]. Together, these findings suggest that in the present study, losartan could be acting via AT1A-receptors outside and within the blood–brain barrier to modulate brain regions involved in the maintenance of the BP response to stress. Additionally, the similar pattern of MAP reactivity to AT1A-receptor blockade in BPN/3J and BPH/2J mice suggests that AngII is likely not mediating the greater pressor response to stress in these neurogenic hypertensive mice.An interesting finding from the present study was that the acute sympathetic inhibition with ganglionic blockade produced greater hypotension during the inactive (day) phase in losartan-treated mice than normal mice, suggesting that the AngII blockade induces SNS activation. This does not occur when the SNS is most active (during the night). Similarly, Gaudet et al. [41] have shown that the combination of α1-adrenoreceptor and chronic AT1-receptor blockade by losartan was more hypotensive compared with the effect of prazosin alone in WKY rats and SHRs. They suggested that the chronic inhibition of the RAS led to increased sympathetic tone [41]. In the present study, this effect was clearly related to the well known circadian pattern of the SNS [42] and occurred when BP was lowest and the SNS inhibited. The mechanism, therefore, may be related to a baroreflex compensation to prevent profound hypotension. Alternatively, the central sympatho-excitatory action of losartan may only be evident when there are relatively low levels of SNA which has been suggested by us previously in studies with conscious rabbits and direct recordings of renal SNA [43].The possibility of a contribution from baroreflex mechanisms is supported by the findings that under losartan, the baroreflex gain was markedly increased. Although this reflects cardiac vagal baroreflex gain rather than vasomotor baroreflex gain, it may be a general increase in the reflex sensitivity. Central actions of losartan on baroreflex sensitivity are well known [44] and could be related to a central action in blocking endogenous AngII within the brainstem to reduce cardiovagal activity [45,46].The profound hypotensive effect of losartan confirms the importance of the RAS in maintaining normal levels of BP. However, the similar effect of losartan in both the normotensive and the hypertensive strains combined with the much greater hypotension produced by acute pentolinium in hypertensive compared with normotensive animals suggests that the hypertension in the BPH/2J mice is primarily due to greater activation of the SNS. Furthermore, the present study provides evidence for a contribution of central AT1A-receptors in the BP control by increasing aversive stress responses and diminishing baroreflex gain. By contrast, during inactivity, the RAS appears to have the opposite effect to inhibit the SNS. Thus, this dual role of central AT1-receptors may provide an effective amplification of the range of sympathetic contribution to BP which might have advantages in terms of coping with adverse environments. This may be relevant clinically as humans with greater reactivity to stress, such as white-coat hypertensive individuals, would be resistant to any central sympatho-inhibitory effects of Ang receptor blockers with central actions [47,48]. Clearly, further studies could evaluate the effect of another antihypertensive drug, such as hydralazine, to remove the central effect of AngII blockade as well as to examine the effects of direct injection of AT1-receptor antagonists centrally.AcknowledgementThis work was supported by grants from the National Health & Medical Research Council of Australia (Project 526662) and Région Ile-de-France and Agence Nationale de la Recherche (ANR08-BLAN-0175-CSD8). 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