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Hypertension. 1996;27:598-606

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(Hypertension. 1996;27:598-606.)
© 1996 American Heart Association, Inc.

Articles

Hypotensive Response to Losartan in Normal Rats

Role of Ang II and the Area Postrema

John P. Collister; Barbara J. Hornfeldt; John W. Osborn

From the Graduate Program in Cellular and Integrative Physiology, Graduate Program in Veterinary Biology, University of Minnesota, St Paul.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Abstract We have reported that the angiotensin II (Ang II) AT1 receptor antagonist losartan markedly lowers arterial pressure in sodium-replete, normotensive rats. We hypothesized that this action of losartan was mediated by its blocking the effects of endogenous Ang II. To test this hypothesis, rats were instrumented with arterial and venous catheters for measurement of arterial pressure and infusion of losartan, respectively. After 3 days of control measurements, losartan was infused for 10 days (10 mg·kg-1·d-1) in rats on a normal daily sodium intake (NNa; approximately 2 mmol/d, n=6) and rats on a high daily sodium intake (HNa; approximately 15 mmol/d, n=7) to suppress endogenous Ang II. Although basal plasma renin activity was markedly suppressed in HNa rats (0.9±0.4 ng Ang I·mL-1·h-1) compared with NNa rats (4.0±0.3 ng Ang I·mL-1·h-1), control arterial pressure was not different between NNa (113±4 mm Hg) and HNa (113±2 mm Hg) rats. Losartan decreased arterial pressure from control levels in NNa rats on the first day of infusion (-12±2 mm Hg) but had no effect on arterial pressure in HNa rats (+4±4 mm Hg). Furthermore, by day 10 of losartan infusion, arterial pressure had decreased further from control levels in NNa rats (-32±2 mm Hg) but remained unchanged compared with control in HNa rats (+5±6 mm Hg). A second study was conducted to test the hypothesis that the area postrema, a circumventricular organ proposed to mediate the long-term neurogenic pressor activity of Ang II, is a site of action for losartan. After 3 control days, losartan was administered for 10 days to area postrema–lesioned rats (APx; n=11) or sham-lesioned rats (n=10) consuming an NNa diet. Control arterial pressure was similar in sham (95±3 mm Hg) and APx (96±2 mm Hg) rats. Basal plasma renin activity was not different between groups (sham, 4.1±1.5 versus APx, 5.3±1.6 ng Ang I·mL-1·h-1). On day 1 of losartan treatment, arterial pressure decreased to a significantly lower level in sham (80±2 mm Hg) compared with APx (90±3 mm Hg) rats. This trend continued through day 4 of losartan infusion, in which arterial pressure in sham rats (72±2 mm Hg) was significantly lower than in APx rats (83±4 mm Hg). However, during the remainder of the losartan infusion, there were no significant differences between groups with the exception of day 8 (sham, 72±2 mm Hg; APx, 84±2 mm Hg). Taken together, these results support the hypothesis that the hypotensive actions of losartan in sodium-replete, normotensive rats are due to blockade of the physiological effects of endogenous Ang II. Furthermore, an intact area postrema is essential for full expression of the hypotensive actions of losartan in normal rats.


Key Words: losartan • receptors, angiotensin type 1 • sympathetic nervous system • blood pressure


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
The RAS plays a major role in both the short- and long-term regulation of arterial pressure. It is well accepted that short-term maintenance of arterial pressure by the RAS is accomplished primarily by the powerful vasoconstrictor effects of Ang II. However, the mechanism whereby the RAS chronically influences arterial pressure is less clear. Some of the confusion is simply due to the numerous physiological effects of the RAS, all acting on different time scales to chronically increase arterial pressure. These include direct vasoconstriction,1 renal retention of sodium and water,2 3 4 increased central and peripheral sympathetic drives,5 and vascular hypertrophy.6

Much of our current understanding of this control system is based on the response of arterial pressure to drugs that block the RAS, including ACE inhibitors and the more recently developed AT1 receptor antagonists (eg, losartan). Not surprisingly, pharmacological blockade of the RAS decreases arterial pressure under physiological conditions in which the RAS is activated, such as hypovolemia and sodium depletion.7 In addition, these drugs are effective antihypertensive agents for the treatment of "renin-dependent" forms of experimental and human hypertension.8 However, long-term blockade of the RAS is also useful for the treatment of human essential hypertension and some forms of experimental hypertension in which PRA is not elevated.8 9 10 Although it has been suggested that this effect may be due to drug effects unrelated to the RAS, such as increased bradykinin levels with ACE inhibitors,8 reports that both ACE inhibitors and losartan are equally effective argue against this explanation.10

The prevention and treatment of "non–renin-dependent" forms of hypertension by long-term blockade of the RAS raise many interesting questions concerning the role of the RAS in the pathogenesis and maintenance of high blood pressure. Most importantly, what physiological effect of the RAS (eg, vascular, renal, neural, structural) is critical to the long-term hypotensive effects of RAS blockade under conditions of normal PRA? Moreover, a recent report from our laboratory suggests that chronic AT1 receptor blockade markedly decreases arterial pressure under conditions of both normal PRA and normal arterial pressure.11 A 10-day intravenous infusion of losartan, at a dose above that required to block the acute vasoconstrictor actions of Ang II, decreased arterial pressure 40 mm Hg from control levels in salt-replete Sprague-Dawley rats.11 The observation that chronic blockade of AT1 receptors has such a profound effect on arterial pressure in normotensive rats with intact intrinsic, neural, and hormonal (other than the RAS) control systems suggests that Ang II may play a greater role in regulation of arterial pressure than previously recognized.

The present study was conducted to address two questions. First, are the hypotensive actions of this dose of losartan in normal rats due to blockade of the physiological effects of endogenous Ang II or secondary to nonspecific effects of the drug? Second, if the responses to losartan are specific to blockade of the RAS, what is the site of action of the drug? One possible site of action of losartan is the central nervous system. Several studies support the idea that long-term intravenous administration of Ang II produces hypertension by increasing sympathetic activity.12 13 14 15 16 17 It has been proposed that circulating Ang II interacts with key sympathetic structures via binding to AT1 receptors in the area postrema, a circumventricular organ lacking a blood-brain barrier.18 This idea is supported by the observation that a lesion of the area postrema attenuates chronic Ang II–induced hypertension in the rat.19

In the present study, experiments were conducted to test the hypothesis that the long-term hypotensive actions of losartan were the result of blockade of the actions of endogenous Ang II on the area postrema. We measured the arterial pressure responses to long-term losartan administration in rats in which endogenous Ang II was suppressed by oral salt loading and in APx rats.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
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Adult male Sprague-Dawley rats (325 to 375 g, Harlan Sprague-Dawley Inc, Indianapolis, Ind) were used in all experiments. All procedures were conducted in accordance with institutional and National Institutes of Health guidelines.

Surgical Procedures
Catheter implantation. Rats were preanesthetized with pentobarbital (32.5 mg/kg IP). Surgical anesthesia was achieved with a second intramuscular injection containing a combination of anesthetic agents (acetylpromazine 0.2 mg/kg, butorphanol tartrate 0.2 mg/kg, ketamine 25 mg/kg). Rats were then instrumented with arterial and venous catheters via the femoral vessels. The catheters exited through the skin on the dorsal surface of the skull and were passed through a flexible spring connected to a single-channel hydraulic swivel to which the venous catheter was attached. At the end of surgery, each rat received a subcutaneous injection of 0.075 mg butorphanol tartrate for analgesic purposes. After recovery from anesthesia, rats were housed individually in metabolic cages with the swivels mounted above. Rats were allowed 3 days to recover from surgery before the experimental protocol began. During this time, each rat received daily prophylactic intravenous antibiotics consisting of 15 mg ampicillin and 1 mg tobramycin. Each rat was also started on a continuous intravenous infusion of sterile 0.9% saline (7 mL/24 h). A 0.4% NaCl diet (Research Diets) and distilled water were provided ad libitum throughout this recovery period, with the exception of one group maintained on an 8.0% NaCl diet as described below.

Area postrema lesion. As described below, one experiment was carried out in APx rats. In that experiment, rats were randomly selected for APx or sham operation 3 weeks before catheter implantation. Rats were anesthetized as described above and placed in a stereotaxic apparatus with the neck flexed. A dorsal midline incision was made through the skin and epaxial musculature. With the aid of a dissecting microscope, the atlanto-occipital membrane was visualized and punctured, and a portion of it was removed. To better visualize the brain stem, a small portion of the base of the skull was removed with rongeurs. The area postrema was visualized on the dorsal surface of the medulla at the caudal extent of the fourth ventricle and removed by suction with a 26-gauge needle attached to a vacuum line as described by Edwards et al.20 With the exception of the attached vacuum line, sham operations were identical to those described for APx rats. The muscular layer was closed with 3-0 chromic catgut suture. Silk sutures (3-0) were placed in the skin for closure. Rats were given 3 weeks for postoperative recovery. Since anorexia and weight loss are known side effects of lesioning of the area postrema, the food intake of sham-operated rats was restricted to a level, established from pilot studies, similar to that of APx rats during the 3-week recovery period. Food intake was restricted to approximately 50%, 60%, and 80% of normal the first, second, and third weeks after sham surgery, respectively. Preliminary studies from our laboratory showed that after 3 weeks, APx rats regain a normal food intake and growth rate.

Experimental Protocol
Two separate experiments were conducted using the same basic protocol initiated 3 days after instrumentation. The first 3 days of the protocol served as a control period during which a continuous infusion of 0.9% sterile saline IV (7 mL/24 h) was maintained. This was followed by a 10-day infusion period of the AT1 receptor antagonist losartan (10 mg·kg-1·24 h-1). Losartan was dissolved in 0.9% sterile saline and infused at a rate of 7 mL/24 h IV. Finally, a 3- to 4-day recovery period identical to the control period completed the protocol. All infusions were given through a 0.2-µm syringe filter.

Throughout the protocol, MAP, heart rate, food intake, water intake, and urine output were measured daily in conscious, unrestrained rats in their home cages. MAP was measured directly by connecting the arterial catheter to a pressure transducer coupled to a polygraph (Grass Instrument Co, Inc). MAP was monitored daily for 15 minutes by computer at a sampling rate of 1 Hz as previously described.21 The resulting 900 data points were used to calculate the average MAP as well as the SD-MAP during the recording period. SD-MAP was used as a quantitative index of baroreceptor reflex function as previously described.21 Heart rate was measured by increasing the chart speed and counting peaks on the pulsatile pressure tracing. Twenty-four–hour food and water intake as well as urine output were measured gravimetrically. Sodium intake was calculated as the sum of sodium received in the daily infusion (1 mmol/d IV) plus the product of food intake and the sodium content of the food, which had previously been determined by flame photometry (0.4% NaCl, 0.07 mmol/g; 8.0% NaCl, 1.00 mmol/g). Urinary sodium content was measured with an ion-specific electrode (Nova Biomedical). Urinary sodium excretion was calculated as the product of urine flow rate and urinary sodium concentration.

Experiment 1. Effect of dietary salt loading on the long-term hypotensive effects of losartan. To investigate the role of endogenous Ang II in the response to losartan, the above protocol was performed in two experimental groups. The control group (n=6) received a diet containing 0.4% NaCl (Research Diets) throughout the 16-day protocol. This resulted in a daily sodium intake (oral plus intravenous sodium) of approximately 2 mmol/d. The second group (n=7) received an 8.0% NaCl diet (Research Diets), which began 2 weeks before instrumentation and continued throughout the protocol, to suppress endogenous Ang II. This resulted in a daily sodium intake of approximately 15 mmol/d.

Experiment 2. Effect of APx on the long-term hypotensive effects of losartan. To examine the role of the area postrema in the response to losartan, the protocol described above was carried out in sham-operated (n=10) and APx (n=11) rats. Both groups were maintained on the same 0.4% NaCl diet.

Measurement of Baseline PRA and Tests of AT1 Receptor Blockade
PRA was measured in all rats on the second control day. Blood (500 µL) was obtained via the arterial catheter and placed into a chilled 1-mL syringe containing 1 mg EDTA in 20 µL. Whole blood was centrifuged, and plasma was collected and stored at -70°C for later radioimmunoassay as previously described.22

To test the efficacy of AT1 receptor blockade, acute pressor responses to bolus injections of Ang II (30 ng IV) were measured in all rats on day 3 of the control period and day 7 of losartan infusion. Responses were measured as the peak response of arterial pressure compared with that immediately before injection.

Histological Verification of Area Postrema Lesion
Upon completion of the protocol, all rats from the second experiment were anesthetized as described above and perfused intracardially with 8% paraformaldehyde. Whole brains were dissected and soaked in 8% paraformaldehyde for 2 days. The brains were then transferred to a 30% sucrose solution and allowed to soak for a minimum of 2 days. Frozen serial coronal sections (40 µm) were made at the level of the obex and mounted on slides. The slides were then stained for Nissl substance (cresyl violet stain). Confirmation of complete area postrema lesioning or intact area postrema (sham-operated rats) was made under light microscopy. All APx rats included in the final analysis of the data were confirmed to have complete lesions of the area postrema.

Statistical Analysis
Statistical comparison within and between experimental groups was performed by a two-way ANOVA with a commercially available statistical package (Abacus Concepts, Inc). Comparisons of specific experimental days (within and between groups) were performed by linear contrast analysis.23 For clarity in data presentation, only between-group differences are shown in all figures. Between-group comparison of baseline control values was done by comparing the average of the 3 control days with an unpaired t test. In addition, an unpaired t test was used for between-group comparisons of body weight, PRA, and pressor responses to Ang II. A value of P<.05 was considered statistically significant for all tests. All values are reported as mean±SEM.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
Experiment 1: Effect of Dietary Salt Loading on the Long-term Hypotensive Effects of Losartan
HNa rats had a significantly lower basal level of PRA (0.9±0.4 ng Ang I·mL-1·h-1) compared with NNa rats (4.0±0.3 ng Ang I·mL-1·h-1). However, as shown in Fig 1Down, the 3-day average control values for MAP were not significantly different between NNa (113±4 mm Hg) and HNa (114±2 mm Hg) rats. More importantly, chronic administration of losartan resulted in a marked, statistically significant decrease of MAP in NNa but not HNa rats. By the first day of losartan treatment, MAP was significantly decreased in NNa rats compared with their own control levels (-12±2 mm Hg) and compared with HNa rats (+4±4 mm Hg). MAP continued to decrease in the NNa group, reaching a level 32±2 mm Hg below control by day 10 of losartan infusion. Losartan administration had no significant effect on MAP at any time during the protocol in HNa rats. During the recovery period, MAP in NNa rats gradually returned toward pretreatment levels, and by day 4 there was no statistically significant difference between NNa and HNa rats.



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  		Figure 1. Line plots show MAP (top) and heart rate (bottom) observed throughout control (3 days saline), treatment (10 days losartan, 10 mg·kg-1·24 h-1), and recovery (3 days saline) in sodium-replete (0.4% NaCl) vs sodium-loaded (8.0% NaCl) rats. *Statistical significance between groups (P<.05).

The efficacy of AT1 blockade was assessed by measuring the pressor responses to 30 ng Ang II on the third control day and day 7 of losartan. Control responses were similar in NNa (+37±2 mm Hg) and HNa (+40±3 mm Hg) rats. On day 7 of losartan, the response was abolished (0±0 mm Hg) in both groups.

The hypotensive response of NNa rats to losartan was associated with a sustained tachycardia (Fig 1Up). Heart rate was significantly elevated above control (371±7 beats per minute) by the second day of losartan (430±20 beats per minute). The tachycardia was maintained throughout losartan treatment in NNa rats, with heart rate returning to control levels during the recovery period. Although HNa rats did not exhibit the same degree of tachycardia, heart rate was significantly elevated compared with control on day 3 of losartan (statistics not shown).

The hypotensive effect of losartan was not correlated with significant alterations in sodium or water balance (within groups). Control values for sodium intake were 2.0±0.1 mmol/24 h in NNa rats and 14.1±1.1 mmol/24 h in HNa rats. With regard to 24-hour sodium balance, losartan had no effect within either group, and there were no significant differences between groups during the entire protocol (Fig 2Down). As expected, control water intake was greater in HNa rats (49±5 mL/24 h) than NNa rats (17±1 mL/24 h). Although losartan did not significantly affect water balance (within groups) in either NNa or HNa rats (Fig 2Down), significant differences between the groups were observed on days 2, 6, 8, and 9 of losartan infusion and days 1 and 2 of recovery.



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  		Figure 2. Line plots show sodium (top) and water (bottom) balances observed throughout control (3 days saline), treatment (10 days losartan, 10 mg·kg-1·24 h-1), and recovery (3 days saline) in sodium-replete (0.4% NaCl) vs sodium-loaded (8.0% NaCl) rats. *Statistical significance between groups (P<.05).

Experiment 2: Effect of APx on the Long-term Hypotensive Effects of Losartan
On the day of APx or sham operation, the body weights of the two groups were not significantly different (339±5 and 336±2 g, respectively). Three weeks later, at the time of catheter implantation, body weights of APx (280±11 g) and sham (288±15 g) rats were not significantly different because of selective food restriction in the sham group. During the 3-day control period, ad libitum food intake was normal in APx rats (13±2 g/24 h) compared with previous studies from our laboratory.24 However, food intake was lower in APx rats compared with sham rats (18±2 g/24 h). This is most likely the result of a slightly increased food intake in sham rats subsequent to a 3-week period of food restriction.

Histological verification of the APx was confirmed in all APx rats. A typical example is shown in Fig 3Down. In all rats, there was minimal destruction, at the light microscopic level, of the adjacent NTS. Further evidence that lesions of the area postrema did not impair NTS sites involved in the baroreceptor reflex was that the lability of MAP (SD-MAP), a quantitative index of baroreceptor reflex sensitivity,21 was not significantly different between sham (4±1 mm Hg) and APx (5±1 mm Hg) rats. This is in agreement with a similar analysis of lability in rats with electrolytic lesions of the area postrema.25



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  		Figure 3. Photomicrographs of 40-µm sections of a typical sham operation (top) and area postrema lesion (bottom). AP indicates area postrema; DMV, dorsal motor nucleus of vagus nerve.

Basal PRA was not different between sham (4.1±1.5 ng Ang I·mL-1·h-1) and APx (5.3±1.6 ng Ang I·mL-1·h-1) rats. Similarly, there was no significant difference in control MAP between APx (96±2 mm Hg) and sham (95±3 mm Hg) rats (Fig 4Down). By day 1 of losartan treatment, MAP was significantly decreased in both APx and sham rats (90±3 and 80±2 mm Hg, respectively), and both groups demonstrated statistically significant decreases in MAP from control throughout the 10-day losartan treatment (data not shown). However, the depressor response to losartan was attenuated by approximately 50% in APx rats compared with the sham group on days 1 through 4 and 8 (Fig 4Down). Throughout the recovery period, both groups of rats maintained significantly lower MAPs compared with their own control level (statistics not shown).



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  		Figure 4. Line plots show MAP (top) and heart rate (bottom) observed throughout control (3 days saline), treatment (10 days losartan, 10 mg·kg-1·24 h-1), and recovery (3 days saline) in APx vs sham-operated rats. *Statistical significance between groups (P<.05).

Pressor responses to 30 ng Ang II were measured as described above during the control period and on day 7 of losartan treatment. Control responses were not significantly different in APx (33±3 mm Hg) compared with sham (38±3 mm Hg) rats. The pressor response to Ang II was completely abolished in both groups (0±0 mm Hg) by losartan.

A significant difference in control heart rate was observed between APx and sham rats, with values averaging 328±9 and 367±7 beats per minute, respectively (Fig 4Up). Both groups showed significant increases in heart rate from control by day 2 of losartan treatment (data not shown), which were sustained through most (sham) if not all (APx) of the losartan treatment. By day 10 of losartan, average heart rate was 373±10 beats per minute for APx rats and 408±8 beats per minute for sham rats (Fig 4Up). By day 3 of recovery, heart rates had returned to control levels for both groups (data not shown) but remained significantly different from each other.

Control sodium intake was not different between APx (1.9±0.1 mmol/24 h) and sham (2.2±0.1 mmol/24 h) rats. Furthermore, no significant differences were observed between APx and sham rats in daily sodium balance throughout the control, treatment, and recovery periods. With regard to control water intake, APx (22±3 mL/24 h) and sham (16±2 mL/24 h) rats were similar. APx rats maintained an average daily water balance of 8.3±2.5 mL/24 h throughout the control period compared with 11.7±2.2 mL/24 h for sham rats (Fig 5Down). Neither group showed any significant difference from control or from each other throughout the losartan treatment.



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  		Figure 5. Line plots show sodium (top) and water (bottom) balances observed throughout control (3 days saline), treatment (10 days losartan, 10 mg·kg-1·24 h-1), and recovery (3 days saline) in APx vs sham-operated rats. *Statistical significance between groups (P<.05).


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
The major findings of this study were as follows. First, long-term administration of the selective AT1 receptor antagonist losartan resulted in profound hypotensive responses in normotensive rats with normal PRA. Second, this response was abolished when PRA was suppressed by chronic salt loading. Finally, the initial hypotensive response to losartan was attenuated in APx rats. Taken together, these findings suggest that the RAS plays a greater role in the maintenance of arterial pressure under normal physiological conditions than previously believed. Also, an intact area postrema is essential for complete expression of the hypotensive effects of losartan in normal rats. The implications of these findings to regulation of arterial pressure and the treatment of hypertension are discussed below.

Long-term Hypotensive Responses to AT1 Receptor Blockade in Normal Renin States: Implications for Overall Control of Arterial Pressure
The recent development of nonpeptide antagonists selective for the Ang II AT1 receptor has provided a valuable pharmacological tool for studying the role of the RAS in the regulation of arterial pressure and the pathogenesis of hypertension. Unlike ACE inhibitors, which also block the enzymatic degradation of the vasodilator bradykinin and other peptides, AT1 receptor antagonists appear to be selective for the RAS and therefore provide a more specific experimental probe. As expected, initial in vivo studies of losartan demonstrated that arterial pressure is acutely decreased by AT1 receptor blockade under conditions in which the activity of the RAS is elevated, such as chronic sodium depletion and hypovolemia.7 Moreover, losartan has been shown to chronically decrease arterial pressure in several forms of "renin-dependent" hypertension.8 This is consistent with a clear role for the RAS in the development and maintenance of these forms of hypertension and for the equally effective response of arterial pressure to administration of ACE inhibitors.

However, both ACE inhibitors and losartan have been shown to be effective antihypertensive agents in "non–renin-dependent" forms of experimental and human essential hypertension as well.10 26 With ACE inhibitors, this effect could be explained by increased tissue levels of the vasodilator bradykinin. In other words, the role of the RAS alone could not be firmly established. However, a recent study demonstrated that the ACE inhibitor benazeprilat and losartan were equally effective in the SHR,10 which is consistent with the idea that ACE inhibitors act via blockade of the RAS alone.

There are two general hypotheses to explain the ability of RAS inhibition to lower arterial pressure in non–renin-dependent hypertension. One is that these drugs block the tissue RAS in addition to the circulating RAS. This would result in a reduction of sympathetic nerve outflow in the case of the brain RAS27 28 and a reduction in vascular resistance in the case of the vascular RAS.6 29 According to this hypothesis, circulating renin levels may not necessarily reflect the activity of the brain or vascular RAS, and, therefore, PRA would not predict the effectiveness of RAS blockade. An alternative hypothesis is that the sensitivity of target tissues to circulating Ang II is increased in these models of hypertension.30 An elevated sensitivity to Ang II coupled with the fact that PRA is not suppressed in animals and humans with chronic hypertension implies that RAS activity is inappropriately high under those conditions.

The novel aspect of the present study is the marked effect of losartan on arterial pressure in normotensive, salt-replete rats. This response occurred under conditions of normal RAS activity and did not require a background of hypertension, which may alter Ang II sensitivity. A qualitatively similar effect of ACE inhibitors on arterial pressure in normotensive salt-replete rats10 31 32 and humans33 34 has been reported, although the magnitude of the response was less than that observed in the present study. Perhaps the most significant aspect of this finding is that this hypotensive response occurred in the presence of other powerful arterial pressure control systems. Indeed, neural and hormonal control systems, as well as the intrinsic pressure-natriuresis mechanism, are known to respond strongly to decreases in arterial pressure to maintain the driving force for blood flow to the tissues. In the present study, losartan decreased arterial pressure from a control level of approximately 115 mm Hg to a steady-state level of 80 mm Hg. To the best of our knowledge, interference with other known control systems, including the sympathetic nervous system, vasopressin, or pressure-natriuresis mechanism, does not result in such profoundly low levels of arterial pressure as those observed in this study with long-term AT1 receptor blockade. This suggests a central role for the RAS in overall long-term control of arterial pressure even under conditions of normal RAS activity and arterial pressure.

The hypotensive response to losartan was characterized by a slow onset and required 5 days to reach maximal effect. The reversal of the response followed a similar time course. This suggests that the response was not simply due to blockade of the vasoconstrictor effects of Ang II. This is consistent with a recent study from our laboratory in which losartan, at a dose of 1 mg·kg-1·24 h-1, shifted the Ang II dose-response curve relating acute Ang II pressor responses 15-fold to the right.11 However, infusion of this same dose over 10 days to salt-replete rats had no effect on arterial pressure or heart rate, suggesting that long-term blockade of the vasoconstrictor actions of Ang II does not impair long-term regulation of arterial pressure in normotensive, salt-replete rats. However, at the higher dose used in this study (10 mg·kg-1·24 h-1), a marked hypotensive response was observed. Since this response was not seen in sodium-loaded rats in which the endogenous RAS was suppressed, it is likely that this effect of losartan was indeed the result of specific blockade of the RAS. On the basis of these observations, we conclude that the dose of losartan used in this study (10 mg·kg-1·24 h-1) chronically lowered arterial pressure by specific blockade of the RAS. In addition, the mechanism of this response does not involve blockade of the well-known vasoconstrictor actions of Ang II. Our findings are in close agreement with a recent study that demonstrated that the slow-response component of losartan in Ang II–induced hypertension predominates when the plasma Ang II level is low and does not involve blockade of Ang II vasoconstrictor activity.35

Previous studies have shown that losartan, at the dose used in this study, had no effect on arterial pressure in normotensive rats.7 However, the majority of those studies examined only the acute responses (ie, blockade of Ang II vasoconstriction) to losartan. A recent study compared the effects of long-term infusion of losartan, at the same dose as used in this study, on arterial pressure in SHR and WKY rats.10 In SHR, losartan decreased arterial pressure approximately 25 mm Hg from a hypertensive level of 150 mm Hg after 7 days of infusion. In contrast, the same dose of losartan decreased arterial pressure in normotensive WKY rats 15 mm Hg from control levels. This observation in WKY rats10 is qualitatively consistent with the present study in Sprague-Dawley rats.

Role of the Area Postrema in the Hypotensive Response to Losartan
Chronic intravenous administration of doses of Ang II that have no acute effect on arterial pressure (ie, subpressor doses) has been shown to result in hypertension in experimental animals.17 36 37 Although the mechanism of "low-dose angiotensin hypertension" is not entirely understood, studies investigating the pathogenic mechanisms of this model provide some insight into possible mechanisms of action of losartan in normal rats. One mechanism of the so-called "slow pressor effect"36 38 39 of low doses of Ang II would be a shift in the renal function curve to a higher operating pressure secondary to renal retention of sodium and water.2 3 4 Another proposed mechanism is Ang II–mediated vascular hypertrophy,6 29 which would elevate peripheral vascular resistance. Finally, others have proposed a neurogenic mechanism.12 13 14 15 16 17 19 This is based on direct measurement of sympathetic nerve discharge16 and the observation that sympatholytic drugs normalize arterial pressure in this model of hypertension.14 15 17 Moreover, ablation of the area postrema virtually abolishes the long-term hypertensive effects of Ang II in the rat.19 This is consistent with the presence of AT1 receptors in the area postrema40 and the observation that systemically administered AT1 receptor antagonists block the pressor response to Ang II injection directly into the area postrema.41 42 The sympathoexcitatory actions of Ang II have been reviewed.43 44 45

In the present study, we tested the hypothesis that the hypotensive response to losartan was the result of blocking the tonic effect of circulating Ang II on sympathetic activity via binding to AT1 receptors in the area postrema. In other words, we predicted that the effect of APx on the hypotensive response to blockade of endogenous Ang II would mirror the effect of APx on the hypertensive response to exogenous Ang II infusion.19 Theoretically, ablation of the area postrema would abolish the hypotensive effects of losartan if this mechanism were solely responsible for the fall in arterial pressure. Although APx rats did indeed exhibit an attenuated response to losartan, this occurred only during the first 4 days of the 10-day infusion. Thereafter, there were negligible differences between sham and APx rats. This observation suggests that an intact area postrema is required for full expression of the hypotensive response. However, the steady-state level of hypotension appears to be independent of the area postrema.

There are several explanations why ablation of the area postrema did not completely abolish the effects of losartan. First, the entire response may be a summation of nonneural and neural mechanisms. For example, intrarenal infusion of the AT1 antagonist valsartan has been shown to decrease arterial pressure in SHRs at a dose that had no effect when administered intravenously.46 Unfortunately, this study was not carried out in WKY rats. Nonetheless, this suggests primarily a renal site of action for the antihypertensive action of this AT1 receptor antagonist. In the present study, the observation that losartan-treated rats were in sodium balance despite a resting arterial pressure of 80 mm Hg, by definition, means that the renal function curve was shifted to a lower pressure level.47 48 However, we cannot discern from our data whether this was a primary effect of losartan or a secondary resetting of the kidney. It is also possible that this dose of losartan resulted in structural alterations in resistance vessels, although this seems unlikely, since the maximal depressor response was achieved in just 5 days. It is also possible that losartan resulted in sympathoinhibition by blocking the effects of circulating Ang II on other circumventricular organs, such as the subfornical organ, in addition to the area postrema. Moreover, there is evidence that losartan can cross the blood-brain barrier and thereby block the brain RAS.49 Finally, we did not investigate the role of AT2 receptors in this study. It is known that chronic blockade of AT1 receptors results in an elevation of PRA,10 presumably the result of interference of the negative feedback effect of Ang II on renin release. Hence, these rats presumably had high circulating levels of Ang II, which could bind to AT2 receptors. At the present time, the physiological role of these receptors remains unclear, but there is a preliminary report that these receptors may serve a vasodilatory role.50 Ironically, elevation of Ang II in the presence of AT1 receptor blockade may provide a mechanism to chronically lower arterial pressure. This possibility remains to be proven.

Technical Considerations for Studies Involving Lesion of the Area Postrema
In the rat, the area postrema can be ablated electrolytically or by suction, as in the present study. The suction technique used in this study resulted in APx rats that were similar to rats in which the area postrema was ablated electrolytically. We observed that resting heart rate in our APx rats was markedly lower than in sham-operated rats, as has been reported by others using the electrolytic technique.51 In addition, our APx rats had normal PRA and arterial pressure lability, as has been reported for rats with electrolytic lesions of the area postrema.25 51

It is also well established that food intake is dramatically reduced for 2 to 3 weeks after lesion of the APx, resulting in a loss of as much as 25% to 30% of body weight. In the present study, we chose to restrict food intake in sham-operated rats to the same extent as APx rats to account for the influence of reduced caloric intake and body weight on the cardiovascular effects of losartan. It is important to note that the response of the food-restricted sham group to losartan (Fig 4Up) was less than that observed in control rats allowed food ad libitum (Fig 2Up). Fig 6Down shows the comparison of the two control groups in this study. It should be noted that control rats in which food intake was restricted to equal that observed after APx had a lower resting level of arterial pressure before infusion of losartan than rats allowed free access to food. Also, it should be noted that the rate of the initial hypotensive response to losartan was similar in the two groups over the first 4 days. Thereafter, the groups merged such that the steady-state level of arterial pressure was not different between them. This observation suggests that alterations in food intake after lesion of the area postrema may influence the cardiovascular responsiveness of these animals. We are currently conducting studies to examine whether this continues to be a factor in APx rats studied months, rather than weeks, after APx ablation.



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  		Figure 6. Line plots show MAP observed throughout control (3 days saline), treatment (10 days losartan, 10 mg·kg-1·24 h-1), and recovery (3 days saline) in sodium-replete (0.4% NaCl) vs food-restricted, sham-operated rats. *Statistical significance between groups (P<.05).


*    Selected Abbreviations and Acronyms
 
ACE = angiotensin-converting enzyme
Ang = angiotensin
APx = area postrema–lesioned (rats); area postrema lesion
AT1, AT2 = angiotensin II type 1, type 2
HNa = high daily sodium intake
MAP = mean arterial pressure
NNa = normal daily sodium intake
NTS = nucleus tractus solitarius
PRA = plasma renin activity
RAS = renin-angiotensin system
SD-MAP = standard deviation of MAP
SHR = spontaneously hypertensive rat
WKY = Wistar-Kyoto


*    Acknowledgments
 
This study was supported by National Heart, Lung, and Blood Institute grant HL-50371. We would like to thank Dr Stephen Katz for analysis of the PRA samples and DuPont Merck Pharmaceutical Company (Wilmington, Delaware) for the donation of losartan.


*    Footnotes
 
Reprint requests to Dr John W. Osborn, University of Minnesota, Department of Animal Science, 1988 Fitch Ave, Room 435, St Paul, MN 55108.


*    References
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*References
 

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