(Hypertension. 1995;25:283-287.)
© 1995 American Heart Association, Inc.
Articles |
Effect of EXP 3174 on Blood Pressure of Normoreninemic Renal Hypertensive Rats
From the Instituto de Investigaciones Cardiológicas, Facultad de Medicina, Universidad de Buenos Aires (Argentina).
Correspondence to Nidia Basso, Instituto de Investigaciones Cardiológicas, Facultad de Medicina, Universidad de Buenos Aires, Marcelo T. de Alvear 2270, 1122 Buenos Aires, Argentina.
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Abstract |
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Abstract This study examined the effect on mean blood pressure of a new orally active nonpeptide angiotensin II (Ang II) receptor antagonist, EXP 3174, in doses that completely block exogenous Ang II action. Anesthetized and conscious two-kidney, two clip chronic renovascular hypertensive rats and sham-operated animals were used. In anesthetized hypertensive rats, intracerebroventricular administration of the inhibitor had no effect on blood pressure, whereas blood pressure was normalized by intravenous injection of the antagonist (163±12 to 110±9 mm Hg, P<.05). In sham anesthetized rats, intravenous injection of EXP 3174 also lowered blood pressure (112±6 to 96±6 mm Hg, P<.05). In conscious rats, intravenous EXP 3174 induced a fall in pressure that was larger in hypertensive (156±9 to 132±5 mm Hg, P<.05) than in sham (104±3 to 94±4 mm Hg, P<.05) rats. Plasma renin activity was very high in anesthetized animals (hypertensive versus sham, 87.8±8.3 versus 95.7±10.2 ng Ang I/mL per hour); differences were not significant either between anesthetized hypertensive and sham or in conscious animals (hypertensive versus sham, 9.42±1.58 versus 6.74±2.32 ng Ang I/mL per hour). Angiotensinogen concentration was higher in cerebrospinal fluid in anesthetized hypertensive rats (36.4±3.0 versus 26.0±2.4 ng Ang I/mL, P<.05) and in the artery wall of hypertensive conscious rats (103.1±10.3 versus 75.2±7.8 ng Ang I/g, P<.05). In summary, the central renin-angiotensin system does not seem to participate in the maintenance of high blood pressure in hypertensive animals. The enzymatic system present in the vascular wall appears to be activated in hypertensive rats. The hypotensive effect of EXP 3174 suggests that Ang II could be one of the factors involved in the maintenance of two-kidney, two clip hypertension.
Key Words: losartan • renin • angiotensinogen • cerebrospinal fluid • central nervous system
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Introduction |
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The renin-angiotensin system (RAS) plays a key role in the control of blood pressure (BP).1 Blockade of the RAS by angiotensin I (Ang I) – converting enzyme inhibitors (CEIs) has opened a new therapeutic approach to the treatment of hypertension and related pathologies.2 3 This fact has initiated the search for different ways to interfere with the enzymatic cascade. Since Ang II is the active effector of all the enzyme complex,4 a more direct way to inhibit the entire system would be to block the Ang II receptor. Nonpeptide orally active Ang II receptor antagonists have been pursued for a long time. Recently, some derivatives of imidazole have proved to be adequate Ang II receptor blockers, orally active, and highly potent. Among these compounds, losartan (DuP 753) and its metabolic derivative EXP 3174 have been shown to be quite selective, competitive, orally active, nonpeptide Ang II receptor antagonists. They do not have any agonistic effects.5 6 7
In high-renin hypertensive rats, losartan given intravenously or orally decreased BP acutely in a way similar to the action of the CEI,8 suggesting a relation between basal plasma renin activity (PRA) and the hypotensive effect of the antagonist in these hypertensive rats. On the other hand, it has been reported that CEI and losartan are able to decrease BP in spontaneously hypertensive rats (SHR),9 10 indicating that the RAS plays a significant role in BP control in these animals. Since SHR are normoreninemic, an enzymatic system other than the one present in the plasma must be involved in BP regulation.
Two-kidney, two clip (2K2C) Goldblatt renovascular hypertensive rats are also normoreninemic; nonetheless, CEIs are able to acutely normalize BP levels in these conscious rats (unpublished observation, 1992). This result suggests that a noncirculating RAS is involved in the maintenance of high BP in the chronic phase of 2K2C renovascular hypertension. In this sense, previous experiments have shown that angiotensinogen concentration (AoC) in the hypothalamus and cerebrospinal fluid was significantly increased in hypertensive 2K2C rats during the chronic stage of hypertension.11
We designed the present experiments to further elucidate the role played by the renal and extrarenal RAS in BP maintenance in this model. We tested the hypotensive effect of EXP 3174 in anesthetized and conscious chronic 2K2C renal hypertensive animals. Anesthetized rats were used to compare the central and peripheral effects of the Ang II receptor blocker on BP to avoid chronic implantation of an intracerebroventricular cannula, which involves much stress and pain and requires short-term manipulation of the conscious animal. The peripheral action of the Ang II receptor blocker was analyzed in conscious animals with chronic vascular implanted cannulas, enabling us to perform the experiment without handling the rat.
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Methods |
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Male Wistar rats of the albino strain (CHbbTHOM) weighing 250±10 g were used. The animals were fed a standard Purina rat chow and offered tap water ad libitum. They were kept in an automatically lighted room (from 7 AM to 9 PM) at a constant temperature (22±1°C). Animals were divided into two experimental groups: (1) hypertensive rats (n=18), in which a silver clip (0.25 mm) was placed in each renal artery through a flank incision with rats under light ether anesthesia, and (2) sham-operated rats (n=12), which underwent a similar surgical procedure but the clips were placed in and immediately removed from the renal arteries. Systolic BP was measured by a plethysmographic tail-cuff method (Narco BioSystems) in conscious rats once a week during the last 2 weeks of the 4-week experimental period. Then, six rats of each group received an injection of diazepam (5 mg/kg IM) followed 10 minutes later by ketamine (200 mg/kg IM). A cerebrospinal fluid sample was obtained from the cisterna magna. The animals were prepared with left femoral artery and femoral vein catheters (PE-50, Clay Adams) and an intracerebroventricular guide cannula stereotaxically positioned just above the roof of the right lateral ventricle. BP and heart rate (HR) measurements were accomplished via the femoral artery catheter connected to transducers (Gould Statham P23Db) and were output to a polygraph (Coulbourn Instruments Transducer Coupler, Tachometer and Blood Pressure Processor). Mean BP and HR were displayed on a Beckman R612 dynograph and recorded on an IBM computer plus a DACA acquisition system and ASYSTANT+ software (Asyst Software Technologies, Inc). A blood sample was obtained from the venous catheter. After a 10-minute stabilization period, basal mean arterial BP was recorded, and a 24-gauge stainless steel hypodermic tubing injector was inserted into the guide cannula. The injector extended 1 to 2 mm beyond the tip of the guide and penetrated the roof of the lateral ventricle. The Ang II receptor antagonist EXP 3174 was dissolved in a mixture of 5% NaHCO3 and 5% dextrose (1:1) at 1 mg/mL, was diluted with Kreb's buffer to 0.5 mg/mL, and was given through the injector in a total dose of 5 µg (10 µL). BP and HR were recorded for 30 minutes, and then the administration of 1 mg/kg IV of the inhibitor was used to test the systemic hypotensive effect in the anesthetized animals.
The remaining animals were used to test the hypotensive effect of EXP 3174 with animals in the conscious state. With rats under ether anesthesia, permanent cannulas (PE-50, Clay Adams) were placed in the femoral artery and vein 24 hours before the experiment; both catheters were exteriorized at the back of the neck. The rats were placed in a cage12 designed to keep the animal with prolongers attached to their cannulas in order to connect them to the recording system and obtain blood samples without disturbing the rat. An adequate wire plug was used to seal the ends of the prolongers. The next morning a blood sample was obtained from the venous cannula; BP and HR were recorded as described above. EXP 3174 was injected through the venous catheter at a dose of 10 mg/kg. BP and HR were continuously registered during 60 minutes after the drug was administered. The animals were killed by decapitation the following day; the heart, aorta, and mesenteric artery were excised. All experimental procedures were performed in accordance with institutional guidelines. PRA, AoC in plasma and cerebrospinal fluid, reninlike activity, and AoC in the artery wall were evaluated. The arteries were homogenized in 20 vol of 8 mmol/L EDTA solution in saline, and the homogenates were centrifuged at 1000g for 30 minutes at 4°C. The supernatants were separated, and an aliquot was incubated in the presence of an optimal concentration of angiotensinase inhibitors (0.05 mol/L 8-hydroxyquinoline, 2 mmol/L 2,3-dimercaptopropanol, 3.5 mmol/L phenylmethylsulfonyl fluoride) with either an excess of semipurified angiotensinogen from plasma of nephrectomized rats for reninlike concentration or an excess of hog kidney renin for AoC evaluation. AoC in plasma and cerebrospinal fluid was estimated by incubating diluted samples with an excess of hog kidney renin; PRA was determined by incubating the samples with adequate angiotensinase inhibitors.13 Incubations were conducted in the presence of 0.04 mol/L Tris chloride buffer (pH 7.2) for 60 minutes for AoC and during 3 hours for reninlike concentration and PRA at 37°C. The presence of Ang I in all samples was evaluated by radioimmunoassay (Du Pont–NEN Research Products). Data are expressed as mean±SEM. Statistical comparisons were performed by t test for either dependent or independent samples.
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Results |
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Preliminary observations have shown that short-term administration of captopril (10 mg/kg IV) induced normalization of BP levels in chronic 2K2C hypertensive conscious rats (160±10 to 100±5 mm Hg, P<.001) and a significant BP fall in sham rats (120±6 to 100±5 mm Hg, P<.05). In 2K2C anesthetized Goldblatt renovascular hypertensive rats, EXP 3174 was given intra- cerebroventricularly in a dose large enough to completely block the central pressor effect of Ang II14 ; the inhibitor did not induce any significant change in BP. HR also was not significantly altered. On the other hand, administration of 1 mg/kg IV of the agent was sufficient to completely normalize the BP level of the same animals immediately after injection (163±12 to 110±9 mm Hg, P<.05; Fig 1), without modifying HR. In sham rats, EXP 3174 slightly lowered BP (112±6 to 96±6 mm Hg, P<.05; Fig 1) and increased HR (368±20 to 387±19 beats per minute, P<.05).
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In conscious animals, 10 mg/kg IV EXP 3174, the dose usually needed to block the peripheral pressor effect of exogenous Ang II,15 induced a slow fall in BP that reached a maximum at 30 minutes. This fall was larger in hypertensive (156±9 to 132±5 mm Hg, P<.05) compared with sham rats (104±3 to 94±4 mm Hg, P<.05; Fig 2); nevertheless, normal BP levels were not attained in hypertensive animals. HR was not significantly altered by intravenous EXP 3174 administration.
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PRA was very high in anesthetized animals (sham versus hypertensive, 95.7±10.2 versus 87.8±8.3 ng Ang I/mL per hour), without significant differences between groups. PRA levels were much lower in conscious experimental and control animals (sham versus hypertensive, 6.74±2.32 versus 9.42±1.58 ng Ang I/mL per hour; P=NS) and also similar in both groups. The same plasma AoC was observed in sham and hypertensive rats whether or not they were anesthetized, even though the levels were much higher in conscious animals (conscious rats: sham versus hypertensive, 1127±127 versus 945±218 ng Ang I/mL; anesthetized rats: 476±107 versus 469±76 ng Ang I/mL). On the other hand, AoC was higher in the cerebrospinal fluid (sham versus hypertensive, 26.0±2.4 versus 36.4±3.0 ng Ang I/mL; P<.05) and the artery wall (sham versus hypertensive, 75.2±7.8 versus 103.1±10.3 ng Ang I/g; P<.05) of 2K2C animals. Reninlike activity in the artery wall was similar in unanesthetized experimental and control animals (sham versus hypertensive, 18.5±1.9 versus 20.7±1.8 ng Ang I/g per hour).
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Discussion |
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The most direct way of inhibiting the RAS is to antagonize Ang II at the level of its receptor for, regardless of the original source of the polypeptide, its function will be specifically turned off. The usually available Ang II receptor antagonists have been some Ang II–like peptides that retain significant agonistic effects, show metabolic instability, and lack oral activity.16 More recently, nonpeptide, very weak but selective Ang II receptor antagonists lacking agonistic activity have been described.17 More potent and orally effective Ang II antagonists were developed until losartan (DuP 753) was finally synthesized.18 EXP 317419 is the active metabolite of losartan. The hypotensive effect of EXP 3174 has been examined in renal artery–ligated rats,7 and results suggest that EXP 3174 may contribute to the antihypertensive effect of its precursor. EXP 3174 and losartan are orally active, potent, and selective Ang II receptor antagonists that do not affect the pressor response to vasopressin and norepinephrine.5 6 8
Preliminary observations had indicated that captopril was able to normalize BP levels in conscious chronic 2K2C renal hypertensive rats. In the present study, the central and peripheral effects of EXP 3174 on BP and HR were analyzed in these anesthetized and conscious hypertensive rats, which are normoreninemic. EXP 3174, given intravenously, exhibited a significant hypotensive effect in anesthetized and conscious chronic 2K2C Goldblatt renovascular hypertensive rats. The effect was acute and larger in the anesthetized animals, which had very high levels of PRA, probably because of the action of anesthetics20 21 and the acute surgical manipulations. In the sham anesthetized rats, the magnitude and characteristics of the hypotensive effect might be related to the inhibitory effect of anesthetics on the central nervous system and also to the high level of circulating Ang II. A similar effect has been described by other authors.22 PRA was higher than expected in conscious rats even though the surgical procedure for implantation of the catheters was performed 24 hours before the agent was tested, and the animals were kept untouched after surgery in an adequate cage to allow BP recording, blood sample extraction, and drug administration without handling. The hypotensive effect was larger in hypertensive than in sham rats, whereas PRA was similar in both groups whether or not they were anesthetized. These data suggest that the RAS plays a role in BP control in this normoreninemic hypertensive model. Since the PRA level is not enhanced in hypertensive rats, either a noncirculating enzymatic system or a different response of the vascular wall to Ang II could be involved in high BP maintenance. Most of the research on Ang II antagonists has been performed using losartan; however, as EXP 3174 is the major metabolite of losartan, its effects are very similar to those of losartan.23 In conscious SHR, losartan reduces arterial pressure by 40 to 70 mm Hg on intravenous administration of a dose similar to that used in this study.10 The same results have been obtained in high-renin renal hypertensive rats; in both cases the effect was slow and reached its maximum approximately 30 to 60 minutes after administration of the agent. These data indicate that the Ang II receptor blocker exerts its antihypertensive action regardless of the levels of the circulating polypeptide. The results obtained in the present study confirmed those observations, suggesting that an enzymatic RAS, other than the circulating one of renal origin, could be involved in the maintenance of high BP in 2K2C renovascular hypertensive rats. In this context, previous studies have shown a significant increment of the AoC in the cerebrospinal fluid and in the hypothalamus in this stage of hypertension development in 2K2C rats11 ; moreover, the presence of one of these changes was confirmed in the present study. Thus, the importance of the central RAS was tested by intracerebroventricular administration of EXP 3174 in the anesthetized rats. No evidence of the involvement of the brain enzymatic system was obtained, as its blockade did not have any significant effect on BP levels in the hypertensive or control groups.
In the present study, we also analyzed the participation of the vascular RAS24 in the maintenance of an increased arterial tone that could contribute to the characteristic elevated peripheral resistance observed in the chronic stage of most experimental and human types of arterial hypertension.25 The RAS localized in vascular tissues could explain certain types of hypertension. Thurston et al26 27 found that CEI lowered BP in 2K1C hypertensive rats even after bilateral nephrectomy and that the aorta reninlike activity 6 weeks after clipping (normoreninemic stage) was higher than in sham-operated controls. Garst et al28 suggested that Ang I–generating activity was increased in the aorta of renal hypertensive rats. Vascular renin-angiotensin activity is increased during the chronic phase of 2K1C hypertension in the rat, when PRA is almost normal.29 The dissociation of vascular and circulating renin-angiotensin activity supports the postulate that a local system is operative in blood vessels and contributes to the control of vascular peripheral resistance.30 31
Renin32 and angiotensinogen mRNA33 have been detected in the vascular tissue supporting local Ang I production. Cultured vascular smooth muscle cells contain reninlike activity, suggesting that the renin-angiotensinogen reaction occurs intracellularly, leading to the synthesis and secretion of Ang II.30 31 34 35
Abnormal tissue renin-angiotensin activity may be involved in high BP maintenance. In this sense, chronic 2K1C renal hypertension29 and SHR of the Okamoto strain36 have revealed the presence of augmented vascular renin levels. The contribution of the tissue RAS to hypertension is elucidated by the depressor response to the RAS inhibition despite normal PRA. Local generation of Ang II has been reported in the vascular wall; however, it is still unclear whether Ang II is produced by locally synthesized components or by plasma-borne proteins incorporated in the artery wall. Swales37 and Loudon et al38 have shown arterial wall uptake of renal renin, and Inagami et al39 have reported involvement of vascular renin of renal origin in SHR, suggesting the participation of plasma-borne components in local Ang II production. Angiotensinogen has been reported to be produced in vascular tissue in a regulated manner,33 40 41 indicating that the local prohormone might be important in Ang I generation. Locally synthesized angiotensinogen may contribute more significantly to the local production of the peptide under a high-renin condition. In the present experiments, an increased content of renin substrate in the vascular wall of 2K2C renal hypertensive rats was detected. The renin-substrate reaction, even in plasma in which a large AoC is present, is not a zero-order reaction because it depends on the concentration of both components of the enzymatic complex. Thus, in local systems where the concentration of both proteins is much lower, an increased substrate concentration could mean a larger release of Ang II very close to its receptor. Even more, when the circulating RAS is enhanced, such as in anesthetized rats, higher vascular renin uptake may occur, and the increase in AoC in the artery wall of hypertensive rats could determine a much greater liberation of the peptide, which could explain the drastic hypotensive effect of EXP 3174 in anesthetized hypertensive animals and also the difference observed between them and conscious rats. Augmented concentration of this component of the enzymatic cascade could play some role in the maintenance of high BP. Data are still premature to indicate a causal relation, but increased vascular Ang II release could be one mechanism responsible for sustained hypertension.
The antihypertensive effect of EXP 3174 in 2K2C renal hypertensive rats was not associated with a significant increase in HR. Apparently, lack of reflex tachycardia is a common effect observed with blockers of the RAS, and its mechanism is still unclear3 ; however, it may be caused by enhanced vagal tone or reduction of the sympathetic baroreceptor response to the fall in BP induced by the RAS inhibition.
In summary, (1) PRA levels were similar in sham and hypertensive animals whether or not they were anesthetized; (2) the central RAS does not seem to play a significant role in BP levels in 2K2C hypertensive rats; (3) the hypotensive effect of EXP 3174 given intravenously was greater in anesthetized rats, which showed high levels of PRA; (4) the hypotensive effect observed after intravenous administration of the Ang II receptor blocker would indicate that Ang II is one of the factors maintaining the elevated BP in this type of hypertension; and (5) since 2K2C renovascular hypertensive rats are normoreninemic and the RAS present in the vascular wall seemed to be activated, the local enzymatic complex may be involved in high BP maintenance.
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Acknowledgments |
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The present work was supported by grants PID 3054400/88 and PID-BID 252-0503-91 from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) de la República Argentina.
Received July 5, 1994; first decision July 27, 1994; accepted September 21, 1994.
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