Kinin-Mediated Antihypertensive Effect of Captopril in Deoxycorticosterone Acetate–Salt Hypertension
Abstract On the basis of evidence suggesting the activation of the kallikrein-kinin system in steroid-induced hypertension, we considered the possibility that the angiotensin-converting enzyme inhibitor captopril would lower the arterial blood pressure in deoxycorticosterone acetate (DOCA)–salt hypertensive rats through kininase II inhibition. In conscious DOCA-salt hypertensive rats with intact kidneys (n=6) or uninephrectomized rats (n=5), the short-term administration of captopril (8 mg/kg IV) decreased mean blood pressure from 141±3 to 118±3 mm Hg (P<.05) and from 176±12 to 158±15 mm Hg (P<.05), respectively. The maximal effect of captopril was manifested between 40 and 50 minutes after its administration, and blood pressure remained depressed for at least 2 hours. The bradykinin B2 receptor antagonist Hoe 140 (500 μg/kg IV) abolished the antihypertensive effect of captopril in the DOCA-salt hypertensive rats, indicating kinin involvement. Losartan, an angiotensin type 1 receptor antagonist, had no effect on blood pressure in another group of DOCA-salt hypertensive rats (n=9) and did not significantly change the response to captopril. No effect of the angiotensin-converting enzyme inhibitor was seen in normotensive control rats (n=5), indicating the absence of a nonspecific hypotensive action of the drug. Plasma renin activity was lower in the DOCA-salt hypertensive rats (0.7±0.2 ng angiotensin I/mL per hour, n=4) than in normotensive control rats (8.8±1.7, n=4). The involvement of kinins in the antihypertensive effect of captopril in DOCA-salt hypertension supports the contention that the kallikrein-kinin system contributes to blood pressure regulation in this hypertension model.
Kallikreins are serine proteases that cleave vasodilator peptides, the kinins, from protein precursors known as kininogens that are present in plasma.1 It is thought that the kallikrein-kinin system plays a role in the regulation of systemic BP and renal function,1 2 and this contention has been strengthened by recent evidence for the presence of kallikrein-like enzymes in blood vessels.3 4 These findings have led to the concept of a local kallikrein-kinin system functioning in a paracrine manner2 like that of the local RAS, with the kallikrein-kinin system fulfilling a vasodilator rather than vasoconstrictor role. As with the RAS, there may be little or no tonic activity of the kallikrein-kinin system under normal physiological conditions, but activation is brought about by specific stimuli such as the mineralocorticoids DOCA and aldosterone.5 6 7 It is interesting that kallikrein excretion is augmented in experimental DOCA-salt hypertension and its clinically related form, primary aldosteronism,5 6 whereas it is decreased in essential hypertension in humans and animal models of genetic hypertension.7 8 Thus, when depressed the kallikrein-kinin system may contribute to hypertension, and on activation it may modulate hypertensive processes.
Because the RAS is suppressed in DOCA-salt hypertension, it was assumed that blockers of the system, such as ACE inhibitors or angiotensin antagonists, would not affect BP in this form of hypertension. This seemed to be true, because BP was not reduced during the long-term administration of ACE inhibitors in DOCA-salt hypertension.9 10 11 However, some studies in which ACE inhibitors were administered acutely12 13 or subacutely14 to DOCA-salt hypertensive animals revealed a decrease in BP. Other investigations in the conscious DOCA-salt hypertensive dog15 and anesthetized rat16 failed to detect such an effect. Recent evidence has further supported the concept that kinins play an antihypertensive role in DOCA-salt hypertension.17 18 Because kinins have a potent effect on sodium excretion and RBF, it is conceivable that these renal actions may be responsible for BP modulation in DOCA-salt hypertension.
Some of these results and the knowledge that ACE or kininase II degrades the potent vasoactive peptide bradykinin to inactive fragments suggest the possibility that ACE inhibition could affect BP and renal hemodynamics in DOCA-salt hypertension through a kinin-mediated effect or effects. Because an antihypertensive effect of ACE inhibitors in steroid-induced hypertension and its mechanism have not been firmly established, we conducted the present investigation. We designed experiments (1) to determine whether the short-term administration of captopril to DOCA-salt hypertensive rats lowers BP, (2) to show whether this effect is kinin mediated, and (3) to see whether an angiotensin antagonist alters the effect of the ACE inhibitor. These experiments were conducted in conscious rats instrumented for direct BP recording. In anesthetized DOCA-salt hypertensive rats we examined the effect of captopril on RBF because a renal effect might have contributed to the BP response seen during its short-term administration.
Experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and with the approval of the local Animal Care Committee. Male Wistar rats (n=40) (Harlan Laboratories, Madison, Wis) weighing 200 to 250 g were fed normal rat chow and allowed free access to water before DOCA administration. For induction of hypertension the rats were given 0.9% saline to drink and twice a week received intramuscular or subcutaneous injections of 10 mg DOCA suspended in sesame oil.
BP Studies in Conscious Rats
Rats in all groups except group 4 had intact kidneys. Group 4 underwent unilateral nephrectomy 2 to 3 days before DOCA and saline administration. After 3 to 4 weeks of DOCA-salt or vehicle, the rats weighed 350 to 450 g, and body weight did not differ among the five groups. Two days before an experiment the rats were anesthetized with 40 mg/kg IP sodium pentobarbital. The femoral artery and vein were catheterized with PE-10 tubing connected to larger bore polyvinyl or Tygon tubing, and the catheters were passed subcutaneously and exteriorized behind the neck. The catheters were anchored to the skin and underlying tissue with a suture and cyanoacrylate and when not in use were filled with heparinized saline and plugged with a metal stylet. Each rat was placed in a separate cage and allowed to recover from the surgery for at least 24 hours. On the day of an experiment systemic arterial BP was recorded by connecting the arterial catheter to a pressure transducer (Gould-Statham) while the rat remained in its cage. BP was recorded continuously on a polygraph (Grass Instruments), and 20 to 30 minutes were allowed for BP to stabilize before an experiment was started. The BP values presented were obtained by averaging readings made 1 minute before, 1 minute after, and at the stated time intervals during an experiment.
Two experiments were conducted on each rat in group 1 (n=6). On the first day a bolus injection of 0.2 mL sterile saline (control for Hoe 140) was injected intravenously 30 minutes before administration of the ACE inhibitor. Captopril was administered at 8 mg/kg, and BP measurements were taken every 10 minutes before and after captopril during the entire 90-minute experimental period. On the second day an experiment was conducted on the same rats for determination of the contribution of kinins to the captopril-induced decrease in BP. Before captopril was given, the bradykinin B2 receptor antagonist Hoe 140 was administered intravenously as a 0.2-mL bolus at 500 μg/kg. An even lower dose, 200 μg, of Hoe 140 was shown to block completely the depressor response to 250 ng bradykinin in the conscious rat.19 BP measurements were made as in the above-described experiments. For determination of whether a reproducible effect of captopril could be obtained on 2 consecutive days as a control for the experiment with the B2 antagonist, the ACE inhibitor was given to six DOCA-salt hypertensive rats in two experiments separated by 24 hours (group 1A).
In Group 1B, 24 hours after femoral artery catheter implantation a 3-mL blood sample was collected from the femoral artery of the DOCA-salt hypertensive (n=4) and normotensive (n=4) rats, and afterwards the rats were killed. PRA was determined by radioimmunoassay with an Ang I–specific antiserum.20
Group 2 (n=5) served as a control for groups 1 and 3 and received a saline vehicle injection instead of DOCA and drank tap water. These rats received captopril 30 minutes after a saline control injection. BP was recorded for the 90-minute experimental period in this as in all groups.
In group 3 (n=9) the Ang II antagonist losartan was injected slowly at 8 mg/kg IV, and after 20 to 30 minutes, 8 mg/kg IV captopril was administered as in group 1. Losartan at 3 mg/kg IV was shown to block the BP response to 0.1 μg/kg IV Ang II by 73% in the conscious rat.21 Thus, we based the doses of Hoe 140 and losartan on those documented in previous studies to block the responses to exogenous bradykinin and Ang II in conscious rats.
Group 4 rats (n=5) underwent two experiments for determination of whether results could be obtained in uninephrectomized DOCA-treated rats that were similar to those in the rats with intact kidneys. The first experiment was carried out as in group 1, and 24 hours later losartan was administered followed by captopril as in group 2. BP determinations were made during the control period, after losartan, and after captopril as described above.
RBF Studies in Anesthetized DOCA-Salt Hypertensive Rats
DOCA-salt hypertensive rats (n=7) prepared as described above for group 1 were used in this part of the study. In general, the procedure followed was that of Ha and Dunham.22 Rats were anesthetized with sodium pentobarbital (50 mg/kg IP). Body temperature was continuously monitored with a digital thermometer and maintained between 38°C and 38.5°C with incandescent lamps. The trachea was intubated and kept free of fluid accumulation. For maintenance of a constant level of anesthesia and hematocrit, a saline/rat serum (2:1) solution containing sodium pentobarbital was infused at 120 μL/kg per minute through a PE-50 catheter in the right jugular vein; the dose infused equaled 21 mg/kg per hour. Another PE-50 catheter was placed in the right carotid artery and connected to a pressure transducer (Gould-Statham) for monitoring of BP. The urinary bladder was exposed via a midline incision, and a polyethylene catheter was inserted to allow the free flow of urine. The left kidney was exposed through a retroperitoneal flank incision, and the rat was suspended from a metal stand to facilitate manipulation of the renal artery. After the artery was exposed, a 33-gauge curved needle attached to PE-10 tubing was inserted at the origin of the renal artery and advanced into the artery. A minute drop of cyanoacrylate was used to secure the needle in place. Heparinized saline infusion was begun immediately at 100 μL/kg per minute intrarenal arterial (IA) while the intravenous infusion was reduced to 80 μL/kg per minute (saline/serum, 1:1). A precalibrated electromagnetic flow probe of appropriate size (3 to 3.9 mm in circumference) was placed around the artery distal to the needle. RBF was measured with an electromagnetic flowmeter (Carolina Medical Electronics). BP and RBF were continuously recorded on a Grass polygraph. Occlusive zero was obtained by placing a small bulldog clamp on the renal artery distal to the flow probe, and the procedure was repeated two to three times over about a 30-minute period until the zero was reproducible. An interval of at least 30 minutes was allowed for stabilization of BP and RBF. Hematocrit was checked by sampling blood from the tail before surgery was begun and again after the stabilization period. Control measurements were taken and then captopril was administered in graded doses intrarenal arterially to localize its effect on the kidney. Each dose of 1, 2, 4, and 8 μg/kg per minute was infused for 10 minutes. The IA infusion rate was maintained constant by adjustment of the combination of drug and heparinized saline totaling 100 μL/kg per minute. At the end of each experiment acetylcholine bromide was injected in bolus doses ranging from 200 to 800 ng until a maximal vasodilator response was elicited. This was done to establish the maximal vasodilator capacity of the kidney in each rat that received captopril. After the experimental protocol was completed, occlusion of the renal artery was repeated to confirm the zero flow level.
Drugs and Chemicals
Captopril was kindly donated by the Squibb Institute for Medical Research and Hoe 140 by Hoechst AG. Losartan was kindly provided by DuPont-Merck Pharmaceutical Co.
Values are presented as mean±SEM. Data were subjected to one-way ANOVA with repeated measures or two-factor nested ANOVA. Dunnett’s and Scheffé’s tests were applied to the means after the one-way ANOVA. A value of P<.05 was considered statistically significant.
BP Response to Short-term Captopril Administration in DOCA-Salt Hypertensive (Groups 1 and 1A) and Normotensive (Group 2) Rats: Effect of Kinin Blockade With Hoe 140
At 2 to 3 weeks the mean BP in the DOCA-salt–treated rats (group 1) was significantly higher than in the vehicle-treated normotensive rats (group 2) (141±3 versus 111±3 mm Hg) (Fig 1⇓). BP was stable in both groups during the 30 minutes before captopril administration. Captopril caused a gradual decrease in BP in the DOCA-salt hypertensive rats, achieving statistical significance at 30 minutes, with the maximal effect at 40 minutes (118±3 mm Hg), and the BP remained depressed for the remainder of the experiment. In the normotensive rats, captopril had no effect on BP.
The bradykinin B2 receptor antagonist Hoe 140 at 500 μg/kg IV caused a slight decrease in BP, but this effect was not statistically significant (Fig 2⇓). Hoe 140 was effective in completely blocking the antihypertensive effect of captopril in the DOCA-salt hypertensive rats. No decrease in BP was seen after kinin blockade. In group 1A, there was an identical response, ie, a decrease in BP, when the dose of captopril was administered on 2 consecutive days (Fig 3⇓), ruling out the possibility of tolerance to the ACE inhibitor or a persistent effect lasting for more than 24 hours. The length of the latter experiments was extended for an additional 60 minutes after captopril administration, and it can be seen that the antihypertensive action lasted for at least 2 hours after dosing. PRA in group 1B normotensive (n=4) and hypertensive (n=4) rats was 8.8±1.7 and 0.7±0.2 ng Ang I/mL per hour, respectively, and the means differed statistically (P<.05).
Effect of Angiotensin Antagonist on BP Response to Short-term Captopril Administration in DOCA-Salt Hypertensive Rats (Group 3)
A comparison of the effect of captopril on the BP of DOCA-salt rats after administration of either saline or losartan (group 3) is shown in Fig 4⇓. To facilitate statistical analysis by ANOVA, the number of experiments in the two groups was equalized by randomly selecting and adding three experiments from group 1A to the saline-captopril group (n=9). Losartan did not significantly change BP in the DOCA-salt hypertensive rats, the BP remaining unaffected during the 30 minutes after administration of the angiotensin type 1 receptor antagonist (Fig 4⇓). The subsequent administration of captopril to the losartan-treated rats decreased BP (P<.05), and the time of onset and duration of the effect paralleled those seen in the saline-treated rats. There appeared to be some attenuation of the BP-lowering response to captopril by losartan in group 3; however, a comparison of the effect of captopril in the two groups by two-factor nested ANOVA failed to reveal a statistically significant treatment factor. When the BP values obtained at each of the 10-minute intervals after captopril administration were averaged, the mean decreases were 8±2 and 17±6 mm Hg for losartan plus captopril and captopril alone, respectively. The difference between these mean values was also not statistically significant by group t test (P>.05).
BP Response to Captopril in Uninephrectomized DOCA-Salt Hypertensive Rats (Group 4)
The control BP of the uninephrectomized DOCA-salt hypertensive rats was higher than in the DOCA-salt hypertensive rats with intact kidneys (176±12 versus 141±3 mm Hg, P<.05). Beginning 20 minutes after captopril administration, BP decreased significantly (to 163±13 mm Hg, P<.05), and as in group 1 the maximal decrease occurred between 40 and 60 minutes (to 158±15 mm Hg, P<.05). The magnitude of the maximal decrease in BP was similar to that seen in the rats with intact kidneys. As in group 3, losartan appeared to slightly attenuate the BP response to captopril in group 4, but again this effect was not statistically significant (data not presented).
Effect of Captopril on BP and RBF in Anesthetized DOCA-Salt–Treated Rats
Control values of BP and RBF and values after graded doses of IA infusions of captopril in this group of rats are shown in the Table⇓. Captopril had no effect on BP except for the highest dose (8 μg/kg per minute), which decreased BP from 138±6 to 128±7 mm Hg (P<.05). No change in RBF was seen with any of the four doses of captopril. The kidney of the DOCA-salt–treated rat had the capability of vasodilating, because acetylcholine administered IA at the end of these experiments raised RBF by a mean of 24.3±8.6%. In the normal anesthetized rat (n=12) (unpublished data, 1995), captopril decreased BP only slightly, from 128±3.3 to 122.9±3.9 mm Hg, with the highest dose of 8 μg/kg per minute but increased RBF significantly (P<.05) by 6.8±1.5%, 10.0±1.8%, 15.1±2.0%, and 18.2±2.6% with the doses of 1, 2, 4, and 8 μg/kg per minute, respectively. The lower doses had no effect on BP.
The main finding in this investigation was the substantial decrease in BP of conscious DOCA-salt hypertensive rats that was evoked by the ACE inhibitor captopril. In DOCA-salt hypertensive rats with intact kidneys (group 1) and also in uninephrectomized rats (group 4) that had an even higher BP, captopril caused a decrease in BP of approximately 20 mm Hg. As seen in group 1A, the effect of captopril on BP lasted for at least 2 hours and thus represented more than a transient response. The BP lowering was not due to some nonspecific effect of the drug because normotensive rats (group 2) were not affected by captopril. Captopril was probably acting by kinin potentiation rather than by blocking the RAS to cause the antihypertensive effect. This statement is based on the following. First, the DOCA-salt regimen resulted in a much attenuated PRA, representing marked suppression of the RAS, and second, losartan had no effect on BP. It is unlikely, therefore, that blockade of the RAS could account for the decrease in BP caused by captopril. Because the BP response to captopril was abolished by Hoe 140, a B2 kinin receptor blocking agent, kinin mediation of the response to captopril is strongly indicated. Administration of the ACE inhibitor ramipril over 1 week caused a gradual lowering of BP in DOCA-salt hypertensive rats, and interestingly this effect was prevented by concomitant dosing with Hoe 140.14 These results of Carretero are quite similar to those of the present study, except that we have demonstrated kinin involvement with the short-term rather than week-long administration of the ACE inhibitor.
Besides blocking the effect of captopril, it might have been expected that the kinin antagonist would have caused a further rise in the BP of the hypertensive rats. Because BP remained unchanged after Hoe 140, it is suggested that in the absence of ACE inhibition the peripheral vasculature of the DOCA-salt hypertensive rats is exposed to a subthreshold vasodilator concentration of kinins. However, when ACE is inhibited, the kinin level is raised above threshold, resulting in vasodilatation and a fall in BP. Madeddu and coworkers18 reported that BP increased to a greater extent in two-kidney DOC-treated (25 mg/wk) rats that were given Hoe 140 over 6 weeks than in rats given DOC alone. The concomitant administration of Hoe 140 and DOC caused a gradual increase in BP that reached a level about 20 mm Hg higher than in the rats given DOC without Hoe 140. The results of the present study, though different in design, appear compatible with the above findings. Our data confirm the presence of a kinin influence in steroid-induced hypertension; however, the short-term administration of Hoe 140 did not reveal that influence in the absence of ACE inhibition. Only after captopril was a kinin-mediated antihypertensive effect uncovered. As suggested by Madeddu et al, sodium retention caused by the antagonism of the natriuretic effect of endogenous kinins by Hoe 140 may be involved in the accentuated hypertension seen in their experiments. Such an action could produce a slowly developing hypertension and explain why an immediate pressor effect of Hoe 140 failed to occur in the present study.
To determine whether captopril had a renal hemodynamic effect in the DOCA-salt hypertensive rat, we infused the drug in graded doses intra-arterially to the kidney. No effect on RBF was observed with any of the four doses; however, BP was decreased by the highest dose of captopril. Apparently, a sufficient quantity of the ACE inhibitor escaped from the kidney to affect the systemic BP. These results suggest that the short-term response to ACE inhibition in the DOCA-salt hypertensive rat is not due to a renal vasodilator effect and that most probably vasodilatation in another regional vascular bed or beds accounts for the BP fall. Our results are in agreement with those of a previous study that reported the lack of effect of intravenously administered enalaprilat on RBF in the anesthetized DOCA-salt hypertensive rat.16 Nakagawa and Nasjletti23 also found no effect on RBF of the combined intravenous administration of captopril and the neutral endopeptidase inhibitor phosphoramidon; however, this drug combination did increase glomerular filtration rate and sodium excretion in anesthetized DOC-treated rats. Because a kinin antagonist reversed these effects, they concluded that kinins were playing a renal regulatory role in DOCA hypertension. Although we did not administer a kinin antagonist in the experiments on anesthetized rats, we did find a difference between the response of the renal vasculature of DOCA-salt–treated and normal rats (unpublished data, 1995) to captopril. RBF in the normal but not the hypertensive rats was increased by ACE inhibition. The difference can be attributed to a normally functioning RAS in the normal rats, whereas it is suppressed in steroid-induced hypertension. It is well known that blockade of the renal influence of an activated RAS results in an increase in RBF. We cannot totally dismiss a renal hemodynamic effect from playing a role in the short-term antihypertensive effect in the conscious DOCA-salt hypertensive rat, because to examine this we used anesthetized rats. There appears to be a difference between the effect of an ACE inhibitor in the conscious and anesthetized DOCA-salt hypertensive rat. In the present study and that of Hollenberg et al,16 BP was decreased only slightly, about 10 mm Hg, in the anesthetized animal. When the rats are conscious BP decreases about 20 mm Hg, suggesting dampening of the response by the anesthetic or surgical trauma. Future experiments should be done in conscious rats to further investigate the mechanism by which ACE inhibitors decrease BP in DOCA-salt hypertension.
To confirm the absence of an RAS influence on the BP of the DOCA-salt hypertensive rat, we tested the effect of the angiotensin type 1 receptor antagonist losartan in the rats in groups 3 and 4. Losartan administered before captopril had no effect on the BP of the DOCA-salt hypertensive rats and insignificantly altered the BP-lowering response to captopril. These results lend further support to our contention that blockade of the RAS did not contribute to the antihypertensive effect of captopril. The absence of effect of an angiotensin antagonist in these experiments and the involvement of kinins in the antihypertensive effect of captopril in this form of hypertension support the view that the kallikrein-kinin system contributes to BP regulation in this hypertension model.
Selected Abbreviations and Acronyms
|Ang I, II||=||angiotensin I, II|
|PRA||=||plasma renin activity|
|RBF||=||renal blood flow|
This research was supported by National Institutes of Health grants HL-44370 and HL-39698.
Previously published in preliminary form (FASEB J. 1995;92:A927).
- Received May 22, 1995.
- Revision received July 25, 1995.
- Accepted August 15, 1995.
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