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(Hypertension. 1995;25:82-87.)
© 1995 American Heart Association, Inc.
Articles |
Blood Pressure After Captopril Withdrawal From Spontaneously Hypertensive Rats
From the Center for Clinical Pharmacology, University of Pittsburgh (Pa) Medical Center.
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Abstract |
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Abstract The purpose of the present study was to compare the effect of chronic captopril treatment on blood pressure in young and adult spontaneously hypertensive rats (SHR) and to assess the time course for development of hypertension after captopril withdrawal. SHR received drinking water or captopril solution from 4 weeks of age and were instrumented with radiotelemetry devices at 18 weeks of age to allow continuous monitoring of blood pressure. At 23 weeks of age, mean blood pressure in the captopril group was 100±1 mm Hg compared with 157±3 mm Hg in the water group. Pulse pressure also was significantly reduced in the captopril-treated rats. Infusion of angiotensin II into a subset of captopril-treated rats increased pulse pressure and restored blood pressure to levels of water-treated rats. Captopril treatment for 6 weeks in adult, 24-week-old SHR did not reduce blood pressure to the level of rats treated from 4 weeks of age. Ten weeks after cessation of captopril, blood pressure was 125±4 and 144±4 mm Hg in SHR treated with captopril from 4 to 30 and from 24 to 30 weeks of age, respectively, compared with control hypertensive rats with mean blood pressure of 160±6 mm Hg. Results from this radiotelemetry study confirm previous findings that captopril treatment prevents the development of hypertension and produces a persistent reduction of blood pressure after treatment in young SHR. Captopril treatment produced a persistent reduction of blood pressure after discontinuation in adult rats; however, the effect was less than that observed with captopril initiated in young rats.
Key Words: captopril • angiotensin II • rats, inbred SHR • angiotensin-converting enzyme inhibitors
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Introduction |
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The spontaneously hypertensive rat (SHR) is the most widely studied animal model of genetic hypertension. The greatest increase of mean arterial blood pressure (MABP) occurs between 6 and 12 weeks of age, and a growing body of evidence implicates the renin-angiotensin system in this developmental phase of hypertension in SHR. Early studies1 2 with the angiotensin-converting enzyme (ACE) inhibitors captopril and cilazapril demonstrated that hypertension could be prevented if treatment was initiated at a young age in SHR (ie, 4 weeks of age). However, the authors of those early studies also noted that discontinuation of ACE inhibitors after 4, 8, 10, or 12 weeks of treatment resulted in the usual development of hypertension.
In contrast, later publications suggest that captopril treatment initiated at an early age in SHR produces profound and lasting effects on blood pressure (BP) long after the drug is discontinued. Freslon and Giudicelli3 prevented the development of hypertension by administering captopril to SHR from 6 to 20 weeks of age, and a reduction of BP persisted for weeks after captopril was withdrawn (135±3 versus 163±2 mm Hg in control SHR). Harrap et al4 studied the long-term effect of shorter ACE inhibitor treatment periods on BP in SHR. In that study, the ACE inhibitor perindopril was administered to SHR from 2 to 6, 6 to 10, or 2 to 10 weeks of age, and systolic BP was measured weekly by an indirect tail-cuff method until 25 weeks of age. Systolic BP increased in each group after discontinuation of the brief ACE inhibitor treatment and reached a plateau of 25 to 30 mm Hg below control values. The reduction in systolic BP was similar and persisted on withdrawal regardless of whether the drug was administered from 2 to 6, 6 to 10, or 2 to 10 weeks of age. Thus, data are conflicting between earlier studies1 2 demonstrating a return to pretreatment pressures and later studies3 4 demonstrating a persistent reduction of BP in SHR after withdrawal of ACE inhibitors.
In addition, ACE inhibition for 4 weeks in older SHR (20 weeks of age) with established hypertension has been shown to produce no long-term reduction of BP on withdrawal.4 Based on such findings, the existence of a critical phase that may be amenable to pharmacological intervention has been proposed in the development of hypertension.5
The intent of the present study was to compare the effect of chronic captopril treatment on BP in young and adult SHR and to assess the time course for development of hypertension after withdrawal of captopril. We used a radiotelemetry system to monitor BP in the SHR, permitting data collection around the clock with minimal human contact.
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Methods |
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SHR were obtained from Taconic Farms (Germantown, NY) and housed in a University of Pittsburgh Animal Facility. Rats were fed Wayne Rodent Blox (135 mmol/kg sodium, 254 mmol/kg potassium) and allowed to drink ad libitum. Four-week-old SHR were randomized into two treatment groups with 6 SHR receiving deionized drinking water and 10 SHR receiving captopril (Interchem Corp) in deionized drinking water (3.7 mmol/L). In previous metabolic studies, captopril-treated SHR were found to consume 100 to 150 mL of fluid daily per kilogram of body weight; thus, this captopril concentration (3.7 mmol/L) provided a daily captopril dose between 0.37 and 0.56 mmol/kg. Institutional guidelines for animal welfare were followed.
The telemetry system used for measurement of BP and heart rate in conscious rats was obtained from Data Sciences. The system is composed of three basic units6 : an implantable transmitter, a receiver, and a software package. The implantable transmitter (TA11PA-C40) is a small cylinder with an attached fluid-filled catheter. The tip of the catheter is filled with a patented gel and coated with an antithrombogenic film to inhibit thrombus formation. Pressure at the catheter tip is referred to the pressure sensor contained in the cylindrical portion of the implant device. The pressure information is converted to a radio frequency signal that is emitted by the implantable transmitter. A stationary radio receiver pad (RA1010) positioned under the rat's cage detects the radio signal and converts it to a digital signal readable by a computer. The digital signals from the receivers are transferred by a consolidation matrix (BCM100) to a computer-based data-acquisition system. An electronic barometer (C11PR) measures atmospheric pressure during data collection, and the Dataquest software package uses this information to convert telemetered waveforms to pressure in millimeters of mercury. The software package stores parameters such as heart rate, systolic and diastolic BP, and MABP for future analysis. In the present study, the system was configured to monitor each rat for 10 seconds every 10 minutes around the clock at a sampling rate of 500 Hz. MABP, systolic and diastolic BP, and heart rate recordings were obtained 144 times per day per rat throughout the length of the experiment. The 144 values were averaged to obtain one daily measurement of each parameter.
At 18 weeks of age, rats were prepared for implantation of radiotelemetry devices. Animals were anesthetized with pentobarbital (50 mg/kg IP), and their abdomens were shaved and scrubbed with polividone-iodine. The SHR were placed in a clean operating field, and body temperature was maintained by adjusting an overhead heat lamp. A midline incision was made in the abdomen of each rat. The descending aorta was exposed and temporarily occluded downstream (caudal) from the renal arteries while a small hole was made in the aorta near the bifurcation of the iliac arteries with a 22-gauge needle. The catheter of the telemetry transmitter was inserted into the abdominal aorta and secured with medical-grade tissue adhesive and a 5x5-mm cellulose fiber patch. The body of the telemetry transmitter was affixed to the inner peritoneal wall during closure of the abdomen with 4-0 silk sutures. The skin was closed using wound clips. The rats were given 5000 U penicillin-G procain (Sigma Chemical Co) and 50 U heparin intramuscularly and were placed under a heat lamp during recovery from anesthesia. The rats were placed in an animal room where they were individually housed in standard polycarbonate cages. The cages were positioned above the appropriate telemetry receivers, and data acquisition through radiotelemetry was initiated.
In previous unpublished experiments, we attempted to implant radiotelemetry devices in chronically captopril-treated SHR and Wistar-Kyoto rats, and we found that although the captopril-treated Wistar-Kyoto rats recovered fully from surgery, the captopril-treated SHR (5 of 5) developed debilitating hindlimb paralysis and required euthanasia. This complication may have been due to hypotension associated with anesthesia in the captopril-treated SHR. However, it has been reported that the renin-angiotensin system is important for maintaining hindlimb perfusion after abdominal aortic ligation.7 As a precaution, the SHR (both water- and captopril-treated groups) in the present study were given subcutaneous infusion of angiotensin II (Ang II) (Sigma) at 50 ng/kg per minute via osmotic minipumps (model 2002, Alza Corp) for 5 days before surgery and 48 hours after surgery to protect against possible hindlimb paralysis. The minipumps were implanted and subsequently retrieved during brief ether anesthesia. There were no signs of hindlimb paralysis in the 6 water-treated SHR after surgery. However, 1 of 11 captopril-treated SHR developed hindlimb paralysis immediately after surgery, and the animal was killed. Two of the remaining 10 captopril-treated SHR exhibited some hesitancy in hindlimb usage suggesting mild hypoperfusion; however, the effect was transient, and the SHR were fully recovered within 5 days after surgery. Rats were weighed periodically throughout the study.
At 24 weeks of age, 7 of the 10 SHR receiving chronic captopril treatment were studied to determine pressor responses to Ang II. Ang II was dissolved in sterile water for injection, and the solution was placed in osmotic minipumps (Alza Corp). The minipumps were implanted subcutaneously during brief ether anesthesia. These captopril-treated SHR received Ang II infusions of 50, 100, and 200 ng/kg per minute from 24 to 25.7, 25.7 to 27.7, and 27.7 to 29.7 weeks of age, respectively. At 32 weeks of age, these SHR were anesthetized with thiobutabarbital (100 mg/kg IP), and the validity of the telemetry system was assessed by comparing radiotelemetry-recorded pressure and heart rate measurements with those obtained simultaneously by a direct carotid catheter attached to a digital BP analyzer (Micro-Med) at 2-minute intervals during a 20-minute period. The BP and heart rate measurements obtained by the two methods were highly correlated (r=.960 and r=1.00, respectively).
The remaining rats were studied to determine the effects of captopril treatment and subsequent withdrawal on BP. Three of the six control SHR were switched from water to captopril (3.7 mmol/L) at 24 weeks of age to determine the hypotensive response to chronic captopril treatment in adult SHR with established hypertension. In a previous, unpublished radiotelemetry experiment, this captopril concentration in drinking water was shown to produce a maximal hypotensive response in adult SHR (ie, doubling the concentration of captopril produced no further reduction of MABP). Captopril was withdrawn from all treated SHR at 30 weeks of age, and the time course for recovery of hypertension was followed for several weeks in the SHR that had been treated from 4 to 30 and 24 to 30 weeks of age. The telemetry radio transmitters were intermittently deactivated by a magnetic switch to preserve battery life on several days per week during weeks 37 to 41 of the experiment. At the end of the study, radiotelemetry-recorded BP and heart rate values were compared with simultaneous measurements via a direct carotid catheter attached to a digital BP analyzer as described above. BP and heart rate measurements obtained by the two methods were highly correlated (r=.939 and r=.999, respectively).
Data were analyzed with a standard personal computer using Student's t test, one-factor ANOVA, or two-factor ANOVA followed by Fisher's least significant difference (Fisher's LSD) test as appropriate.
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Results |
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Development of hypertension was prevented by chronic captopril treatment in young SHR (Fig 1). MABP of 23-week-old SHR treated from 4 weeks of age with captopril was 100±1 mm Hg compared with control water-treated SHR with an MABP of 157±3 mm Hg (P<.0001, t test). In addition, pulse pressure (Fig 2) was significantly reduced (P<.0001, t test) in the 23-week-old SHR that received chronic captopril treatment from 4 weeks of age (44±1 compared with 70±1 mm Hg in control SHR).
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Replacement of Ang II (50, 100, and 200 ng/kg per minute SC by osmotic minipump) restored MABP to control values in the chronically captopril-treated SHR (Fig 1). MABP in 28-week-old, captopril-treated SHR during Ang II infusion was similar to that in control SHR (157±6 and 156±5 mm Hg, respectively) and differed from that in captopril-treated SHR in the absence of angiotensin supplementation (P=.0001, one-factor ANOVA; P<.05, Fisher's LSD). In addition, pulse pressure (Fig 2) during Ang II infusion was similar to that in control water-treated SHR (65±2 versus 70±3 mm Hg, respectively) and differed from that in captopril-treated SHR in the absence of Ang II infusion (P<.0001, one-factor ANOVA; P<.05, Fisher's LSD). Discontinuation of Ang II by removal of the osmotic minipumps resulted in a reduction of pulse pressure and an immediate fall of MABP to preinfusion pressure.
Captopril treatment initiated in 24-week-old SHR with established hypertension caused a significant reduction in MABP below control values (Fig 1); however, MABP was not reduced to the level of SHR treated from 4 weeks of age (P=.0001, one-factor ANOVA; P<.05, Fisher's LSD). Likewise, pulse pressure was significantly reduced below control values during captopril treatment in the adult SHR (Fig 2) but not to the level of SHR treated from 4 weeks of age (P=.0002, one-factor ANOVA; P<.05, Fisher's LSD).
A biphasic increase of MABP followed on captopril withdrawal in SHR treated from 4 to 30 and 24 to 30 weeks of age (Fig 3). MABP increased by 15 to 20 mm Hg within the first week after withdrawal, and a gradual increase of 5 to 10 mm Hg occurred during the following 9 weeks. A modest and transient depressor response followed the early pressor response at 7 to 14 days after captopril withdrawal in the SHR treated from 4 weeks of age but not in those treated from 24 weeks of age.
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Pulse pressure increased after captopril withdrawal. Ten weeks after cessation of captopril, pulse pressure was 59±3 and 61±2 mm Hg in SHR treated from 4 to 30 and 24 to 30 weeks of age, respectively, compared with 67±4 mm Hg in control water-treated SHR (P=.2595, one-factor ANOVA).
MABP of SHR after captopril withdrawal did not increase to the level of control water-treated SHR (Fig 3). Ten weeks after cessation of captopril treatment, MABP was 125±4 mm Hg in SHR treated from 4 to 30 weeks of age and 144±4 mm Hg in SHR treated from 24 to 30 weeks of age compared with 160±6 mm Hg in control water-treated SHR (P=.0093, one-factor ANOVA). Post hoc analysis by Fisher's LSD in the 41-week-old SHR (ie, 10 weeks after captopril withdrawal) demonstrated that MABP in the SHR treated from 4 to 30 weeks of age differed from that in the other two groups at a significance level of P<.05, and MABP in all three groups differed at a significance level of P<.075. In addition, MABP in the 41-week-old SHR treated with captopril from 24 to 30 weeks of age differed significantly from the MABP values recorded just before captopril treatment in the same rats at 23 weeks of age (P=.0012, paired t test). In contrast, MABP of the control water-treated SHR was not significantly different at 23 compared with 41 weeks of age (P=.4296, t test). The group of SHR treated with captopril from 4 to 30 weeks of age was followed out to 50 weeks of age, and MABP was 124±4 mm Hg (ie, approximately 35 mm Hg below control SHR) 5 months after captopril withdrawal.
Body weight was significantly less in the SHR treated with captopril from 4 to 30 weeks of age compared with that in control SHR or SHR that received captopril from 24 to 30 weeks of age (Table).
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Discussion |
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The results from this radiotelemetry experiment provide further evidence that the renin-angiotensin system plays an important pathogenic role in the developmental phase of hypertension in SHR. Hypertension was prevented by chronic captopril treatment in young SHR as has been previously reported.1 2 3 4 In addition, captopril treatment in adult SHR with established hypertension did not reduce BP to the level of SHR treated with captopril from 4 weeks of age. The implication of this observation is that treatment must be initiated before the full expression of hypertension in SHR in order to achieve the maximal hypotensive effect with ACE inhibitors. That is, the renin-angiotensin system apparently initiated an effect on BP regulation in SHR during the developmental phase of hypertension that can be blocked at an early age but not wholly reversed at a later age.
Interestingly, replacement of Ang II by subcutaneous infusion resulted in an increase of MABP to control SHR values in the captopril-treated SHR; however, MABP fell to preinfusion values within hours after discontinuation of the Ang II infusion. In a previous study,8 infusion of Ang II at 200 ng/kg per minute SC for 10 to 12 days was shown to induce vascular hypertrophy in Sprague-Dawley rats, and in unpublished studies (1994), we observed significant increases of the wall-to-lumen ratio in renal, preglomerular resistance vessels of chronically captopril-treated SHR during a 2-week infusion of Ang II (200 ng/kg per minute SC). Thus, it appears likely that the Ang II infusions in the present study induced vascular structural alterations in the captopril-treated SHR; however, this had no apparent lasting effect on BP. Similar findings previously were reported in two-kidney, one clip renovascular hypertensive rats9 in which BP fell rapidly to normal within 24 hours after removal of the constricting clip. Such observations suggest that structural alterations are an important adaptive response to increased pressure and/or Ang II concentrations but cast doubt as to the role vascular alterations may play in the long-term maintenance of BP.
The observation that a residual antihypertensive effect persists after captopril treatment is intriguing. Such findings are consistent with previous studies3 4 describing a persistent reduction of MABP in SHR on withdrawal of captopril given from an early age. However, in contrast to earlier findings,4 the present study demonstrated a persistent reduction of BP after withdrawal of captopril treatment initiated in adult SHR. The discrepancy between studies may relate to differing methodologies (ie, it may be difficult to detect modest differences of approximately 15 mm Hg with the more traditional methods of measuring BP in conscious rats).
The precise mechanism by which antihypertensive agents may produce a long-term reduction of BP after withdrawal is unknown, and a great many controversies abound in this area. Several studies have demonstrated a persistent reduction of BP after withdrawal of ACE inhibitors3 4 10 11 and nonpeptide angiotensin type 1 receptor antagonists.12 13 Some studies suggest that the effect may be specific to antagonists of the renin-angiotensin system,3 11 14 whereas others provide evidence to the contrary.15 16 17 The degree of the hypotensive response during treatment does not appear to account for the persistent effect because several studies3 11 have demonstrated that SHR treated with hydralazine had BP values similar to those receiving captopril during the treatment period, but BP rapidly returned to control SHR levels on withdrawal of hydralazine.
In the present study, body weight was significantly lower in SHR that had received captopril from 4 weeks of age compared with control SHR. The growth-attenuating effect of ACE inhibitors administered to young SHR has been reported in previous studies.12 18 Interestingly, hydralazine also has been shown to inhibit growth in SHR.14 Inasmuch as hydralazine did not produce a persistent reduction of MABP on cessation of therapy in that study, it is unlikely that the growth-inhibitory effect of ACE inhibitors is related to the mechanism involving persistent reduction of MABP.
It has been suggested that the ability of a drug to produce a persistent reduction of BP on withdrawal may correlate with the ability of the drug to prevent or produce regression of vascular structural alterations. However, several experiments have demonstrated a dissociation between the effects of an agent on vascular structure and long-term effects on BP.12 19 20
Additional studies have demonstrated significant reductions in response to centrally administered Ang II10 as well as decreases in angiotensin receptor number21 22 23 24 25 in portions of the brain (and primary neuronal cultures) of captopril-treated SHR, suggesting that a decrease in the brain renin-angiotensin system may contribute to the persistent reduction of BP on captopril withdrawal.
There is also experimental evidence to suggest that the permanent reduction of BP after withdrawal of ACE inhibition in SHR is associated with changes in renal function.4 18 26 27 Transplantation of kidneys from control 14-week-old SHR into SHR recipients that had been treated with perindopril from 6 to 10 weeks of age resulted in a rise of BP to control pressure values, thereby negating the long-term reduction of BP normally observed after treatment withdrawal.27
Wu and Berecek10 reported an intriguing observation that the reduction of BP is an inheritable trait; that is, the offspring of captopril-withdrawn SHR also had BP values significantly below control SHR values despite the absence of exposure to captopril at any time. Because of this report, it has been suggested that in utero exposure to hypertension is required for full development of hypertension in SHR.10 28 However, this is not consistent with findings of Smeda et al14 in which withdrawal of hydralazine from SHR that had been treated in utero and postnatally and had normal BP throughout life resulted in the rapid onset of hypertension. Further investigation is required to verify these findings and provide additional information regarding the mechanisms involved.
Interestingly, recent results from Thybo et al20 suggest that the persistent effect on BP of SHR after withdrawal of chronic treatment with an ACE inhibitor may be inversely related to the dose of ACE inhibitor administered. The authors reported a dose-dependent effect on BP of SHR during treatment with perindopril; however, the persistent effect on BP measured 12 weeks after perindopril withdrawal was negatively correlated with the perindopril dose administered. Only the lowest dose (0.4 mg/kg per day) of perindopril produced a significant persistent reduction of MABP after withdrawal, whereas the higher doses (0.8 and 1.5 mg/kg per day) produced no such effect. These findings are in contrast to earlier results11 19 using the same doses of perindopril, and the authors offer the possible explanation that the higher doses of perindopril produced such profound hypotension during treatment (in the more recent study20 ) as to result in a rebound hypertensive response that overrode the persistent effect. However, our results do not support this theory. In the current study, a similar level of BP control was achieved in SHR during chronic treatment with captopril (MABP, 100±1 versus 157±3 mm Hg in control) compared with the highest dose of perindopril (MABP, 105±4 versus 164±4 mm Hg in control) used in the study by Thybo et al20 ; however, a significant persistent effect on BP was observed after captopril withdrawal in the present study. Thus, some alternate explanation must exist regarding the lack of a persistent BP reduction in SHR after withdrawal of higher doses of perindopril.
Importantly, our findings indicate that captopril-treated SHR have reduced pulse pressure relative to control SHR and that Ang II increases pulse pressure in SHR. The major determinants of pulse pressure are stroke volume and the aortic impedance modulus.29 In general, Ang II has little effect on stroke volume,30 31 so it is unlikely that changes in stroke volume account for the pulse pressure changes observed in this study. The aortic impedance modulus can be altered by changes in compliance of the aorta and/or by changes in the stiffness of the entire arterial system including the resistance arteries. Ang II is known to cause hypertrophy of vascular smooth muscle cells and to stimulate the deposition of fibrous collagen in the blood vessel wall, effects that would decrease aortic compliance. Captopril, by blocking the actions of Ang II, would have the opposite effects in SHR. Therefore, it is possible that the effects of Ang II and captopril on pulse pressure in the present study were mediated by alterations of vascular structure. However, the rapid normalization of pulse pressure after withdrawal of Ang II is a strong argument against this hypothesis. Another possibility is that Ang II and captopril, by altering total peripheral resistance, induced a shift in the aortic impedance modulus that may have caused reflected pressure waves to have summated differently with the systolic pressure waves. Further studies are required to uncover the precise mechanism by which captopril and Ang II alter pulse pressure.
In summary, the present study provides additional evidence that early treatment with ACE inhibitors prevents the development of hypertension and results in a persistent reduction of BP in SHR after cessation of treatment. Furthermore, captopril treatment initiated in adult SHR with established hypertension caused a significant reduction in MABP both during treatment and after discontinuation of treatment; however, the effect of captopril in adult SHR was less than that observed when treatment was initiated at a young age. The change of MABP on withdrawal of captopril consisted of a biphasic response; the largest increase occurred within the first 7 days, followed by a more gradual increase that reached a plateau well below control SHR pressures. Although some insight has been gained, the mechanism regarding this persistent reduction of BP has remained elusive.
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Acknowledgments |
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This work was supported by the National Institutes of Health (HL-35909 and HL-14192), Bethesda, Md.
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Footnotes |
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Reprint requests to Curtis K. Kost Jr, PhD, Center for Clinical Pharmacology, 623 Scaife Hall, University of Pittsburgh Medical Center, 200 Lothrop St, Pittsburgh, PA 15213-2582.
Received May 16, 1994; first decision June 22, 1994; accepted September 20, 1994.
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