(Hypertension. 1996;28:622-626.)
© 1996 American Heart Association, Inc.
Articles |
Cardiac Transplantation, Perindopril, and Left Ventricular Hypertrophy in Spontaneously Hypertensive Rats
the Genetic Physiology Unit, Department of Medicine, University of Melbourne (Victoria, Australia), Austin Hospital.
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Abstract |
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Angiotensin-converting enzyme inhibitors reduce blood pressure and cardiac mass but may also have a direct effect on myocardial growth. To test this hypothesis, we studied the effects of perindopril on the weight of transplanted hearts in which the left ventricle does not pump blood. Hearts were transplanted between littermate 10-week-old male spontaneously hypertensive rats, and recipients were treated for 2 weeks with vehicle (n=10), perindopril (3 mg/kg per day) (n=9), perindopril (3 mg/kg per day) plus the selective bradykinin B2 receptor antagonist Hoe 140 (500 µg/kg per day) (n=13), or angiotensin II (200 ng/kg per minute) (n=12). Perindopril reduced blood pressure and native left ventricular weight and also caused a significant decrease in the weight of the transplanted left ventricle compared with controls. Hoe 140 did not significantly alter blood pressure or native left ventricular weight of perindopril-treated rats but caused a significant increase in the weight of the transplanted left ventricle compared with rats treated with perindopril alone. Angiotensin treatment resulted in a significant increase in blood pressure and native left ventricular weight but no significant change in the weight of the transplanted left ventricle. Blood pressure and left ventricular weight for native but not for transplanted hearts were positively correlated. Therefore, in the absence of mechanical load, the weight of the left ventricle of spontaneously hypertensive rats responds little to angiotensin II but can be reduced by angiotensin-converting enzyme inhibition. The effect of perindopril on transplanted hearts of spontaneously hypertensive rats appears to depend on bradykinin.
Key Words: angiotensin • bradykinin • hypertension, genetic • hypertrophy • transplantation
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Introduction |
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The weight of the left ventricle depends largely on hemodynamic load and is increased in conditions such as hypertension and after myocardial infarction. However, nonhemodynamic factors may also influence heart growth. Certain vasoactive substances may not only alter hemodynamics but also exert effects on the growth of cardiovascular cells in vitro.1 2 Cardiac hypertrophy involves hypertrophy of myocardial cells and hyperplasia of fibroblasts that can be stimulated in vitro by Ang II via the type 1 Ang II receptors.3 4 The observed increase in type 1 receptors in response to increasing BP5 raises the possibility that angiotensin plays a role in the maintenance of cardiac hypertrophy.
Some analyses6 but not others7 suggest that for the same reduction in BP, ACE inhibitors reduce cardiac hypertrophy more than other antihypertensive agents. Different treatments may alter heart weight independently of BP effects. The potential role of angiotensin in this respect is supported by the correlation between plasma angiotensin and LV mass in healthy young adults independent of body size and BP.8 However, in relation to ACE inhibition, the accumulation of bradykinin9 may also be relevant. For example, bradykinin administration has been shown to prevent the development of LV hypertrophy in hypertensive rats,10 and some studies indicate that the reversal of cardiac hypertrophy by ACE inhibitors can be prevented by blockade of the bradykinin B2 receptor.11
However, it is difficult to identify direct trophic actions of ACE inhibitors in vivo because of changes in cardiovascular hemodynamics. The mechanical load on the heart depends not only on mean arterial pressure but also on pulse pressure, cardiac output, the arterial pressure waveform, and cardiac preload. Few studies of ACE inhibition attempt to measure these variables,12 most relying on BP measurements only. Changes in heart weight during ACE inhibitor treatment when BP remains stable could be explained by direct growth effects, but equally, changes in unmeasured hemodynamic variables could be important.
To control and minimize hemodynamic factors and highlight possible direct trophic effects of ACE inhibitors, we studied the heterotopically transplanted heart. Such hearts are perfused normally by the coronary arteries and beat rhythmically. However, no blood is pumped by the left ventricle, and the closed aortic valve isolates the LV cavity from changes in the pressures of the recipient systemic circulation. We chose to investigate the SHR because cardiac hypertrophy in this model can be reduced by ACE inhibition.13
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Methods |
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We used male SHR. The inbreeding of these rats has been confirmed by DNA fingerprinting analysis14 and previous transplantation studies.15 All experimental procedures were approved by the Austin Hospital Animal Welfare Committee.
Heterotopic heart transplants were performed16 17 in 10-week-old rats with littermates as donor-recipient pairs. After chloral hydrate anesthesia (26 mg/100 g IP), two lateral incisions were made through the rib cage before the diaphragm and anterior chest wall were divided. The heart was then perfused in situ via the inferior vena cava with 10 mL cold (4°C) heparinized (100 U/mL) physiological saline. The lungs, inferior vena cava, and superior vena cavae were ligated, and the aorta and pulmonary artery were trimmed for anastomosis. The heart was stored in saline at 4°C. Once the recipient was anesthetized with choral hydrate, a midline incision from sternum to pubis allowed the bowel to be removed from the abdomen, exposing the aorta and vena cava. After careful dissection of these vessels, ties were placed proximally and distally, providing a blood-free zone in which end-to-side anastomosis with 8-0 monofilament nylon suture was performed. The donor aorta and pulmonary artery were anastomosed to the recipient aorta and inferior vena cava, respectively. Upon the release of clamps, hearts were checked for rapid and even perfusion and the early return of a regular heart beat. The flow of blood was from the recipient abdominal aorta, retrogradely down the donor aorta into the transplant coronary arteries, which drained into the right atrium via the coronary sinus and finally pumped through the right ventricle via the pulmonary artery into the recipient vena cava. The usual ischemia time from removal from the donor until clamp release after anastomoses was 30 minutes. The success of the transplant was assessed by a firm and regular abdominal heart beat postoperatively and by careful inspection at the end of the experiment.
Recipient SHR received one of four treatments for 2 weeks after transplantation. Treatments began approximately 12 hours after surgery was complete: (1) water by gavage as controls (n=10), (2) perindopril (3 mg/kg per day) by daily gavage (n=9), (3) perindopril (3 mg/kg per day) plus the selective bradykinin B2 receptor antagonist Hoe 140 (500 µg/kg per day) by subcutaneous osmotic minipump (n=13), or (4) Ang II (200 ng/kg per minute) by subcutaneous osmotic minipump and water by gavage (n=12). Doses and infusion rates were based on previous studies.9 11 18 Rats were gavaged each morning between 8 and 9 AM.
At the end of 2 weeks of treatment, mean arterial pressure was measured in conscious SHR. The rats were anesthetized briefly with methohexital (50 mg/kg IP) for insertion of polyethylene catheters (PE-50) into the left carotid artery. Catheters were exteriorized in the interscapular region, and rats were allowed to recover in individual cages overnight with free access to food and water. The following morning, rats received their usual treatment at 8 AM. Between 9 and 11 AM in their own cages, rats had a BP transducer (model DPT 3003-S, Peter von Berg) attached to the intra-arterial catheter via an additional length of PE-50 tubing. Transducer signals were preamplified (model 7C preamplifier, Grass Instruments) before analog-to-digital signal conversion (Maclab/8, Analog Digital Instruments Pty Ltd) for data recording, storage, and off-line analysis. Up to four rats were studied at one time; the calibration of each transducer was checked daily. Once the rats were resting quietly and BP appeared stable, recordings were made for half an hour with continuous sampling, and the average of these readings was used for estimation of mean arterial BP.
After BP measurements, rats were given an overdose of pentobarbital. The native and transplant hearts were then removed immediately, and the free right ventricular wall was dissected from the interventricular septum and LV wall to allow for separate measurements of right ventricular and LV weights. The left ventricles were then fixed in 10% buffered formalin for histomorphometric analysis. The left ventricles were sectioned transversely into 1-mm-thick slices. These were examined under low-power magnification for differentiation of normal myocardial tissue in the transplants from any subendocardial fibrosis or clot organization within the ventricular cavity. In both transplant and native left ventricles, the Cavalieri technique was used for determination of myocardial volume.19
Summary data are presented as mean±SE. The effects of treatment on BPs and heart weights were compared by ANOVA. In analyses of heart weights, body weight was included as a covariate.
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Results |
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There were no significant differences between the initial recipient or donor body weights of the four groups (data not shown), and the body weights of the recipient and donor pairs were well matched (average difference, 3.4±2.4 g). All rats recovered well from the operation and were eating, drinking, and behaving normally within 12 hours. The four groups did not differ significantly in body weight of the recipients at the end of the treatment period (Table 1
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Table 1
shows mean arterial pressures of the groups. As expected, treatment had significant effects on BP (ANOVA: F3,43=53.9, P<.0001). Ang II infusion resulted in the highest pressures (P<.01). Perindopril-treated rats had significantly lower pressures than controls (P<.001). SHR treated with both perindopril and Hoe 140 had the lowest pressures although they were not significantly different from pressures of rats treated with perindopril alone.
Native Hearts
LV mass in the native hearts showed the same pattern among groups as BP, being greatest in SHR treated with Ang II and lowest in the two groups that received perindopril (Table 1; ANOVA: F3,43=22.9, P<.0001). The difference between rats treated with perindopril and perindopril plus Hoe 140 was not significant statistically. These results were corroborated by estimates of LV myocardial volume (ANOVA: F3,43=10.3, P<.0001).
The Figure (top) shows the close linear correlation between the LV mass of native hearts and mean arterial pressure. The correlation coefficient when all points were included was .937 (F1,84=604, P<.0001). When the variance of native LV mass was analyzed after correction for covariation in mean arterial pressure, the effects of treatment disappeared.
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indicates angiotensin infusion (200 ng/kg per minute); 
, vehicle; 
, perindopril (3 mg/kg per day); and 
, perindopril (3 mg/kg per day) plus Hoe 140 (500 µg/kg per day).Neither heart rate nor right ventricular mass of the native hearts was significantly different among the treatment groups.
Transplant Hearts
Table 2 shows study parameters for the transplant hearts. The left ventricles of transplant hearts were smaller than those of native hearts on average by approximately 26%, representing the regression in weight associated with denervation and the reduction in mechanical load.
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Different treatments were associated with significant effects on transplant heart weight (ANOVA: F3,43=6.32, P=.001). The transplanted left ventricles of perindopril-treated rats were significantly smaller than those of controls (P<.01). In contrast, the LV mass of rats treated with perindopril and Hoe 140 was no different from that in controls and was significantly (P<.05) greater than that in rats receiving perindopril alone. The highest LV mass was found in the SHR transplanted hearts exposed to Ang II, although compared with control hearts, this difference was not significant. Transplant LV mass and mean arterial pressure were not correlated (Figure, bottom).
Volumetric analysis revealed that on average, 4.3±0.98% of the transplant LV myocardial volume was composed of organizing clot in the LV cavity and/or subendocardial fibrosis. This component did not differ significantly among treatment groups. Reflecting the differences in weight, the volume of intact myocardium was the lowest in perindopril-treated SHR.
The right ventricular mass of transplanted hearts was also smallest in the perindopril-treated SHR, but this did not achieve statistical significance.
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Discussion |
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These studies deal with the reversal of cardiac hypertrophy that accompanies ACE inhibitor treatment in the SHR. The novel aspect of this study was the ability to compare the effects of ACE inhibition in native and heterotopic transplanted hearts, both of which are exposed to the same circulating hormonal milieu but only one of which pumps blood. In the native heart, the left ventricle pumps the cardiac output against systemic pressure. In the transplant, the left ventricle contains no blood and the closed aortic valve isolates the cavity from systemic pressures. The principal new finding was that perindopril significantly reduced the weight of the hemodynamically unloaded transplanted SHR heart. The implication of these findings is that even when cardiac work is minimized, perindopril exerts an additional and presumably direct effect on the regression of SHR hypertrophy.
Consistent with previous studies,20 the reduction in BP with perindopril was associated with a significant reduction in LV weight in the native SHR heart. The direct correlation between mean arterial pressure and the LV mass of native hearts indicates that a substantial component of the reversal of cardiac hypertrophy can be ascribed to the reduction in BP and, therefore, mechanical workload.
In the left ventricles of the transplanted hearts, the reduction in mechanical work is far more substantial because the pressure and volume loads associated with pumping blood are absent. As a result, the weight of the transplanted hearts regressed compared with their native counterparts in all treatment groups. Nevertheless, transplanted hearts do not show rejection when inbred animals are used,21 and they retain the ability to respond to a wide range of growth stimuli.17 22 23
The reduction in weight of the transplanted heart in perindopril-treated SHR is not likely to be explained by changes in systemic hemodynamics, given that transplanted left ventricles are not exposed to either preload or afterload. The only contact with the systemic circulation is through blood flow in the coronary arteries, which is normally well autoregulated by local factors related to metabolic demands. Although lower BP in the perindopril-treated rats might reduce coronary blood flow and, therefore, nutrient delivery to transplanted hearts, this seems an unlikely explanation of the effect of perindopril. Mean arterial pressure and transplant LV weight were not correlated, and in rats that received perindopril and Hoe 140, BP was slightly lower than in rats exposed to perindopril alone, yet their transplanted hearts were significantly larger.
A more plausible explanation for the effect of perindopril on cardiac growth is reduced activity of circulating or tissue ACE, resulting in decreased Ang II and increased bradykinin.9
Despite the efficacy of ACE inhibitors in SHR, we have demonstrated that the circulating levels of ACE are reduced in our SHR.24 Furthermore, cardiac levels of Ang II are not increased and fall as BP rises into adulthood.24 The cardiac Ang II–Ang I ratio, which is indicative of ACE activity, is normal in our SHR.24 However, we have also shown that the SHR heart exhibits higher concentrations of bradykinin-(1-7) and bradykinin-(1-9) than controls.25 The present experiments with angiotensin and bradykinin blockade offer another perspective.
In cells from normal hearts, angiotensin causes hypertrophy of cardiomyocytes3 and hyperplasia of fibroblasts4 in cell culture. The responses of SHR cells have not been studied. However, in vivo, the contribution of the myocardial renin-angiotensin system depends not only on the specific model of cardiac hypertrophy but also on the stage of the hypertrophic process.12 26 It appears that mechanical stretch per se can lead to an increase in myocardial renin mRNA,27 myocyte angiotensin release,28 myocardial ACE activity,29 and the number of cardiac type 1 angiotensin receptors.5 When exposed to angiotensin levels sufficient to increase mean arterial pressure and the weight of the native left ventricle, the transplanted left ventricle did not show any significant increase in weight. This relative unresponsiveness may be explained by a reduction in type 1 angiotensin receptor number with mechanical unloading.5 Although another transplantation study reported that an infusion of "subpressor" doses of Ang II caused an increase in LV weight and protein synthesis,30 this previous study was performed with normotensive animals rather than SHR.
If the activity of the renin-angiotensin system and the number of angiotensin receptors are proportional to mechanical load,5 28 then the potential for perindopril to exert its effect through angiotensin may be limited in the transplanted left ventricle. Alternatively, an increase in bradykinin in perindopril-treated SHR may be important.
It has been proposed that bradykinin has an antitrophic effect on the heart through nitric oxide generation.31 Also, bradykinin improves glucose uptake by cardiac myocytes32 33 and energy stores.34 Metabolic efficiencies may allow myocardial cells to generate the necessary energy while economizing on size.
In the aortic coarctation model, low doses of ACE inhibitors caused a reduction in LV weight without affecting BP,11 and this effect was prevented by blockade of the bradykinin B2 receptors. Other studies suggest that ACE inhibitor–induced changes in bradykinin alter the ventricular sarcoplasmic reticulum Ca2+-ATPase as part of their antihypertrophic effects.35 However, unlike other experimental models, low-dose ACE inhibitor treatment does not affect heart weight in the SHR13 although it appears to improve myocardial metabolism.36 As reported previously,18 37 38 bradykinin antagonism did not reverse the antihypertensive effects of high doses of ACE inhibitor treatment in SHR. Nevertheless, our findings do support a role for bradykinin in the nonhemodynamic effects on heart weight because bradykinin blockade with Hoe 140 significantly attenuated the antitrophic effects of perindopril on the transplanted hearts.
In the absence of a rat group treated with Hoe 140 alone, we cannot be certain that the Hoe 140 effect is due to antagonism of bradykinin rather than a nonspecific effect on heart weight. However, such an effect has not been observed previously,10 and in our own studies of 4 weeks of Hoe 140 treatment in SHR, we found no significant difference (unpublished observations, 1996) in LV myocardial volume (958±30 µm3) versus control SHR (989±38 µm3).
In summary, our findings suggest that perindopril reduces the weight of the transplanted heart of the SHR by a mechanism independent of BP. The relative unresponsiveness of the transplanted SHR heart to Ang II and the antagonism of the effects of perindopril by blockade of the bradykinin receptors suggest that the effects of ACE inhibition may depend on bradykinin, although a nonspecific effect of Hoe 140 cannot be excluded. These effects in transplanted hearts contrast with those in native hearts, in which, in the short term, BP seems to be the major determinant of LV weight.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Prof Harrap was supported in this work as an R. Douglas Wright Fellow of the National Health and Medical Research Council of Australia. This work was supported by a grant from Institut de Recherches Internationales Servier, Courbevoie, France. We should like to acknowledge the expert technical assistance of Lisa Purcell.
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Footnotes |
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Reprint requests to Prof Stephen B. Harrap, Department of Physiology, University of Melbourne, Parkville, Victoria 3052, Australia. E-mail s.harrap@physiology.unimelb.edu.au.
Received March 25, 1996; first decision April 30, 1996; accepted May 31, 1996.
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