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Basic Res Cardiol 94: 128 – 135 (1999) © Steinkopff Verlag 1999

J. Su F. Barbe R. Houël T. T. Guyene B. Crozatier L. Hittinger

ORIGINAL CONTRIBUTION

Comparison between angiotensin receptor antagonism and converting enzyme inhibition in heart failure Differential acute effects according to the renin-angiotensin system activation

Received: 22 September 1998 Returned for revision: 14 October 1998 Revision received: 23 November 1998 Accepted: 8 December 1998

J. Su · F. Barbe · R. Houël · B. Crozatier L. Hittinger, M.D., Ph.D. (Y) INSERM U 400 Hôpital Léon Bernard Place des Marronniers 94456 Limeil-Brévannes Cedex France e-mail: [email protected] T. T. Guyene Unité 367 Hôpital Broussais 75005 Paris France

Abstract This study was designed to assess the influence of the activation status of the renin angiotensin system (RAS) on the hemodynamic effects of EXP 3174 (an angiotensin AT1 receptor antagonist) and enalaprilat (an angiotensin converting enzyme inhibitor) in tachycardia-induced heart failure. Thirteen dogs were chronically instrumented to measure left ventricular (LV) pressure, its first time derivative (LV dP/dt), atrial and aortic pressures, and cardiac output. EXP 3174 (0.1 mg/kg, iv) or enalaprilat (1 mg/kg, iv) were administered in conscious dogs with heart failure induced by right ventricular pacing (250 beats/min, 3 weeks). EXP 3174 and enalaprilat produced significant vasodilation but the effects of EXP 3174 on mean aortic pressure (MAP), cardiac output, and total peripheral resistance (TPR) were only 50 % of those produced by enalaprilat. When dogs were grouped according to their baseline plasma renin activity (PRA) values, in dogs with normal PRA (0.5 ± 0.1 ng/ml/h) EXP 3174 did not produce significant change in MAP and TPR, while enalaprilat decreased significantly MAP and TPR. In contrast, in dogs with high PRA (6.7 ± 3.2 ng/ml/h), EXP 3174 produced significant reductions in MAP and TPR, which were similar to those produced by enalaprilat. Thus, in conscious dogs with heart failure, enalaprilat is effective whether the RAS is activated or not. In contrast, EXP 3174 is effective only when the RAS is activated. These results may help in the choice of inhibitors of the RAS in heart failure. Key words Congestive heart failure – conscious dog – angiotensin II receptor antagonist – angiotensin converting enzyme inhibitor – vascular tone

Introduction

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The renin angiotensin system (RAS) is involved in the pathophysiology of chronic congestive heart failure. By inhibiting the RAS and by protecting the bradykinin breakdown by angiotensin converting enzyme (ACE), ACE inhibitors have demonstrated their ability to reduce morbidity and mortality in patients with heart failure (31, 32). Recently, specific angiotensin AT1 receptor antagonists have been developed. It has been shown that acute administration of angiotensin AT1 receptor antagonists can reduce workload of heart through a

vasodilator effect in animals (7, 23) and in patients with heart failure (4, 9) and chronic treatment with AT1 receptor antagonists can improve hemodynamics in dogs (20) or in pigs during development of heart failure (28) and generate the beneficial effect in LV remodeling in rats with myocardial infarction (17, 24, 26). However, some studies have not found a beneficial effect of AT1 blockade on cardiac function (28, 29) and on LV remodeling (20, 28, 29) when the animals were treated with an AT1 receptor antagonist only. Although it is logical to hypothesize that the effects of an AT1 receptor antagonist may depend on RAS activation, no study has examined this

J. Su et al. ACE inhibitor and AT1 antagonist in heart failure

question. The present study was, therefore, designed to examine the influence of the activation status of the RAS on the hemodynamic effects of EXP 3174 (an active metabolite of losartan) and enalaprilat in the same chronically instrumented dogs with chronic heart failure induced by rapid ventricular pacing. It may be hypothesized that, when the RAS is not activated, the RAS may play a small role in the vascular tone and an AT1 antagonist may produce little vasodilator effects, while an ACE inhibitor which can produce vasodilator effect through the inhibition of bradykinin degradation. In contrast, when the RAS is activated, an AT1 receptor antagonist may produce, as an ACE inhibitor, a potent vasodilator effect because of the increased role of the RAS and possible activation of bradykinin pathway secondary to the activation AT2 receptors by increased angiotensin level following AT1 receptor blockade (17).

Methods

Preparation of the model Thirteen mongrel dogs of either sex, weighting 17–29 kg, were sedated with sodium thiopenthal (20 mg/kg, iv, Specia, Paris, France) and anesthetized using halothane (1 vol%). As described previously (1), a thoracotomy was performed, under sterile conditions, through an incision in the fifth left intercostal space for implantation of Tygon catheters in the descending aorta and in the left and right atria to measure aortic and atrial pressures, a micromanometer in the left ventricular (LV) cavity through the apex to measure LV pressure and LV dP/dt, an ultrasonic flow around the ascending aorta to measure cardiac output (CO), and two stainless steel pacing leads on the right ventricle. Catheters and leads were externalized infrascapularly, and the thoracotomy was closed in layers. Animals were given daily post-operative care. Animals used in this study were maintained in accordance with the official regulations of the French Ministry of Agriculture.

Experimental protocol After 2–3 weeks of recovery from surgery, baseline recordings in the control state were performed in dogs fully awake, lying quietly on their right side. Then, continuous right ventricular pacing was initiated at a rate of 250 beats/min, using a miniature pacemaker (model 5320, Medtronic Inc), worn externally in a vest. Dogs were examined daily to confirm the maintenance of pacing and to monitor incipient signs of heart failure. After development of heart failure (average 3 weeks of right ventricular pacing), experiments were performed in dogs fully

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awake, lying quietly on their right side. Hemodynamic parameters were recorded on a multichannel graphic recorder (model MT 95000, AstroMed Inc) and on a multichannel tape recorder (model 3968A, Hewlett-Packard). Baseline measurements in sinus rhythm were taken following a 15 min stabilization period subsequent to deactivation of the pacemaker. To examine the stability of the model, saline injection was performed in 5 dogs and the hemodynamic parameters were monitored for 20 min. In all 13 dogs, EXP 3174 (2-nbutyl-4-chloro-1-[(2’-(1H-tetrazol-5-yl)biphenyl-4-yl) methyl] imidazole-5-carboxylic acid, Merck Sharp Dohme, West Point, PA), or enalaprilat (Merck Sharp Dohme, West Point, PA) were administered in random order on different days separated by 48 h. Specific attention was made to keep baseline hemodynamics similar before enalaprilat or EXP 3174 injection. Prior to injection, EXP 3174 was dissolved in 5 ml of a solution prepared with 10 ml of NaHCO3 and 6.7 ml of 5 % glucose and enalaprilat was dissolved in 5 ml of a physiological saline solution, respectively. The 1 mg/kg dose of enalaprilat or the 0.1 mg/kg dose of EXP 3174 was injected as bolus over a 1 min period of time. Hemodynamic parameters were monitored for 15 min after the onset of the injection. The dose of 1 mg/kg of enalaprilat was used since it has been previously shown that this dose produced nearly complete blockade of the RAS in normal dogs (10) and in dogs with heart failure (1); this dose also blockaded by 30 mmHg the pressor effect of angiotensin I and decreased mean aortic pressure (MAP) by 20 mmHg in furosemidetreated dogs (25). The choice of the dose of 0.1 mg/kg of EXP 3174 was based on the previous studies that showed that this dose can reduce by 30 mmHg the pressor response to angiotensin II in normal rats (36) and produced 20 mmHg reduction in MAP in furosemide-treated rats and dogs (34). Furthermore, to verify the extent of the RAS blockade with the dose of 0.1 mg/kg of EXP 3174, in four dogs with heart failure, 20 min after first injection, an additional dose of 1 mg/kg of EXP 3174 was injected intravenously. Hemodynamic parameters were again monitored for 15 min following the second injection. To determine the changes in the RAS during the development of heart failure, blood samples were collected from the aortic catheter in heparinized vacuum tubes for measuring plasma renin activity (PRA) and in EDTA-K3 tubes containing a mixture of inhibitors for measuring plasma angiotensin II in 10 dogs in the control state and in 13 dogs in heart failure. To determine the hormonal effects of each compound, blood samples were taken 15 min after deactivation of the pacemaker and 15 min after the injection of each inhibitor in 13 dogs with heart failure. PRA and angiotensin II were measured as described previously (1). In heart failure, data were subsequently analyzed according to the baseline PRA values of dogs in heart failure in comparison with the mean control PRA value measured in the control

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Basic Research in Cardiology, Vol. 94, No. 2 (1999) © Steinkopff Verlag 1999

state. Dogs with baseline PRA within the mean control PRA plus two standard deviations were assigned to the group with normal baseline PRA. Dogs with baseline PRA above the mean control PRA plus two standard deviations were assigned to the group with high baseline PRA.

Statistics Data were analyzed using superANOVA software (v1.11, Abacus Concepts, Inc., Berkeley, CA). Results are presented as means ± SEM. One-way analysis of variance for repeated measures was used for intradrug studies. When a significant trend was found, the comparisons between means were performed using the contrast. Two-way analysis of variance for repeated measures was used for comparison of the effects of two drugs. For the comparisons between dogs with normal and high PRA treated with EXP 3174 and enalaprilat, two way analysis of variance was performed which was followed by Student-Newman-Keuls multiple comparison test. When only two means were compared, an appropriate t-test was used. Differences were considered as significant for p < 0.05.

Results

Baseline measurements before and after induction of heart failure After 3 weeks of rapid right ventricular pacing, dogs developed heart failure as indicated by peripheral congestive signs (dyspnea, ascites) and by hemodynamic changes (Table 1). Compared with the control values, in heart failure, PRA tended to be increased (from 0.7 ± 0.1 to 3.1 ± 1.5 ng/ml/h) and plasma angiotensin II concentration increased significantly from 3.0 ± 0.5 to 8.1 ± 1.9 pg/ml (p < 0.05). In heart failure,

Fig. 1 Comparisons of changes (D) in mean aortic pressure (MAP), cardiac output (CO) and total peripheral resistance induced by injection of enalaprilat (1mg/kg iv) or EXP 3174 (0.1 mg/kg iv) in conscious dogs with heart failure (n=13). Enalaprilat induced larger hemodynamic effects than EXP 3174. *: p < 0.01 and † p < 0.001 as compared with baseline. P value in each panel is obtained by ANOVA for the comparison between the effects of enalaprilat and EXP 3174.

Table 1 Baseline hemodynamics in the same thirteen conscious dogs in the control state and after induction of heart failure Heart failure Control State

Heart Rate (beats/min) Mean Arterial Pressure (mmHg) LV End-Diastolic Pressure (mmHg) Cardiac Output (l/min) LV dP/dt (mmHg/s) Total Peripheral Resistance (mmHg/l/min)

All dogs before EXP 3174 (n = 13)

Normal PRA

High PRA

(n = 13)

All dogs before enalaprilat (n = 13)

(n = 7)

(n = 6)

106 ± 4 101 ± 2 8.8 ± 1.1 2.24 ± 0.18 3091 ± 158 48.4 ± 3.4

139 ± 3† 85 ± 2† 28.6 ± 1.3† 1.40 ± 0.11† 1430 ± 80† 60.1 ± 3.3*

138 ± 5† 83 ± 2† 28.2 ± 2.3† 1.36 ± 0.12† 1440 ± 85† 60.7 ± 3.8*

141 ± 8* 85 ± 3* 31.4 ± 3.4* 1.35 ± 0.10* 1471 ± 114* 58.8 ± 3.3*

134 ± 7* 80 ± 2* 24.5 ± 2.3* 1.37 ± 0.24* 1406 ± 127* 62.0 ± 7.6*

LV: left ventricular. *: p < 0.05 and † p < 0.01 as compared with control state


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baseline PRA and plasma angiotensin II levels were closely correlated (log angiotensin II = 0.77 log PRA + 0.6, r = 0.82, p < 0.001).

Hemodynamic and hormonal effects of enalaprilat and EXP 3174 In a group of 5 dogs, saline injection (used as control) did not produce any significant changes in any measured hemodynamic parameters and in PRA and plasma angiotensin II concentration throughout the time of recordings (data not shown). In all studied dogs, there was no significant difference in baseline hemodynamics before enalaprilat or EXP 3174 injection. Both enalaprilat (1 mg/kg) and EXP 3174 (0.1 mg/kg) decreased significantly heart rate (–6 ± 2 and –8 ± 3 beats/min, respectively, both ps < 0.05). Enalaprilat decreased significantly LV end-diastolic pressure (–4 ± 1 mmHg, p < 0.001), while EXP 3174 did not modify significantly LV end-diastolic pressure. In association with significant decreases in MAP and in total peripheral resistance (TPR), enalaprilat increased CO but EXP 3174 did not increase CO significantly (Fig. 1). The effects of enalaprilat were significantly larger than those of EXP 3174. Both inhibitors increased significantly stroke volume (+2.3 ± 0.3 ml and +1.1 ± 0.4 ml, respectively, both ps < 0.01) without significant change in LV dP/dt max. There was no difference between the baseline values for PRA and plasma angiotensin II level before injection of enalaprilat and EXP 3174 (Table 2). Both enalaprilat and EXP 3174 increased PRA to a similar level, but enalaprilat decreased plasma angiotensin II concentration and EXP 3174 increased it; the difference between the two inhibitors was significantly different. In four dogs, the additional 1 mg/kg dose of EXP 3174 after the first dose of 0.1 mg/kg increased further PRA and plasma angiotensin II level (PRA from 3.7 ± 1.3 at baseline to 5.6 ± 1.6 and 17.0 ± 8.2 ng/ml/h, and angiotensin II from 14.7 ± 5.0

Fig. 2 The response of mean aortic pressure (MAP), cardiac output (CO), and total peripheral resistance to EXP 3174 (0.1 mg/kg and 1.0 mg/kg) in four conscious dogs with heart failure. EXP 3174 at tenfold dose did not produce a larger vasodilatory effect.

Table 2 Hormonal effects of enalaprilat and EXP 3174 in heart failure

Enalaprilat (1 mg/kg) EXP 3174 (0.1 mg/kg)

baseline response baseline response

Plasma Renin Activity (ng/ml/h)

Angiotensin II (pg/ml)

All dogs (n = 13)

Normal PRA (n = 7)

High PRA (n = 6)

All dogs (n = 13)

Normal PRA (n = 7)

High PRA (n = 6)

3.1 ± 1.5 7.3 ± 2.6 3.4 ± 1.7 9.8 ± 4.1*

0.9 ± 0.3 1.2 ± 0.3 0.5 ± 0.1 0.5 ± 0.1

5.6 ± 3.3 14.4 ± 4.3 6.7 ± 3.2 20.3 ± 6.8*

8.1 ± 1.9 1.0 ± 0.4* 8.0 ± 1.6 23.7 ± 8.0*#

4.0 ± 1.1 0.3 ± 0.3* 4.1 ± 1.1 15.5 ± 12.0

12.9 ± 3.0† 1.9 ± 0.9* 11.2 ± 2.3† 33.4 ± 9.7*#

Baseline values were obtained 15 min after pacing deactivation. Response values were measured 15 min after each inhibitor injection. *p < 0.05 for response vs baseline, † p < 0.05 for the comparison at baseline between dogs with high PRA and dogs with normal PRA, and # p < 0.05 response to EXP 3174 vs response to enalaprilat

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at baseline to 15.5 ± 3.4 and 25.5 ± 5.3 pg/ml at 0.1 and 1 mg/kg, respectively). However, 1 mg/kg of EXP 3174 did not induce larger hemodynamic changes than the dose of 0.1 mg/kg (Fig. 2). Thus, the dose of 0.1 mg/kg of EXP 3174 was considered as inducing maximal hemodynamic effects in this preparation.

Vasodilator effect of enalaprilat and EXP 3174 in the dogs with normal and high baseline PRA level In heart failure, seven dogs having a baseline PRA value below the control mean + 2SD (i.e., 1.3 ng/ml/h) were included in the group of dogs with normal baseline PRA (Table 2), the other six dogs having a baseline PRA value above 1.3 ng/ml/h were included in the high baseline PRA group (Table 2). There was

Fig. 3 Comparisons of changes (D) in mean aortic pressure (MAP; top panel) and in total peripheral resistance (TPR; bottom panel) 10 min after injection of enalaprilat (1mg/kg iv) or EXP 3174 (0.1 mg/kg iv) in dogs with heart failure with normal plasma renin activity (PRA, n = 7) and with high PRA (n = 6). In dogs with normal PRA, enalaprilat decreased significantly MAP and TPR while EXP 3174 did not change these parameters. In dogs with high PRA, EXP 3174 produced significant reductions in MAP and in TPR which were not significantly different from those induced by enalaprilat. *: p < 0.02 as compared with effects of EXP 3174 in dogs with normal PRA.

no significant difference for baseline hemodynamics between the two groups (Table 1). In dogs with normal baseline PRA, enalaprilat decreased significantly MAP and TPR (Fig. 3) and plasma angiotensin II concentration (Table 2). In contrast, EXP 3174 did not change significantly these parameters. In dogs with high baseline PRA, enalaprilat and EXP 3174 produced similar decreases in MAP and TPR (Fig. 3), and enalaprilat decreased plasma angiotensin II concentration while EXP 3174 increased it; the difference between the effects of two inhibitors was significant (Table 2).

Discussion Pacing-induced heart failure is a well-recognized model of heart failure (15). Stability and reproductibility of hormonal and hemodynamic parameters after pacing deactivation have been previously demonstrated in our laboratory (1, 30) and confirmed in the present study by saline injection. In the present study, hemodynamic hallmarks of heart failure were present as indicated by decreased arterial pressure, LV dP/dt max, and cardiac output, and by elevated LV end-diastolic pressure and total peripheral vascular resistance. During enalaprilat and EXP 3174 injections, heart rate was significantly decreased. This may result from the removal of a presynaptic facilitatory action of angiotensin II on the sympathetic nervous system by ACE inibition and angiotensin II antagonism (13, 16). In the case of EXP 3174, the decreased heart rate may also be related to the inhibitory effect of AT2 receptors on AT1 mediated chronotropic effect (19). Our results that EXP 3174, an active metabolite of losartan, can exert vasodilator and hormonal effects in dogs with heart failure are in agreement with previous experimental or human studies performed with losartan (4, 7, 9). However, our data indicate that the vasodilator effect of EXP 3174 is smaller than that of enalaprilat when all dogs are considered together. This difference might have been due to the dose of angiotensin II antagonist or ACE inhibitor used in the present study. The absence of a larger vasodilator effect after an additional dose of 1.0 mg/kg of EXP 3174 ruled out this possibility (Fig. 2). The result of the lack of additional effect with a larger dose of EXP 3174 is consistent with the data reported by Gottlieb et al. who observed that the dose of 75 and 100 mg of losartan did not produce, despite a larger increase in plasma angiotensin II, a larger hemodynamic effect than that of 25 mg, which was explained by a possible neurohormonal activation (9). Although PRA and plasma angiotensin II concentration were elevated in heart failure in the present study, a heterogeneity in the baseline levels between dogs was observed. Similar findings have been previously reported in the literature and ascribed to the degree and stage of heart failure in which


PRA was measured (2, 22). In both experimental animals and humans, PRA is elevated acutely after the first acute episode of heart failure and during advanced, decompensated heart failure but returns to nearly normal value during chronic stable phase (6, 8, 11, 14). In experimental studies, and probably in humans, the heterogeneity in baseline values of PRA may reflect an individual difference in heart failure development. This may affect the effects of ACE inhibitors and angiotensin receptor antagonists. Different effects of ACE inhibitors depending on the RAS activation were previously described in patients with heart failure (5). The present study shows a tendency toward to a larger vasodilator effect of enalaprilat in dogs with high PRA than in dogs with normal PRA (Fig. 3) but the difference between the two groups was more marked with an angiotensin AT1 receptor antagonist. Indeed, when dogs were grouped according to their baseline value of PRA to take into account the individual difference, we found that, in dogs with high baseline PRA value, enalaprilat and EXP 3174 exerted a similar vasodilator effect which is in agreement with the results of Fitzpatrick et al. who showed similar hemodynamic effects with captopril and losartan in ovine heart failure after 6 d of rapid ventricular pacing (7) and with those of Murakami et al. who showed in dogs with pacing-induced heart failure that losartan and captopril produced similar decrease in MAP despite different cardiac output response (23). In dogs with normal baseline PRA value, in contrary to enalaprilat, EXP 3174 did not induce significant hemodynamic effects which is similar to that observed in healthy volunteers with a normal preexisting PRA (12). Therefore, our data support the idea derived from experiments in rats with high renin hypertension (35) or in furosemide-treated dogs (25, 34) that the hemodynamic effects of angiotensin AT1 receptor antagonists may depend upon the prevailing level of RAS activation and our data extend this concept to the field of heart failure. The difference between the hemodynamic effects induced by enalaprilat and EXP 3174 in dogs with normal baseline PRA suggests that the hypotensive effect of enalaprilat is not solely related to the blockade of the RAS. Indeed, we have previously shown that bradykinin contributes to the acute hemodynamic effects of enalaprilat in pacing-induced heart failure because the hypotensive effects of enalaprilat were significantly reduced by Hoe 140, a specific bradykinin B2 receptor antagonist and enalaprilat can potentiate the effect of bradykinin (1). This is in accordance with previous studies that

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reported a significant role of bradykinin in the cardioprotective and anti-remodeling effects of chronic ACE inhibitor treatments in heart failure (17, 21). In addition, ACE inhibitors also alter the formation and degradation of several other vasoactive substances such as substance P and ANF which are probably involved in the effect of ACE inhibition as suggested by the observations that ACE inhibitors potentiate the effect of substance P (3) and neutral endopeptidase inhibition (18), but the contribution of these substances to the effects of ACE inhibitors is unclear. There are some experimental data suggesting that bradykinin may also contribute to the effect of angiotensin AT1 receptor blockade (17, 27, 33). Increased angiotensin II level following AT1 receptor blockade may activate AT2 receptors (17). AT2 receptor activation, in turn, results in the formation of local kinin (27) which may be involved in the improved cardiac function, cardioprotective effect, and antiremodeling effect of AT1 antagonist. However, it appears that beside AT2 receptors, AT1 receptors are also involved in the formation of local kinin and their blockade by losartan reduce the NO generation attributable to local kinin activation induced by angiotensin I, II, III, and angiotensin (1–7) (27). Furthermore, even if there is a formation of local kinin during AT1 antagonism, in contrast with ACE inhibition by which the degradation of the kinin is inhibited, the kinin may be destroyed rapidly by metabolic enzymes, explaining the only partial suppression of the beneficial effect of AT1 antagonist on cardiac function in rats with experimental myocardial infarction by a bradykinin B2 antagonist, Hoe 140 (17). Thus, the contribution of local kinin activation in the effect of AT1 receptor blockade in heart failure remains to be determined. This study analyzed the effects of single injection of drugs and should thus not be extrapolated directly to chronic drug administration. However, our study demonstrates that, in experimental heart failure, when the RAS is not activated, an ACE inhibitor produces larger acute hemodynamic effects than an angiotensin AT1 receptor antagonist, suggesting that in this setting of heart failure, ACE inhibition may be more appropriate. In contrast, when the RAS is activated, an angiotensin AT1 receptor antagonist produces, as an ACE inhibitor, a potent vasodilation and decreases the workload of the heart, suggesting that both agents may be used. Acknowledgments We thank Dr Sweet (Merck Sharp Dohme Ltd, West Point, PA) for the generous supply of enalaprilat and EXP 3174.

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