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(Circulation. 2001;104:939.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Cardioprotective Effects of Ramipril and Losartan in Right Ventricular Pressure Overload in the Rabbit

Importance of Kinins and Influence on Angiotensin II Type 1 Receptor Signaling Pathway

Jean L. Rouleau, MD; Gaston Kapuku, MD; Stéphane Pelletier, MSc; Hugues Gosselin, DT; Albert Adam, PhD; Caroline Gagnon, BSc; Chantal Lambert, PhD; Sylvain Meloche, PhD

From the Departments of Medicine, Montreal Heart Institute (G.K., H.G., J.L.R.); the Institut de recherches cliniques de Montréal (S.P., S.M.); the Department of Pharmacology (S.P., C.G., C.L., S.M.) and the Faculty of Pharmacy (A.A.), University of Montreal; and the University of Toronto (J.L.R.), Canada.

Correspondence to Jean Rouleau, MD, Toronto General Hospital, Eaton North 13-212, 200 Elizabeth St, Toronto, Ontario, Canada, M5G 2C4. E-mail jean.rouleau{at}uhn.on.ca

	Abstract

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Background—— The role of kinins in the cardioprotective effects of ACE inhibitors remains controversial.

Methods and Results—— Right ventricular pressure overload in rabbits was produced by pulmonary artery banding for 21 days. Rabbits were untreated, or they received the ACE inhibitor ramipril with or without bradykinin B₁ and B₂ receptor blockers or the angiotensin (Ang) II type I (AT₁) receptor blocker losartan. Pulmonary artery banding caused right ventricular hypertrophy, depressed papillary muscle contractility, and loss of Ang II contractile effects because of a signaling defect downstream of AT₁ receptors. Paradoxically, AT₁ receptor density and G protein subunits q and i1/2 increased. Inotropic responsiveness to the -receptor agonist phenylephrine was normal. Ramipril preserved cardiac contractility, but this effect was attenuated by simultaneous use of kinin receptor blockers. Ramipril also maintained responsiveness to Ang II and prevented AT₁ receptor and G protein upregulation. The simultaneous use of a kinin receptor blocker attenuated but did not prevent upregulation in the AT₁ receptor and G protein. Losartan had no effect on baseline contractility, but it maintained cardiac inotropic responsiveness to Ang II, prevented upregulation of AT₁ receptors, but did not modify G protein upregulation.

Conclusions—— Pressure overload of the right ventricle decreases contractility, uncouples AT₁ receptors to downstream signaling pathways, and changes the expression of components of the AT₁ receptor signaling pathway. Ramipril attenuates these effects via kinins. Interventions that prevent local increases in Ang II or block AT₁ receptors also prevent decreased responsiveness of the AT₁ receptor in this model.

Key Words: angiotensin • kinins • ramipril • losartan • receptors

	Introduction

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The cardioprotective effect of ACE inhibitors was originally thought to be nearly exclusively the result of inhibition of the conversion of angiotensin (Ang) I to Ang II. Other enzymes, however, are also capable of converting Ang I to Ang II, the most important of these being chymase.^1,2 Indeed, in the heart and vasculature, chymase is an important mechanism for the conversion of Ang I to Ang II.^1,2 More recently, inhibition of kinin metabolism by ACE inhibitors has also been shown to have important cardioprotective effects.³ Increasing kinin levels results in an increase in nitric oxide and vasodilatory prostaglandins, both of which have numerous actions that counter the effects of vasoconstrictor–growth-promoting substances and stimuli.³ These effects include vasodilatation, attenuation of cardiac and vascular growth, antiatherogenic and antithrombotic effects, and improved myocardial metabolic efficiency.³ Their cardioprotective effects appear to be both direct and indirect. The importance of the cardioprotective effects of bradykinin were most elegantly demonstrated in bradykinin B₂ receptor–knockout mice, which were found to have hypertension and both left ventricular dilatation and dysfunction.⁴

A new class of medication, the Ang II type I (AT₁) receptor blocker, has been developed to better block the vasoconstrictor–growth-promoting effects of Ang II directly at the receptor level.⁵ The AT₁ receptor is responsible for most of the known biological effects of Ang II.⁵ The aortic banding pressure overload model of left ventricular hypertrophy in rats by Weinberg et al^6,7 suggests that in this setting, ACE inhibitors may have some advantages over AT₁ receptor blockers. The only clinical study comparing the 2 classes of drugs is the ELITE 2 study,⁸ which found a statistically insignificant trend in favor of the ACE inhibitor (12% reduction in mortality, P=0.16). Thus, the superiority of one class over the other still remains controversial and may depend on the setting in which it is studied. More studies comparing the cardioprotective effects of these 2 classes of medications would be helpful, particularly after the HOPE study,⁹ which demonstrated that the ACE inhibitor ramipril significantly reduced the mortality of patients with atherosclerosis.

In this study, we created right ventricular (RV) pressure overload by banding the pulmonary artery of rabbits and studied them 21 days later. Rabbits were untreated for control, or they received the ACE inhibitor ramipril with or without bradykinin (B₁ and B₂) receptor blockers or the Ang II AT₁ receptor blocker losartan. B₁ and B₂ receptor blockers were given because with inflammation, such as may occur in this model, B₁ receptors may be expressed and exert effects similar to those of B₂ receptors. Cardiac hypertrophy and myocardial contractility were assessed. We then evaluated the changes in Ang AT₁ and AT₂ receptors and in G protein subunit q and i1/2 expression and the effects of these changes on the integrity of the cardiac angiotensin II signaling pathway by using an isolated papillary muscle bioassay.

	Methods

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New Zealand White male rabbits (Charles River, St-Constant, Québec) weighing 1.95 kg were used. The protocols used in this study were approved by the Institutional Animal Research Ethics Committee, and all animals were treated and prepared in accordance with the guidelines of the "Canadian Council on Animal Care Regulations."

Creation of the Model and Therapeutic Interventions
RV heart failure was induced in 90 rabbits by pulmonary artery banding according to methods previously described by Alpert and Mulieri.¹⁰ Once the rabbits were sedated, a spiral model metal coil (inside diameter 2.8 to 3.2 mm; length 6.6 mm; 2.5 turns; 0.7-mm-diameter wire) was applied to the outside of the central end of the pulmonary artery.

The rabbits were separated into 5 groups: (1) sham-operated controls; (2) banded, no therapy; (3) banded, ramipril (Avantis Pharmaceuticals) 37.5 µg/kg IP 1 hour after surgery, then 1 mg · kg^-1 · d^-1 in the drinking water¹¹; (4) banded, with the same ramipril regimen, except that the kinin B₁ and B₂ receptor blockers Lys-[Leu 8]desArgBK at 1 mg/kg and HOE 140 at 1 mg/kg (Avantis Pharmaceutical), respectively, were also given by osmotic pump placed subcutaneously at the time of surgery³; and (5) banded, losartan 0.25 mg/kg IP 1 hour after surgery, then 50 mg · kg^-1 · d^-1 in the drinking water.¹¹

Experiments were conducted 21 days after surgery, after ramipril was stopped for 72 hours, the kinin receptor antagonists for 24 hours, and losartan for 48 hours to permit adequate washout of the medications before further studies.

Hemodynamic and Morphological Studies
Animals were anesthetized with halothane 0.5% to 1% and RV pressure measured by cannulating the jugular vein and advancing a 5F Millar catheter (Millar Instruments Inc) connected to a Gould 2400s recorder (Gould Inc Instruments Division) to the RV. The animals were then euthanized, and 1 or 2 RV papillary muscles were removed and mounted in an isolated bath. The heart was then separated into the left ventricular free wall, the septum, the RV free wall, and the atria before being weighed and rapidly frozen in liquid nitrogen for measurements of Ang II AT₁ and AT₂ receptor density and G protein subunit expression.

Papillary Muscle Studies
Papillary muscles were mounted in an isolated bath with Krebs-Henseleit solution at 29°C (in mmol/L: NaCl 118, KCl 4.7, MgSO₄ · 0.7H₂O 1.2, CaCl₂ · H₂O 1.25, KH₂PO₄ 0.18, NaHCO₃ 24, glucose 5, and albumin 6.01x10^-4) and bubbled with 95% O₂/5% CO₂. The base of the muscle was held by a Lucite clamp, and the other end was tied to a lever with an electromagnetic feedback system previously described¹² to allow control of force, length, and velocity. Only muscles with a cross section <1.2 mm² were accepted.

The muscles were stimulated at 6 stimuli/min and stabilized at L_max for 15 minutes. Isometric, isotonic, and unloaded (V_max) contractions were recorded as previously described.¹²

A cardiac inotropic concentration-response relationship was performed with Ang II (Sigma Chemical Co) by increasing doses from 1x10^-10 to 1x10^-5 mol/L. Then, to assess maximum contractile capacity, extracellular calcium concentration was increased to 10 mmol/L. At each concentration, isometric, isotonic, and unloaded muscle contractions were recorded.

An additional 6 papillary muscles from rabbits with pulmonary artery banding but no treatment had a phenylephrine concentration-response relationship (10^-10 to 10^-5 mol/L) done, in the presence of propranolol 10 µmol/L, to assess responsiveness of phospholipase C to stimulation by another receptor system.

Ang II AT₁ and AT₂ Receptor Binding Assays
[Sar¹, Ile⁸]Ang II (sarile) was iodinated by a solid-phase method, and the monoiodinated peptide was purified by high-performance liquid chromatography.¹³ Radioligand binding assays were conducted as previously described.¹³ Equilibrium binding constants are reported as dissociation constant (K_d), and receptor concentrations are expressed as fmol/mg protein.

Immunoblot Analysis of G Protein Subunits
Cardiac membranes were isolated as described.¹³ Equal amounts of membrane proteins (50 µg) were resolved on 10% acrylamide gels and analyzed by immunoblotting using the following polyclonal antibodies: anti-q W082-8 (1:1000) and anti-i1/2 SG2.5 (1:5000). Protein bands were quantified by densitometric analysis, and the area of each band was evaluated with NIH Image software.

Statistics
Values are expressed as mean±SEM. Quantitative data were compared between groups by 1-way ANOVA and adjusted for inequalities of variances with a Brown-Forsythe’s test. Student’s t test or, when appropriate, a Tukey or Bonferroni t test was used to compare individual differences between groups. Statistical significance was determined by a value of P<0.05.

	Results

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Pulmonary Artery Banding and Therapeutic Interventions
Survival
The survivals of the various pulmonary artery banded groups beyond the first 24 hours after operation were similar: untreated 94%, ramipril 83%, losartan 82%, and ramipril+kinin B₁ and B₂ receptor blockers 90%.

Hemodynamics and Measurements of Cardiac Hypertrophy
Heart rate was similar in all groups whether pulmonary artery banding had been performed or not (Table 1). RV systolic pressure and maximum rate of pressure rise (+dP/dt) and decline (-dP/dt) increased similarly in the pulmonary artery banded groups. RV end-diastolic pressure was unchanged.

View this table: [in this window] [in a new window]   Table 1. RV Hemodynamics

The ratios of RV to body weight and heart to body weight were significantly increased in all banded groups (Table 2), although there was a tendency for this increase to be smaller in the treated groups.

View this table: [in this window] [in a new window]   Table 2. Morphological Characteristics of the Hearts

Isolated Papillary Muscle Studies
Papillary muscles from untreated banded rabbits demonstrated marked depression of all tension-generating and shortening indices and lost responsiveness to Ang II (Tables 3 and 4). Muscles responded normally to addition of calcium or phenylephrine 10^-5 mol/L, however, indicating that the signaling pathway from phospholipase C to the myofibril was still functional. With the addition of phenylephrine, tension increased from 17 to 51 mN/mm² and +dT/dt from 39 to 206 mN · mm^-2 · s^-1, both P<0.001.

View this table: [in this window] [in a new window]   Table 3. Isometric Papillary Muscle Contractile Characteristics

View this table: [in this window] [in a new window]   Table 4. Isotonic Papillary Muscle Contractile Characteristics

Ramipril best preserved cardiac contractility, particularly in isometric contractions in which contractility and responsiveness to Ang II were normal. The beneficial effects of ramipril during isotonic contraction were less marked, but inotropic responsiveness to Ang II was maintained. Blockade of the kinin B₁ and B₂ receptors significantly attenuated the cardioprotective effects of ramipril. This was most obvious during isometric contractions in which values were essentially identical to those of the untreated banded group. Interestingly, the use of the kinin receptor blockers with ramipril also resulted in significant prolongation of twitch duration. Treatment with the kinin receptor blockers did not modify the normal response to Ang II and extracellular calcium.

The Ang II AT₁ receptor blocker losartan had no obvious beneficial effect on contractile indices during baseline isometric or isotonic contractions. It did, however, preserve contractile responsiveness to Ang II. Interestingly, treatment with losartan resulted in the greatest prolongation of twitch duration (time to half tension decline from initiation of twitch of 671 ms).

Ang II AT₁ and AT₂ Receptor Binding Properties
AT₁ receptor density was significantly upregulated in the banded group compared with control animals (Table 5). Treatment with ramipril completely prevented this upregulation of the AT₁ receptor, whereas the combined administration of kinin receptor antagonists and ramipril only partially prevented the increased expression of the receptor (not significantly different from the banded group). Losartan also completely blocked the upregulation of AT₁ receptors observed after pulmonary artery banding. No significant change in the affinity of losartan for the AT₁ receptor was observed between the various experimental groups (Table 5). We also measured the expression of the AT₂ receptor subtype in these membrane preparations. The AT₂ receptor density was very low and represented <5% of the total ¹²⁵I-labeled sarile binding activity. No detectable change in the abundance of AT₂ receptors was observed between control rabbits or the various pulmonary artery banded rabbit groups (data not shown).

View this table: [in this window] [in a new window]   Table 5. AT1Receptor Binding Properties

Analysis of G Protein Subunit Expression
Pulmonary artery banding significantly increased the expression of q and i1/2 subunits (Figure). Treatment with ramipril completely reversed the increased expression of G_i1/2 proteins but had no significant effect on the expression of G_q. Interestingly, coadministration of kinin B₁/B₂ receptor antagonists with ramipril restored the high-level expression of G_i1/2 subunits. In contrast to ramipril, treatment with losartan failed to prevent the upregulation of G_i1/2 expression in the RV of banded rabbits.

View larger version (31K): [in this window] [in a new window]   Expression levels of Gq and Gi1/2 in RV. Cell membranes were purified from RVs of indicated experimental groups. Equal amounts of proteins were resolved by SDS-gel electrophoresis and transferred to nitrocellulose membranes. Membranes were then probed with specific anti-q (A) or anti-i1/2 (B) antibody and proteins were visualized by chemiluminescence. Amount of protein was quantified by densitometric analysis. Results are mean±SEM of 5 rabbits and are representative of 2 independent evaluations. *P<0.05 vs control group. aP<0.05 vs pulmonary artery banded group. bP<0.05 vs ramipril-treated group.

	Discussion

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This study demonstrates that pressure overload of the RV in the rabbit results in marked RV hypertrophy and depression of myocardial contractility. It also results in the nearly total loss of responsiveness to the inotropic effects of Ang II by a mechanism occurring downstream of the AT₁ receptor, despite an increase of AT₁ receptor density and G protein q and i1/2 subunit expression. Of the 2 therapeutic interventions evaluated, the one that best preserved cardiac contractility and best normalized AT₁ receptor density and G protein expression was the ACE inhibitor ramipril. This difference compared with the AT₁ receptor blocker losartan appeared to be largely due to its effect on kinins, because many of the beneficial effects of ramipril were eliminated by the simultaneous use of kinin receptor blockers. All therapeutic interventions preserved the contractile responsiveness to Ang II, suggesting that reduction in the production of Ang II or blockade of the AT₁ receptor prevents the functional uncoupling of the receptor to downstream signaling events.

The importance of specific enzyme systems in the conversion of Ang I to Ang II varies according to the species and the tissue being studied.^1,2 For this reason, in pilot studies (data not shown), we verified that in the rabbit, the conversion of Ang I to Ang II occurred at the cardiac level. We also determined that the major enzyme involved in that conversion was ACE, chymase being a less important enzyme for this conversion. The combined use of an ACE inhibitor and a chymase inhibitor resulted in much greater inhibition of the contractile effects of Ang I than either alone, however, indicating that when one pathway is inhibited, the other compensates by increasing the conversion rate of Ang I to Ang II.

Cardioprotective Effect of the ACE Inhibitor Ramipril Compared With the Ang II AT₁ Receptor Blocker Losartan: Importance of Kinins
RV pressure overload led to significant RV hypertrophy and papillary muscle dysfunction. Despite this marked reduction in contractility, no in vivo reduction in RV function was documented, perhaps because of the contribution of compensatory hypertrophy and in vivo activation of compensatory mechanisms such as neurohumoral activation.

The ACE inhibitor ramipril had the most important cardioprotective effect of the 3 therapeutic interventions evaluated. Although ramipril tended to reduce RV hypertrophy, this did not reach statistical significance, perhaps because of the fixed afterload of pulmonary artery banding as reflected by similar RV systolic pressures in all groups, or the relatively short follow-up period. The lack of effect of losartan on RV hypertrophy in this model was reported by Koide et al.¹⁴ Ramipril nearly completely prevented the decrease of contractility, however, this effect being more marked for isometric contractions than isotonic contractions. The more marked effect on isometric contractions may result from changes in expression of myosin isozymes to a slower, more energy-efficient one in this model.¹⁰ As a result, contraction would be slowed and prolonged, such that tension-generating abnormalities would be minimized while abnormalities in velocity of shortening would be maximized.

The protective effects of ramipril on cardiac contractility were significantly reduced by the simultaneous infusion of kinin B₁ and B₂ receptor blockers. The mechanisms remain speculative and probably multifactorial; however, this may result in part from nitric oxide–mediated improvement in cardiac metabolism.¹⁵ With left ventricular hypertrophy, subendocardial blood flow reserve is reduced¹⁶ such that improved cardiac metabolism and coronary flow would be expected to improve cardiac energetic balance and be cardioprotective. The effects of ramipril without its kinin component were comparable to those of losartan, suggesting that the major cardioprotective effect of ramipril in this model is due to its effect on kinins.

Functional Uncoupling of the Ang II AT₁ Receptor: Effects of ACE Inhibition and AT₁ Receptor Blockade
There was complete functional uncoupling of the AT₁ receptor from its contractile effects despite an increase in AT₁ receptor density. In previous studies,^17,18 AT₁ receptor density and affinity were evaluated in various models of ventricular dysfunction and overload, but little information exists as to the functional ability of these receptors. One study in the pacing-overdrive model of heart failure demonstrated a loss of the positive inotropic effects of Ang II, but they did not measure the integrity of the Ang II signaling pathway.¹⁹ In the present study, we found significant upregulation of AT₁ receptor expression despite functional uncoupling of the AT₁ receptor, indicating a functional defect beyond the receptor. Although the pattern of uncoupling of Ang II to its effector organ response differs somewhat from that of the ß-adrenergic system,²⁰ the end result is protection against chronic overactivation of an endogenous neurohumoral system. Whether protection of the integrity of the AT₁ signaling pathway with the various interventions that we tested is beneficial or potentially detrimental if the drug is discontinued, as occurs with ß-blockers, remains to be determined, but a risk of rebound overactivation clearly exists.

We did not find any modification in AT₂ receptor expression. This finding is consistent with previous studies in heart failure¹⁷ and cardiac hypertrophy,¹⁸ in which AT₂ receptor density has been found to be unchanged. The expression of the G protein subunit q, which is primarily responsible for coupling the AT₁ receptor to phospholipase C-ß and Ca²⁺ mobilization in cardiomyocytes,²¹ increased by 65% in banded rabbits, excluding the possibility that the loss of Ang II responsiveness was due to a decreased expression of G_q. Also, the contractile effects of phenylephrine, another potent agonist of the G_q–phospholipase C-ß²² signaling pathway, were preserved, if not exaggerated, indicating that the signaling pathway from phospholipase C to the myofibril was intact.

Interestingly, all pharmacological interventions tested reestablished the cardiac responsiveness to Ang II, suggesting that the functional uncoupling of the AT₁ receptor in the untreated banded group results from the local increase in Ang II levels and the chronic stimulation of the receptor. The most plausible explanation to reconcile all these observations is that the increased level of agonist in cardiac tissue uncouples the AT₁ receptor from the G_q protein, resulting in functional desensitization of the receptor.

The expression of G protein i subunits increases in heart failure and in various models of cardiac hypertrophy.^23–25 We found that expression of the G_i1/2 proteins was upregulated and that treatment with ramipril, but not with losartan or the combination of ramipril with kinin receptor blockers, completely prevented this increase. These results suggest that the increase in G protein i1/2 subunits may be causally linked to the contractile dysfunction observed in these animals but not related to the desensitization of the AT₁ receptor.

	Acknowledgments

 
This work was supported in part by grants from the Medical Research Council of Canada (MT-8566 and MT-14168). S. Pelletier has a studentship from the Heart and Stroke Foundation of Canada. Dr Meloche is a Scientist of the Medical Research Council of Canada.

Received January 25, 2001; revision received April 5, 2001; accepted April 24, 2001.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rouleau, J. L. Articles by Meloche, S. Search for Related Content PubMed PubMed Citation Articles by Rouleau, J. L. Articles by Meloche, S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB LOSARTAN POTASSIUM Related Collections Cardiovascular Pharmacology Receptor pharmacology ACE/Angiotension receptors