Effects of a DA2/[alpha] 2 Agonist and a [beta] 1-Blocker in Combination with an ACE Inhibitor on Adrenergic Activity and Left Ventricular Remodeling in an …

! " ! ## $ % ! $ &! ' ((( )())) Journal of Cardiovascular Pharmacology: September 1999 Volume 34 Issue 3 pp 321 326 Articles # $ $ % % ( *+ + ! , *+ & " % ,( *& 3, # ' ( " *( ,0 *& ,*0 ! " # *,1 ") , ! *( % *# % , & 22 % , . /% *& * 3, % Department of Cardiovascular Research, Instituto di Ricerche Farmacologiche "Mario Negri," Milan; and *Chiesi Farmaceutici SpA, Parma, Italy Received November 5, 1998; revision accepted February 18, 1999. Address correspondence and reprint requests to Dr. R. Latini at Dept. Cardiovascular Research, Instituto "Mario Negri," Via Eritrea, 62, 20157 Milan, Italy. E mail: latini@irfmn.mnegri.it Renin angiotensin aldosterone and sympathetic nervous systems overactivity play a major role in worsening the extent of heart failure. Attenuation of neurohumoral activation with angiotensin converting enzyme (ACE) inhibitors and β blockers has proven beneficial in congestive heart failure. Because ACE inhibition is a recommended treatment for heart failure, this study was designed to test the effects on neurohumoral activation, hemodynamics, and left ventricular (LV) volume of the combination of an ACE inhibitor (delapril) with a DA2 dopaminergic receptor/α2 adrenoceptor agonist (CHF 1024) or a β1 adrenoceptor antagonist (metoprolol) after a moderate to large myocardial infarction (MI) in rats. MI was induced by left coronary artery ligation in 134 rats, and six were not operated on. After 2 months, the animals with ECG evidence of MI were treated for 1 more month with CHF 1024, 0.33 mg/kg/day or with metoprolol (10 mg/kg/day), delivered through implanted osmotic minipumps, in addition to delapril (6 mg/kg/day) in the drinking water. Daily urinary excretion of norepinephrine (NE) and circulating concentration were measured. Hemodynamic variables were measured, and three dimensional morphometric analysis was done on the diastole arrested hearts to quantify infarct size and LV geometry. In conscious animals, delapril alone or with CHF 1024 or metropolol did not modify heart rate or systolic blood pressure. Both combination treatments, however, significantly reduced heart rate in anesthetized animals compared with the group receiving vehicle. Infarct size was not different between treatments, averaging 20 22% of LV volume. The threefold increase of LV chamber volume in infarcted rats was significantly attenuated by delapril alone or with CHF 1024 or metoprolol ( 37 to 44%, p < 0.05). Treatment with a combination of the ACEi and CHF 1024 tended to normalize the shape of the LV cavity. Urinary NE excretion was unaffected by delapril alone but was reduced by the addition of CHF 1024 or metoprolol. In conclusion, 1 month of treatment with doses of delapril having no hemodynamic effect, reduced LV volume in a model of chronic heart failure. When CHF 1024 or metoprolol was given with delapril, sympathetic activation decreased with no unwanted effects, such as excessive hypotension. Left ventricular remodeling after infarction involves progressive dilatation of the chamber, hypertrophy of the ) ( )* ) * ! " ! ## $ % ! $ &! ' ((( )())) surviving myocytes, rearrangement of the extracellular matrix, and neurohumoral activation. Drugs that influence this neurohumoral response, particularly angiotensin converting enzyme inhibitors (ACEi), have beneficial effects in the treatment of myocardial infarction (MI) and congestive heart failure (CHF) (1 4). We previously found that a 4 week treatment of rats with MI and left ventricular dysfunction (LVD) with a dopaminergic (DA2)/adrenergic (α2) agonist (CHF 1024) markedly reduced circulating and urinary norepinephrine (NE) and myocardial interstitial collagen (5). The same dose of CHF 1024 did not have substantial hemodynamic effects. In the same study, metoprolol alone markedly lowered heart rate (HR), with no effect on plasma or urinary NE, and reduced interstitial collagen content less than CHF 1024. None of these compounds influenced LV dilatation (5). Because (a) ACE inhibition is now recommended therapy in patients with CHF (6,7), and (b) CHF 1024 and β blockers act at different levels on cardiac and renal neurohumoral activation, it is of interest to assess the effect of a combined treatment by using these drugs with an ACEi in a rat model of LVD. The purpose of this study was therefore (a) to investigate the effects of a 4 week infusion of CHF 1024 on morphologic, hemodynamic, and neurohumoral variables in rats with LVD receiving an ACEi, and (b) to compare these effects with a 4 week treatment with an ACEi together with a β blocker or alone. Compared with ACEi alone, the combination of the ACEi with the DA2/α2 agonist CHF 1024 reduced adrenergic tone, partially reversed LV chamber enlargement, and normalized the LV apical shape, suggesting that CHF 1024 might provide additional benefit with ACE inhibition by reducing sympathetic hyperactivity in heart failure. ( 14) + 5 A total of 140 male Sprague Dawley rats (BW, 290 ± 3 g) was used for this study: 134 underwent left coronary artery ligation and six were left without surgery. The acute postoperative mortality at 48 h was 29%. Two months after surgery, the animals entered a 4 week treatment phase if they had at week 7 after surgery a pathologic Q wave on surface ECG at leads I, II, aVL, and V, and a respiratory rate >110/min, indicative of MI and heart failure, respectively. They were then randomly allocated to one of the following treatments: (a) delapril, 6 mg/kg/day (n = 12); (b) delapril, 6 mg/kg/day, and CHF 1024, 0.33 mg/kg/day (n = 13); (c) delapril, 6 mg/kg/day, and metoprolol, 10 mg/kg/day (n = 13); or (d) vehicle (0.05% ascorbic acid; n = 12). At week 4 of treatment, the rats were placed in individual metabolic cages to collect 24 h urine samples for measuring catecholamine excretion. On completion of the treatment phase, the animals were anesthetized with pentobarbital, 50 mg/kg, i.p. A microtip pressure transducer was inserted into the right carotid artery to record systolic and diastolic blood pressure (SBP, DBP), and advanced into the LV for measurement of LV pressures. The heart was then arrested in diastole for LV histomorphometry. Only rats with mean infarct size ≥12%, histologically determined in six to 10 serial cross sections as percentage of LV area, were analyzed. The numbers of animals analyzed in each experimental group were six (vehicle), six (delapril alone), eight (delapril and CHF 1024), seven (delapril and metoprolol), and six not operated on. " The rats, supplied by Charles River (Calco, Italy), were maintained on a 12:12 h light/dark cycle, with free access to tap water, and were fed standard chow. During ether anesthesia, the coronary artery was occluded as previously described (5) . In brief, after left thoracotomy, the heart was exposed, and a ligature placed around the left anterior descending coronary artery. Ampicillin was injected i.m. once (7.0 mg/kg within 1 h of surgery). Procedures involving animals and their care were conducted in conformity with the institutional guidelines that are in compliance with national (D.L. n. 116, G.U. suppl. 40, 18 Febbraio 1992, Circolare No. 8, G.U., 14 Luglio 1994) and international policies (EEC Council Directive 86/609, OJ L 358, 1, Dec. 12, 1987; Guide for the Care and Use of Laboratory Animals, U.S. National Research Council, 1996). % CHF 1024 (5,6 dihydroxy 2 methyl aminotetraline hydrochloride) and delapril hydrochloride were supplied by Chiesi Farmaceutici (Parma, Italy). Metoprolol tartrate was purchased from Sigma Chemicals (Milan, Italy). ) ( )* ) * * ! " ! ## $ % ! $ &! ' ((( )())) Delapril was dissolved in drinking water at the final concentration of 0.043 mg/ml. The delapril solutions were freshly prepared every third day, and their concentration adjusted to body weight every 15 days to obtain an average dose of 6 mg/kg/day. CHF 1024 and metoprolol were administered continuously for 4 weeks through osmotic minipumps. The pumps (model 2ML4, Alzet, Palo Alto, CA, U.S.A.), with a nominal delivery rate of 2.5 Ol/h, were implanted subcutaneously behind the neck under light ether anesthesia, followed by ampicillin injection. Concentrated solutions of CHF 1024 were dissolved in 10% ascorbic acid in distilled water at a final concentration of 40 m (mean delivery rate, 0.33 mg/kg/day). Metoprolol was dissolved in distilled water at the final concentration of 170 m to give mean delivery of 10 mg/kg/day. All solutions were stable for ≥1 month under these conditions. 4 " SBP and HR were measured by the tail cuff method (Letica LE 5002, Barcelona, Spain) in conscious rats 1 and 3 weeks after starting drug or vehicle infusion. Invasive hemodynamic measurements were made at the end of the study (3 months) under pentobarbital anesthesia (50 mg/kg, i.p.) with the minipumps still infusing drugs. A microtip pressure transducer (Millar SPC 320, Houston, TX, U.S.A.) connected to a recorder (Windograf; Gould Electronics, Valley View, OH, U.S.A.) was inserted into the right carotid artery to record SBP and DBP. The pressure transducer was then advanced into the LV to measure LV systolic (LVSP) and end diastolic (LVEDP) pressures, the first derivative of LV pressure over time (+dP/dt), and HR. 6 " Rats were housed individually in metabolic cages, and 24 h urine was collected on 1 ml HCl, 6N. Water intake was measured. Urine samples were weighed, and aliquots immediately frozen at 70°C until assayed. Urine catecholamines were extracted on Bondelut C18 columns (Varian, Harbor City, CA, U.S.A.), separated by high pressure liquid chromatography (HPLC; Apex II C18, 3 Om, 50 × 4.5 mm analytic column; Jones Chromatography, Mid Glamorgan, U.K.) and quantified with an electrochemical detector (Coulochem II; ESA, Chelmsford, MA, U.S.A.) (8). NE also was assayed in plasma as previously reported (5). ( " ! On completion of the hemodynamic measurements, the heart was arrested in diastole with a bolus injection of 3 4 ml 2.5 KCl into the femoral artery, removed from the chest, and rinsed in KCl (0.15 ) to maintain complete diastole. The heart was blotted and weighed, the LV chamber was filled with a cryostatic freeze medium (W. Pabish, Milan, Italy) through the ascending aorta at a hydrostatic pressure equivalent to the LVEDP measured in vivo. The heart was rapidly frozen in hexane cooled on dry ice. LV height (from base to apex) was measured with a gauge, and the heart stored at 70°C until morphometric analysis. Morphometric bidimensional and three dimensional analyses of the LV were done according to a method previously described, and ampliated for three dimensional evaluations (9). In brief, eight to 11 40 Om thick transverse and serial sections of LV stained with nitroblue tetrazolium were acquired by a B/W XC 77CE CCD video camera (Sony, Tokyo, Japan). The digital images were processed on an IBAS 2.0 (Kontron Zeiss, Munich, Germany) image analysis system by using software specifically developed (9). A single operator, blinded to treatment, interactively defined the boundaries of the interventricular septum, and the infarcted area on each section was semiautomatically identified as the area of unstained ventricular tissue. The software automatically calculated a set of geometric parameters including mean thickness and angular extension (9) for each component of the ventricular section defined as the chamber, septum, infarcted area, infarcted LV wall, and viable LV wall. The data obtained during the previous image analysis step were then elaborated to yield a three dimensional analysis of LV morphology. This involved an interpolation of the data between each single histologic section along the major ventricular axis to create a longitudinal profile of each ventricular component defined earlier. To ensure faithful reconstructions of profiles and to optimize the number of tissue sections needed to represent LV morphology correctly in those regions presenting great longitudinal variations, tissue sections were not sampled at equidistant points but at progressively increasing distances moving from apex to base. Base and apex morphometric values for each LV component were calculated according to their values in the closest sampled ) ( )* ) * + ! " ! ## $ % ! $ &! ' ((( )())) regions and to the base height measured on the whole heart. Along the ventricular major axis, the mean outer radius and circular extension of each component were fitted with third order polynomials to obtain the longitudinal profiles of the circular extension and mean radial amplitude of the component. The volumes of each component of the cavity and of the whole heart were then calculated by integrating the longitudinal profile of their mean radial amplitude along the ventricular major axis and according to their angular extension profile. Finally, the apex deformation after MI was analyzed by fitting the LV cavity radii from the apex to the transverse equatorial plane with the following potential curve: H = C0 × RC1, where H represents the distance of a given section from the apex; R, the inner radius of LV chamber for this section; and C0 and C1, the parameters of the fitting curve that better represents the inner apical shape of the ventricle. + Differences between the nonsurgical and vehicle treated groups were tested by Student's unpaired test (two tailed). Changes in continuous variables among the groups of infarcted animals were studied by one way analysis of variance, and the significance of the results was determined with Duncan's test (SPSS X; SPSS Inc., Chicago, IL, U.S.A.). A p value of <0.05 compared with the vehicle treated group was considered significant. Data are presented as mean ± SEM. & +7#1+ Early mortality after the coronary artery occlusion (CAO) averaged 29% of the operated on animals in the first 48 h. There was no further mortality. 6 ! ! #$ " Before starting experimental treatments, conscious control rats with MI (vehicle) had a higher respiratory rate and lower BP than did non operated on animals (p = 0.004). Mean respiratory rates were not different among MI rats, ranging from 117 to 139/min. HR was not modified by MI, but SBP was significantly lower in rats with MI receiving vehicle (Table 1). At the end of the study (i.e., 13 weeks after CAO), body weight was the same in all groups. Delapril alone did not modify either HR or BP (Table 1). However, in combination with CHF 1024 or metoprolol, it tended to lower BP and HR compared with baseline. Table 1 In anesthetized animals, dP/dtmax, an index of cardiac contractility, was reduced and LVEDP was increased in the rats with MI receiving the vehicle compared with non operated on animals (Table 1). All three treatment groups had significantly lower LVSP than the vehicle group. Metoprolol or CHF 1024 in combination with delapril reduced HR compared with the vehicle, whereas only the combination with metoprolol reduced dP/dt. Delapril alone or in combination did not reduce LVEDP to the level observed in non operated on rats. None of the therapies improved dP/dtmax. # ! % " Heart mass significantly increased in all operated on animals, independent of the treatment (Table 2). Whole body weight was not affected by either CAO or treatment, so the HW/BW ratio was significantly higher after CAO. LV geometry was affected by infarction, as reflected by increases in LV chamber radius at the equatorial level (+30%; p = 0.005), total LV height (+8%; p = 0.047), and by a shift of the LV chamber center ("chamber shift"; p < 0.001) in the vehicle infused MI group compared with non operated on animals (Table 2). LV chamber volume almost tripled in rats with CAO given vehicle (1,006 ± 156 mm3) compared with non operated on animals (350 ± 29 mm3). Higher LVEDP combined with chamber enlargement produced a striking ninefold elevation of diastolic equatorial wall stress in untreated rats with MI. ) ( )* ) * , ! " ! ## $ % ! $ &! ' ((( )())) Table 2 The infarct size, measured on six to 10 serial cross sections, did not differ in the treatment groups, and and its mean value ranged from 20 to 22% of the LV cross sectional area. Delapril alone, or with CHF 1024 or metoprolol, normalized LV volume, reducing the chamber equatorial radius by 11, 14, and 8%, respectively. Chamber volume was significantly reduced in all treatment groups by 44, 38, and 40% (Table 2). The pharmacologic treatments did not normalize LV chamber asymmetry to any extent. Alterations in LV chamber geometry after infarction were further investigated by fitting the cavity radii of the ventricle apical region (Fig. 1). The inner profile of the LV apical portion of the LV chamber was more flat after infarction, adopting a round bottom shape. Treatment with a combination of the ACEi and CHF 1024 tended to normalize the apical shape of the LV cavity, whereas delapril alone or in combination with metoprolol did not significantly change the apical shape (Fig. 1). Fig. 1 7 " ' Because increased sympathetic activation is one of the mechanisms involved in the progression of LV dysfunction to CHF, urinary excretion of NE was measured during treatment. This is an estimate of daily NE spillover in the conscious, unrestrained animal. Figure 2 shows NE excretion over 24 h, measured at treatment. Animals with MI receiving the vehicle excreted NE similarly to non operated on rats (1.64 ± 0.16 vs. 1.71 ± 0.38 Og/24 h; p = NS). Delapril alone did not alter urinary NE excretion (1.80 ± 0.47 Og/24 h). However, when the ACEi was given with either CHF 1024 or metoprolol, the daily urinary excretion of NE was reduced by 40 and 44% with respect to the vehicle group (p = 0.07 by one way ANOVA; Fig. 2). These changes could not possibly be explained by changes in water intake or urine volume, because these variables were not influenced by treatment. Delapril alone or in combination with CHF 1024 (but not metoprolol) tended to reduce the plasma concentration of NE (data not shown). Fig. 2 + 7++ )6 In rats with 3 month old MIs treated for the last month with an ACEi with or without a β blocker or a DA2/α2 agonist, we found that (a) at a dose that did not show appreciable hemodynamic effects, the ACEi delapril alone reduced LV chamber dilation; (b) given together with delapril, CHF 1024 reduced daily urinary excretion of NE (and less markedly its plasma concentration), while preserving the volume reduction effect of delapril alone, and even improving it, as seen with LV apical shape; and (c) metoprolol given with delapril reduced the urinary ) ( )* ) * - ! " ! ## $ % ! $ &! ' ((( )())) excretion of NE but not its circulating level, limited LV chamber dilatation, but did not restore its apical profile. We previously showed that CHF 1024 reduced adrenergic overactivity and collagen deposition in a similar experimental model of LVD (5). CHF 1024 is the active metabolite of a new aminotetraline derivative effective on oral administration, with a clear affinity for prejunctional DA2 and α2 receptors (10,11). In this study, we wanted to compare the efficacy of metoprolol and CHF 1024 on top of ACE inhibition, a recommended treatment for heart failure. ACE inhibition is now background therapy in heart failure patients in some countries (6,7), but little is known about the effects of combined renin angiotensin and adrenergic system inhibition, experimentally or clinically. Because an excessive decrease in BP was the most feared consequence of the combined treatment, special attention was paid to dose finding for the three agents. As no data are available on delapril administration to the rat with heart failure after CAO, we chose a low dose to inhibit ACE, with minimal hemodynamic consequences. In a preliminary experiment, 6 mg/kg/day infused over 7 days reduced the BP increase induced by a bolus injection of 150 ng/kg BW of angiotensin I by 69% (data not shown). In this study, delapril given for 3 weeks at the same dose did not lower SBP in conscious rats compared with the group receiving vehicle (Table 1). Favorable effects of ACEi at a nonhemodynamic dose on post MI LV remodeling, as obtained in this report confirms experimental observations (12). The infusion rate of 0.33 mg/day CHF 1024 was chosen because this gave maximal reduction of systemic NE without hemodynamic changes (5). The metoprolol infusion rate of 10 mg/kg/day was the same as in this previous study. SBP decreased in conscious rats given the combined treatment for 3 weeks, but not significantly by no more than 9 mm Hg on average compared with the vehicle group, in which SBP did not change (Table 1). HR in the conscious rat was not affected by treatment, although it tended to be lower in the metoprolol group. The CHF 1024 and metoprolol groups had a significantly lower HR than the vehicle group during anesthesia, but this might be due to an unexplored interaction with pentobarbital. LVEDP was increased, as expected, in rats 3 months after CAO, with no differences between treatment groups. Peak dP/dt of the LV was decreased in infarcted rats, as expected, this being an indirect index of LV contractility. The significantly lower dP/dt with metoprolol can be attributed to the lower HR in the vehicle group (Table 1). In conclusion, hemodynamics were little or not affected by ACE inhibition with or without an agent reducing adrenergic activity. This suggests that the drugs were safe in this model at the selected doses. Treatment had major effects on LV volume and apical shape. Because the changes depend on infarct size, this was measured in six to 10 serial cross sections as the area of scar tissue over the total area of the LV wall, and the mean values for all four treatment groups were almost identical, ranging from 20 to 22% (Table 2). In this context, any difference in LV shape and volume can be more confidently attributed to drug effects. LV chamber volume in diastole of control rats with CAO was almost 3 times that of non operated on animals and almost halved in the delapril group. ACE inhibition has been shown to reduce LV dilation in animals (1,13,14) and humans (3,15). The effect observed here with delapril is impressive considering that active treatment was given for 1 month, starting 60 days after CAO. Although the scar in the rat can be considered stable 7 days after CAO, progressive dilation of the LV chamber due to the sustained high LV wall stress occurs in moderate to large MIs. Pfeffer et al. (2) reported that LV diastolic volume in noninfarcted rats was 0.47 ± 0.03 ml/kg at 2.5 mm Hg of distending pressure, and volumes between 2.5 and 3.0 ml/kg in hearts with moderate to large infarcts at 20 mm Hg of distending pressure, 106 days after CAO. In that study, LV volumes were measured by ex vivo infusion of saline in hearts arrested in diastole. In our study, hearts arrested in diastole were inflated with OTC compound to the LVEDP measured in vivo (Table 1), and LV volume was calculated by 3D evaluation from six to 10 serial sections with an image analyzer. The agreement in the increase of LV volumes over ≥3 months is acceptable, being almost fivefold in Pfeffer's study (2) and almost threefold in our study. Because one of the reported consequences of MI was a change in LV shape, from ellipsoid to the less favorable cylindric (16), we used a 3D image analysis software allowing a quick estimate of the shape of the apical region. It was assumed that a lower curvature would indicate a tendency toward a cylindric shape. In fact, the inner apex curvature was more marked in non infarcted than in infarcted rats treated with vehicle. Neither delapril alone nor delapril plus metoprolol appeared to affect the inner shape of the LV apex. Unexpectedly, the inner shape of the apex in the infarcted rats treated with the combination of delapril and CHF 1024 was similar to that of ) ( )* ) * . ! " ! ## $ % ! $ &! ' ((( )())) noninfarcted animals. Combined treatment with delapril and CHF 1024 reduced adrenergic tone, as revealed by decreases of urinary and circulating NE. Delapril alone did not affect urinary excretion of NE, but together with metoprolol, it reduced urinary but not plasma NE. These findings are essentially consistent with our previous report that CHF 1024 reduced urinary and circulating NE concentrations in rats with MI (5). Similarly, ibopamine alone or with an ACEi (17) , the DA2 dopaminergic receptor agonist bromocriptine (18), or the α2 selective adrenergic agonist clonidine (19) reduced the plasma NE concentration. Together with the inhibition of aldosterone secretion by the adrenal cortex (20), this should help reduce collagen deposition in the interstitium of the spared myocardium (5). Possible repercussions of a reduction of myocardial collagen on morphologic parameters, for instance, on the apex profile as observed here, remain to be investigated. In conclusion, delapril attenuated late LV dilatation, and the addition of metoprolol or CHF 1024 did not affect this; only the LV of rats also receiving CHF 1024 did not take a cylindric shape. It is difficult to explain this observation, which would have been missed if we had not made a 3D analysis of the LV, based on serial cross sections. On a more general basis, the association of an ACEi with DA2/α2 agonist effective in reducing circulating NE in heart failure appears to be beneficial, as long as doses not affecting hemodynamics are used. 8 This study was supported in part by Chiesi Farmaceutici (Parma, Italy) and grants from "Fondazione A. e A. Valenti" (F.F. and M.T.). S.M. is a fellow of the "Training and Mobility of Researchers" program from the EU. & - & 6 + 1. Pfeffer MA, Pfeffer JM, Steinberg C, Finn P. Survival after an experimental myocardial infarction: beneficial effects of long term therapy with captopril. 1985;72:406 12. 2. Pfeffer JM, Pfeffer MA, Fletcher PJ, Braunwald E. Progressive ventricular remodeling in rat with myocardial infarction. 1991;260:H1406 14. 3. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). 1987;316:1429 35. 4. 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