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Effects of selective dopaminergic receptor stimulation on ventricular remodeling after experimental myocardial infarction in rats
Journal of Cardiac Failure Vol. 3 No. 3 1997
Effects of Selective Dopaminergic Receptor Stimulation on Ventricular Remodeling After Experimental Myocardial Infarction in Rats A R D C. H. T E I S M A N , EGBERT
P h D , * D I R K J. V A N V E L D H U I S E N ,
SCHOLTENS,*
WOJCIECH
MASELBAS,
MD,'~
MD,*
W I E K H. V A N G I L S T , P h D * t
Groningen, The Netherlands
Abstract Background: The disappointing results of the nonselective dopaminergic agonist ibopamine in the treatment of heart failure may be caused by nonselective receptor stimulation. Therefore, a search for more selective dopaminergic agonists remains important. Z1046 is such a compound. Methods and Results: Forty-two normotensive rats with a myocardial infarction (MI) and 18 sham-operated rats were studied. Rats with MI were treated for 6 weeks with Z1046 (n = 12) or ibopamine (n = 12) or were not treated (n = 18). Sham-operated control rats were not treated (n = 18). Assessments during the trial included those of plasma catecholamine levels, cardiac function, and morphology. Z1046 significantly decreased heart rate and blood pressure in rats with MI. Ibopamine affected only blood pressure. Compared with control rats with MI (736 + 66 pg/mL), plasma norepinephrine was significantly lower both after Z1046 (508 + 44 pg/mL) and after ibopamine (561 _+ 28 pg/mL). Infarct size was significantly reduced both by Z1046 and by ibopamine (P < .05). Z1046, but not ibopamine, normalized baseline left ventricular pressure (P < .05, treated rats vs MI control rats). Conclusions: The new (relatively selective) dopaminergic agonist Z1046 appears to have a more pronounced effect in protection against remodeling than ibopamine; this results in preservation of cardiac function. The effects appear to be mediated by both a reduced sympathetic drive and an improved hemodynamic profile. Key words: dopaminergic agonist, Z1046, ibopamine, experimental myocardial infarction.
There is now compelling evidence that ventricular remodeling after myocardial infarction (MI) is related not only to hemodynamic but also to neurohumoral factors. Inhibition of the activated local and circulating angiotensin-converting enzyme has been shown to atten-
uate this remodeling process (1). Another potential target in modulating remodeling after MI is the reduction of sympathetic activation (2). In this respect dopaminergic agonists may provide an adequate therapeutic approach, as plasma catecholamines may be reduced by stimulation of inhibitory presynaptic D2-1ike receptors, and vasodilation may be induced by Dl-tike receptor activation on the smooth muscle (3). Previous experiments have shown that the nonselective orally active dopamine agonist ibopamine (which is rapidly hydrolyzed to the active metabolite epinine) has beneficial effects on remodeling and neurohormones in a rat model of MI (4). In humans, however, results were inconclusive. Positive results were reported in patients with mild to moderate heart failure (5,6). A recent survival study in patients
From the * Department of Clinical Pharmacology, University of Groningen, and ?Department of Cardiology/Thoraxcenrer, University Hospital Groningen, Groningen, The Netherlands. Supported by the Zambon Group, Milan, Italy. Manuscript received Jan. 31, i997; revised manuscript received April 25, 1997; revised manuscript accepted June 18, 1997. Reprint requests: A. C. H. Teisman, Department of Clinical Pharmacology, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands. 01997 Churchill Livingstone Inc.
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Journal of Cardiac Failure Vol. 3 No. 3 September 1997
with advanced heart failure (PRIME-2), however, was stopped because of an excess of deaths in the ibopaminetreated group (7). It should be emphasized that ibopamine not only acts as a dopamine receptor agonist, but at higher concentrations it also acts as an alpha- and beta-adrenergic receptor agonist (9-11). Particularly in severe heart failure, with a concomitant reduced metabolism and clearance, this nonselective receptor activation may occur. The dopaminergic concept of reducing sympathetic drive and afterload remains interesting in the treatment of heart failure, as currently used intervention strategies in heart failure are still not fully satisfactory (12), however, a search for a more selective, dopaminergic agonist remains important. Recently, a new dopamine agonist, with a receptor profile different from that of ibopamine, has been developed. This compound, Z1046 ((S)-6-[[6[[2-(2-methoxyphenoxy)ethyl] amino]propylamino]-5, 6,7,8-tetrahydro- 1,2-naphthalenediol] dihydrochloride), is more selective for D2-1ike receptors (13,14). Its affinity for this type of receptor is approximately 10 times higher than for the Dl-like receptors (13). Furthermore, Z1046 has no effect on beta-adrenergic receptors. At high dosages, Z1046 exerts alpha-2-agonistic and alpha1-antagonistic effects (13,14). For details on agonistic and antagonistic values of ibopamine and Z1046 see Table 1. Because of its different receptor profile, Z1046 may possibly be more effective than ibopamine in reducing neurohumoral activity and remodeling in severe heart failure. The main objective of this study was to compare treatment with the new dopaminergic agonist Z1046 with treatment with ibopamine with respect to effects on neurohumoral and hemodynamic parameters and remodeling, in a chronic rat model with MI.
Materials and Methods Design of the Study The study consisted of 60 normotensive male Wistar rats (240-315 g). In 42 rats a MI was induced by means
of ligation of the left anterior descending coronary artery, as described previously (15), and the jugular vein was cannulated according to Steffens (16). Eighteen rats were sham operated. After operation, rats were left to recover for 1 week on normal rat chow; thereafter, animals were treated for 6 weeks, via rat chow, with either Z1046 or ibopamine. Control rats with MI and sham-operated rats were on control food. All animals were housed individually, under standard conditions. Food uptake and body weight were registered during the trial. Before the operation, 1 week after MI previous to active drug treatment, and after 6 weeks of treatment, tailcuff registrations were made from blood pressures and heart rates. Before starting the medication, groups were balanced for MI-induced reduction in blood pressure. Hence, groups were also balanced for infarct size, as reduction in blood pressure is linearly correlated with infarct size, as shown by Pfeffer et al. (17) and Fletcher et al. (18). Thus, rats with MI were randomized to two treatment groups of 12 animals each and one untreated group of 18 animals. The shamoperated group consisted of 18 animals. This study was performed according to the guidelines of the Ethical Committee for Animal Experiments of the University of Groningen.
Surgical Procedures In short, rats were anesthetized with a mixture of (2:1) and 1-1.5% fluothane, intubated, and mechanically ventilated. During the operation rats were placed on a homeothermic blanket. A left-side thoracotomy was made, and the left anterior descending artery was ligated with a 6-0 silk suture, 1 to 2 mm dorsal from its origin. Then the thorax was closed, and the rats were extubated. Thereafter, the right jugular vein was cannulated with a silicon rubber tube (16). The cannula was attached to an L-shaped steel tubing and fixed to the head with dental cement and a screw. Cannulas were filled with 500 IU/mL heparinized, 60% polyvinylpyrolidone and sealed with a polyethylene cap. Shamoperated rats underwent identical surgery, but did not sustain a MI. N20/O2
Table 1. Receptor Profiles of the Dopamine Agonists Ibopamine and Z1046 Receptor Subtype Drlike D2-like Alpha-1 Alpha-2 Beta-1 Beta-2
Ibopamine (Epinine) (pDa)
Z1046 (pD2)
6.2 8.4 5.4 NT 5.9 5.1
6.8 9.8 pA2 = 6.6 6.4 < 4.5 < 4.5
Data on each receptor subtype are based on comparable protocols. NT, not tested. Agonistic effect is expressed as pD2; antagonistic activity is expressed as pA2. Data are from Ferlenga et al. (14) and Ferrini and Miragoli (11).
Drugs and Dosages Both ibopamine and Z1046 were provided by the Zambon Group, (Milan, Italy). The actual dosage of Z1046 (7.7 mg/kg/d) was based on previous experiments that showed a reduction of blood pressure in SHR rats in this dosage range (19). The actual ibopamine dosage (16.1 mg/kg/d), was based on previous experiments in this MI model (4). At Che start and end of the trial, drug content of the food was determined by means of highperformance liquid chromatography, and average daily drug dosages per gram body weight were calculated.
Dopaminergic Agonists in Rats With MI
Plasma Catecholamines Blood samples were collected between 9 and 10 a.m., from the right atrium, by means of the permanent jugular vein cannula. After MI, average values of two samples collected (3 days apart) before and two samples collected (3 days apart) 1 week after active drug treatment were calculated. Blood samples were temporarily stored in ethylenediaminetetraacetate tubes on ice; thereafter, red blood cells were spun down by cooled centrifugation (2000 rpm, 10 minutes, -4°C), and plasma was collected and stored at -80°C before further analyses. The permanent cannulas were flushed with a 1 mL physiologic salt solution once a week, additionally to blood sampling. Norepinephrine (NE) was extracted from 100 BL plasma by a fluid-fluid extraction method and plasma concentrations were determined using highperformance liquid chromatography with electrochemical detection (20).
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were measured by means of a computerized planimeter. Infarct size was expressed as the percentage scar length at the circumference of total left ventricular circumference. Infarct volume and left ventricular cavity volume were expressed as the infarct area (cavity area) of each transverse slice multiplied by the distance between the transverse slices.
Statistics Reported values are means + SEM. One-way analysis of variance for multiple comparisons according to Duncan was used to evaluate differences between the groups, and post hoc within-group analysis were performed with paired Student's t-tests for differences in plasma NE levels. Differences with a P value less than .05 were considered statistically significant.
Results
Hemodynamic Registrations
Animals
Mean blood pressure and heart rate were recorded by means of a computerized tall-cuff method under anesthesia. Animals were sedated with a mixture of N20/O2(2:1) and 1-1.5% fluothane for 5 minutes; then three registrations were made, each 1 minute apart.
Overall mortality of rats with MI before randomization to the treatment groups was 24%. Mortality during surgery was 13 %, and mortality within 3 days of surgery was 11%. One week after surgery 42 rats with MI were divided into three groups. Care was taken to balance these three groups, as described. Thus, groups comparable at baseline for plasma NE level (Fig. 1), heart rate, and blood pressure were obtained (Table 2). After 6 weeks, 10 of 12 (83%) rats survived after Z1046, 8 of 22 (67%) after
Isolated Heart Preparation After 6 weeks of drug treatment the rats were anesthetized with ether and heparinized. The hearts were excised and immediately arrested in ice-cold 0.9% NaC1 (_+ 4°C). Retrograde perfusion of the aorta was started with a modified Tyrode buffer according to the method of Langendorff. The buffer was led through a 1.2-gmpore-sized filter before reaching the heart. The temperature, measured in the aorta cannula tip, was kept between 38.0 and 38.5°C. Coronary flow was registered with a microprocessor, which was maintained at a constant perfusion pressure of 60 mmHg. End-systolic pressure (left ventricular pressure [LVP]) was determined with a catheter inserted into the left ventricle, connected to a pressure transducer. Baseline LVR coronary flow, dP/dt+, dP/dt-, and heart rate were registered after 20 minutes of equilibration.
Fixation and Histology After perfusion, hearts were arrested in diastole in a 1M KC1 solution (4°C), and left ventricles were stored in Bouin's at 4°C. Hearts were dehydrated and embedded in paraffin. Transverse slices (10 gm) were cut off every millimeter, 4 to 7 mm from the apex. The sections were stained by a method coloring both collagen and protein, as described before (4). In all heart sections total left ventricular circumference, length of the scar at the circumference, left ventricular cavity area, and infarct area
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Fig. 1, Plasma norepinephrine level at baseline after myocardial infarction (MI) and after treatment. Data shown are means + SEM. #Significant by one-way analysis of variance versus sham-operated rats (P < .05). *Significant by one-way analysis of variance versus control rats with MI (P < .05). ^Significant by paired Student t-test versus baseline after MI (P < .05).
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Journal of Cardiac Failure Vol. 3 No. 3 September 1997
Table 2. In vivo Hemodynamic Profile at Baseline After Myocardial Infarction of All Experimental Groups (Before Treatment) Rats With Myocardial Infarction
Sham-operated Rats Control Treatment
Control Treatment
Ibopamine
Z1046
396 + 20
424 + 9
410 + 7
397 + 8
77 _+3
80 + 4
76 _+3
Heart rate (beats/min) NS Mean blood pressure (mm Hg) NS
79 + 4
Data are from tailcuff registration. NS, no significant differences between the groups at P < .05.
ibopamine, and 13 of 18 (72%) after control treatment, resulting in overall survival during the treatment trial of 74% after MI. All sham-operated rats survived. Neurohumoral Changes At baseline, that is, after surgery and before treatment, plasma NE was higher in all three MI groups when compared with sham-operated rats. During the treatment period, plasma NE increased significantly in control rats with MI (Fig. 1). This increase was not found in sham-operated rats or in rats with MI treated with either Z1046 or ibopamine. After treatment, plasma NE levels were significantly lower in Z1046treated (508 _+44 pg/mL) and ibopamine treated (561 + 28 pg/mL) rats, when compared with control animals with MI (736 + 66 pg/mL). In all rats with MI, however, plasma NE was significantly higher than in sham-operated rats (339 + 20 pg/mL). Hemodynamics Compared with control rats with MI, both heart rate and mean blood pressure were significantly lower after
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Z1046 treatment (Fig. 2). Ibopamine reduced only blood pressure (Fig. 2). Heart rate was significantly higher in control rats with MI than in sham-operated rats. Mean blood pressure was significantly reduced by ibopamine and Z1046, but not in control rats with MI. Isolated Heart Preparation Perfusion experiments showed a significantly higher LVP after Z1046, when compared with control rats with MI (Table 3). In this group, both LVP and dP/dt+ were comparable to those of sham-operated rats. After ibopamine and in control rats with MI, LVP was significantly lower than in sham-operated rats. In all rats with MI, coronary flow and dP/dt- were significantly lower than in sham-operated rats. Heart rates were not significantly different (Table 3). Histologic Parameters Left ventricular cavity volumes were significantly larger after MI than after sham operation (Fig. 3). Treatment with both ibopamine and Z1046 resulted in signifi-
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Dopaminergic Agonists in RatsWith MI
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Teisman et al.
203
Table 3. Baseline Characteristics of Langendorff Heart Perfusion in All Experimental Groups (After Treatment) Sham-operated Rats
Left ventricular pressure (mmHg) dP/dt+ (mm Hg/s) dP/dt- (mm Hg/s) Heart rate (beats/min) Coronary flow (mL/min/g heart weight)
Rats With Myocardial Infarction
Control Treatment
Control Treatment
Ibopamine
Z1046
90-+4 3179 _+200 2597 _+ 139 270 _+20 8.1 _+0.7
64_+5* 2396 _+ 145" 1482 +_ 164" 304 _+ 14 6.4_+0.3*
67_+8* 2303 _+383* 1399 + 202* 259 -+ 7 6.0_+0.4*
84_+4** 2825 _+ 184 1711 _+ 118" 264 -+ 11 6.2_+0.4*
Data are means -+ SEM. * P < .05 versus sham-operated rats. ** P < .05 versus control rats with myocardial infarction.
candy smaller cavity volumes compared with control rats with MI. Volumes of infarcted tissue were not significantly different between control rats with MI (101 + 7 mm 3) and ibopamine-treated (91 + 7 mm 3) or Z1046treated (94 + 9 mm 3) animals. Infarct size, however, was significantly smaller after both Z1046 (30.7 + 1.0%) and ibopamine (34.2 + 2.4) treatment, when compared with control rats with MI (39.7 _+ 1.7%) (Fig. 3). Heart weights (corrected for body weight) were not significantly different between the rats with MI, but were significantly higher than those of sham-operated rats (Table 4).
Discussion The main finding of this study is that the new (relative selective) dopaminergic agonist Z1046 exerts beneficial effects on ventricular remodeling after experimental MI in rats. The effects on remodeling were comparable to those of ibopamine. After Z1046, however, the reduction in left ventricular cavity dilation and the concomitant
decrease in infarct size were accompanied by preservation of left ventricular function. This preservation of left ventricular function was found only after treatment with the primarily D2-selective agonist Z1046, but not after ibopamine treatment. In a previous experiment from our laboratory, in which treatment was started immediately after MI, ibopamine was found to favorably affect ventricular remodeling after MI (4). In that study, it was hypothesized that both a reduction in sympathetic drive and an improvement of hemodynamic status could contribute to the observed favorable effect on remodeling of the myocardium. In this study, Z1046 showed a more pronounced effect on remodeling than ibopamine. Protocol differences may account for these different results. Although treatment was started in the subacute phase after MI, Z1046 markedly reduced plasma NE levels. This reduction in plasma NE levels may be explained by the inhibitory effect of D2-1ike receptors on the release of NE from the sympathetic nerve endings, as shown in
45 •
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Fig. 3. Infarct size and left ventricular (L.V.) cavity volume (after treatment). Data shown are means + SEM. #Significant by one-way analysis of variance versus sham-operated rats (P < .05). *Significant by one-way analysis of variance versus control rats with myocardial infarction (MI control) (P < .05).
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204
Journal of Cardiac Failure Vol. 3 No. 3 September 1997 Table 4. Left Ventricular Weight-to-Body Weight Ratios and Left and Right Ventricular Weights of the Experimental Groups (After Treatment) Sham-operated Rats
Left ventricular weight (g) Right ventricular weight (g) Left ventricular weight-to-bodyweight ratio (mg/g)
Rats With MyocardialInfarction
Control Treatment
Control Treatment
1.20+0.04 0.34 _+0.01 3.0 + 0.1
1.67_+0.07" 0.42 _+0.02* 4.5 _+0.2*
Ibopamine 1.76_+0.11" 0.45 _+0.03* 4.6 _+0.4*
Z 1046 1.73_+0.05" 0.44 + 0.01" 4.3 + 0.2*
Data are means + SEM. * P < .05 versus sham-operatedrats.
several species (21-23). The reduction of blood pressure in this study could be due to direct vasodilation D 1receptor stimulation, but it may also be secondary to the reduction in sympathetic drive (13,24). Furthermore, the alpha-i-antagonistic effect of Z1046 may play a role, although its importance is unclear. From this experiment no differentiation between these two factors can be made, as they are both influenced in the treated groups. Still, reduction in wall stress alone is probably not sufficient to affect remodeling beneficially, as treatment with direct-acting vasodilators demonstrated no effects on cavity volume (25). We did not actually assess infarct size at baseline; therefore, imbalance for infarct size before start of medication cannot be excluded. After MI but before randomization to treatment, however, the three groups with MI were comparable with respect hemodynamic and neurohumoral parameters. Also, volumes of infarcted tissue were comparable among the groups with MI after treatment. Therefore, it is not likely that rats in the active treated groups had smaller infarcts than control rats with MI at baseline. The effect on infarct size of Z1046, therefore, appears not to be related to salvation of myocytes, but more to reduced ventricular dilation. It is difficult to assess whether the present favorable effects of Z1046 will be observed in humans. Z1046 acts by receptor activation; therefore, eventual effects may be different between species because of different receptor profiles (24,26). Considering the receptor profile of Z1046, however, side effects due to nonselective receptor activation (which could occur especially in heart failure) will probably be less significant. A strict comparison between Z1046 and ibopamine in terms of importance of total receptor profiles is difficult from these data, as single dosages were used. This is a limitation of this study.
Conclusion The doparninergic agonist Z1046 has a beneficial influence on the process of ventricular remodeling after MI in
rats. The different receptor profile of Z1046 (ie, higher affinity for D2-1ike receptors and absence of beta-1-agonistic and alpha-l-antagonistic effects) is probably more useful in the treatment of heart failure, in comparison to the receptor profile of ibopamine; however, as plasma concentrations and half-lives of the drugs differed, a strict comparison is difficult to make from these data. Our results may be particularly useful in a discussion of the findings of the recently presented PRIME-2 trial, in which efficacy and safety of ibopamine, as an adjunct to angiotensin-converting enzyme inhibitors in patients with advanced heart failure, was investigated (7).
Acknowledgments We thank Katja Wolters-Keulemans and Alexander Horsch for their technical assistance. We are also indebted to Dr. Claudio Semeraro and Francesco Marchini (Zambon Group, Milan, Italy) for constructive remarks on the design of the protocol.
References 1. Pfeffer JM, Pfeffer MA, Braunwald E: Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res 1985;57:84-95 2. Rupp H, Dhalla KS, Dhalla NS: Mechanisms of cardiac cell damage due to catecholamines: significance of drugs regulating central sympathetic outflow. J Cardiovasc Pharmacol 1994;24:S16-24 3. Rajfer SI, Davis FR: Role of dopamine receptors and the utility of dopamine agonists in heart failure. Circulation 1990;82(suppl. 2):I97-102 4. Van Gilst WH, Van Veldhuisen D J, Hegeman H, Buikema H, Scholtens E, De Graeff PA, Lie KI: Effects of ibopamine on ventricular remodeling after experimental myocardial infarction: a comparison with captopril. J Cardiovasc Pharmacol 1994;24:171-4 5. Van Veldhuisen DJ, Man ink Veld AJ, Dunselman PHJM, Lok DJA, Dohmen HJM, Poortermans JC, Withagen AJAM, Pasteuning WH, Brouwer J, Lie KI, on behalf of the DIMT Study Group: Double-blind placebo-controlled
Dopaminergic Agonists in RatsWith MI
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study of ibopamine and digoxin in patients with mild to moderate heart failure: results of the Dutch Ibopamine Multicenter Trial (DIMT). J Am Coll Cardiol 1993; 22:1564-73 Szab6 B, Van Veldhuisen DJ, van der Burgh PH, Kruik J, Girbes ARJ, Lie KI: Clinical and autonomic effects of ibopamine as adjunct to angiotensin-converting enzyme inhibitors in chronic hear failure. J Cardiac Failure 1996; 2:185-192 Hampton JR, Van Veldhuisen D J, Kleber FX, Cowley AJ, Ardia A, Block P, Cortina A, Cserhalmi L, Follath F, Jensen G, Kayanakis J, Lie KI, Mancia G, Skene A, for the Prime-II Investigators: Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure. Lancet 1997;349:971-7 Marchetti GV: Pharmacological profile of ibopamine: a summary of experiments on anesthetized dogs. Cardiology 1990;77:22-9 Spencer C, Faulds D, Fitton A: Ibopamine, a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in congestive heart failure. Drugs Aging 1993;3:556-84 Henwood JM, Todd PA: Ibopamine: a preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy. Drugs 1988;36:11-31 Ferrini R, Miragoli G: Activity of ibopamine on some isolated organs. Arzneimittelforschung 1986;36(I):312-7 Frishman WH, Hotchkiss H: Selective and nonselective dopamine receptor agonists: an innovative approach to cardiovascular disease treatment. Am Heart J 1996;132: 861-70 Pocchiari F, Allievi L, Zanzottera D, Marchini F, Semeraro C: Z1046, a new potent and specific peripheral dopamine agonist. Can J Physiol Pharmacol 1994;72 (suppl. 1): 132 (abstr) Ferlenga R Zanzottera D, Marchini IF, Semeraro C: Peripheral dopaminergic activity of Z1046, a new mixed Dl-like/ D2-1ike receptor agonist. Pharmacol Res 1995;31 (suppl.):243 (abstr) Buikema H, Van Gilst WH, Van Veldhuisen DJ, De Smet BJGL, Scholtens E, Lie KI, Wesseling H: Endothelium dependant relaxation in two different models of chronic
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heart failure and the effect of ibopamine. Cardiovasc Res 1993;27:2118-24 Steffens AB: A method for frequent sampling of blond and continuous infusion of fluids in the rat without disturbing the animal. Physiol Behav 1969;4:833-6 Pfeffer MA, Pfeffer JM, Fishbein MC, Fletcher PJ, Spadaro J, Kloner RA, Braunwald E: Myocardial infarct size and ventricular function in rats. Circ Res 1979;44: 503-12 Fletcher PJ, Pfeffer JM, Pfeffer MA, Braunwald E: Left ventricular diastolic pressure volume relation in rats with healed myocardial infarction: effects on systolic function. Circ Res 1981;49:618-26 Pradella L, Brambilla N, Palazzolo L, Marchini F, Semeraro C: Z1046, a new dopaminergic agent, reduces blood pressure in conscious SHR rats and cynomolgus monkeys. Pharmacol Res 1995;31(suppl.):251 (abstr) Westerink BHC: Analysis of trace amounts of catecholamines and related compounds in brain tissue: a study near the detection limit of liquid chromatography with electrochemical detection. J Chromatogr 1983;6:2337-51 Langer SZ: Presynaptic regulation of the release of catecholamines. Pharmacol Rev 1981 ;32:337-62 Goldberg LI: Cardiovascular and renal actions of dopamine: potential clinical applications. Pharmacol Rev 1972;24:1-29 Missale C, Castelletti L, Memo M, Curruba MO, Spano PF: Identification and characterization of postsynaptic D 1and D2-dopamine receptors in the cardiovascular system. J Cardiovasc Pharmacol 1988; 11:643-50 Ferrini R, Miragoli G: Effect of ibopamine on diuresis and arterial blood pressure in anaesthetized rats and its interaction with dopaminergic and alpha- and beta-adrenergic antagonists. Arneimittelforschung 1986;36:323-6 Packer M: Vasodilator and inotropic drugs for the treatment of chronic heart failure: distinguishing hype from hope. J Am Coll Cardiol 1988; 12:1299-317 Bristow MR, Sandoval AB, Gilbert EM, Diesher T, Minobe W, Rasmussen R: Myocardial c~- and ~-adrenergic receptors in heart failure: is cardiac-derived norepinephrine the regulatory signal? Eur Heart J 1988;9(suppl. H): 35-40
Effects of Selective Dopaminergic Receptor Stimulation on Ventricular Remodeling After Experimental Myocardial Infarction in Rats A R D C. H. T E I S M A N , EGBERT
P h D , * D I R K J. V A N V E L D H U I S E N ,
SCHOLTENS,*
WOJCIECH
MASELBAS,
MD,'~
MD,*
W I E K H. V A N G I L S T , P h D * t
Groningen, The Netherlands
Abstract Background: The disappointing results of the nonselective dopaminergic agonist ibopamine in the treatment of heart failure may be caused by nonselective receptor stimulation. Therefore, a search for more selective dopaminergic agonists remains important. Z1046 is such a compound. Methods and Results: Forty-two normotensive rats with a myocardial infarction (MI) and 18 sham-operated rats were studied. Rats with MI were treated for 6 weeks with Z1046 (n = 12) or ibopamine (n = 12) or were not treated (n = 18). Sham-operated control rats were not treated (n = 18). Assessments during the trial included those of plasma catecholamine levels, cardiac function, and morphology. Z1046 significantly decreased heart rate and blood pressure in rats with MI. Ibopamine affected only blood pressure. Compared with control rats with MI (736 + 66 pg/mL), plasma norepinephrine was significantly lower both after Z1046 (508 + 44 pg/mL) and after ibopamine (561 _+ 28 pg/mL). Infarct size was significantly reduced both by Z1046 and by ibopamine (P < .05). Z1046, but not ibopamine, normalized baseline left ventricular pressure (P < .05, treated rats vs MI control rats). Conclusions: The new (relatively selective) dopaminergic agonist Z1046 appears to have a more pronounced effect in protection against remodeling than ibopamine; this results in preservation of cardiac function. The effects appear to be mediated by both a reduced sympathetic drive and an improved hemodynamic profile. Key words: dopaminergic agonist, Z1046, ibopamine, experimental myocardial infarction.
There is now compelling evidence that ventricular remodeling after myocardial infarction (MI) is related not only to hemodynamic but also to neurohumoral factors. Inhibition of the activated local and circulating angiotensin-converting enzyme has been shown to atten-
uate this remodeling process (1). Another potential target in modulating remodeling after MI is the reduction of sympathetic activation (2). In this respect dopaminergic agonists may provide an adequate therapeutic approach, as plasma catecholamines may be reduced by stimulation of inhibitory presynaptic D2-1ike receptors, and vasodilation may be induced by Dl-tike receptor activation on the smooth muscle (3). Previous experiments have shown that the nonselective orally active dopamine agonist ibopamine (which is rapidly hydrolyzed to the active metabolite epinine) has beneficial effects on remodeling and neurohormones in a rat model of MI (4). In humans, however, results were inconclusive. Positive results were reported in patients with mild to moderate heart failure (5,6). A recent survival study in patients
From the * Department of Clinical Pharmacology, University of Groningen, and ?Department of Cardiology/Thoraxcenrer, University Hospital Groningen, Groningen, The Netherlands. Supported by the Zambon Group, Milan, Italy. Manuscript received Jan. 31, i997; revised manuscript received April 25, 1997; revised manuscript accepted June 18, 1997. Reprint requests: A. C. H. Teisman, Department of Clinical Pharmacology, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands. 01997 Churchill Livingstone Inc.
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Journal of Cardiac Failure Vol. 3 No. 3 September 1997
with advanced heart failure (PRIME-2), however, was stopped because of an excess of deaths in the ibopaminetreated group (7). It should be emphasized that ibopamine not only acts as a dopamine receptor agonist, but at higher concentrations it also acts as an alpha- and beta-adrenergic receptor agonist (9-11). Particularly in severe heart failure, with a concomitant reduced metabolism and clearance, this nonselective receptor activation may occur. The dopaminergic concept of reducing sympathetic drive and afterload remains interesting in the treatment of heart failure, as currently used intervention strategies in heart failure are still not fully satisfactory (12), however, a search for a more selective, dopaminergic agonist remains important. Recently, a new dopamine agonist, with a receptor profile different from that of ibopamine, has been developed. This compound, Z1046 ((S)-6-[[6[[2-(2-methoxyphenoxy)ethyl] amino]propylamino]-5, 6,7,8-tetrahydro- 1,2-naphthalenediol] dihydrochloride), is more selective for D2-1ike receptors (13,14). Its affinity for this type of receptor is approximately 10 times higher than for the Dl-like receptors (13). Furthermore, Z1046 has no effect on beta-adrenergic receptors. At high dosages, Z1046 exerts alpha-2-agonistic and alpha1-antagonistic effects (13,14). For details on agonistic and antagonistic values of ibopamine and Z1046 see Table 1. Because of its different receptor profile, Z1046 may possibly be more effective than ibopamine in reducing neurohumoral activity and remodeling in severe heart failure. The main objective of this study was to compare treatment with the new dopaminergic agonist Z1046 with treatment with ibopamine with respect to effects on neurohumoral and hemodynamic parameters and remodeling, in a chronic rat model with MI.
Materials and Methods Design of the Study The study consisted of 60 normotensive male Wistar rats (240-315 g). In 42 rats a MI was induced by means
of ligation of the left anterior descending coronary artery, as described previously (15), and the jugular vein was cannulated according to Steffens (16). Eighteen rats were sham operated. After operation, rats were left to recover for 1 week on normal rat chow; thereafter, animals were treated for 6 weeks, via rat chow, with either Z1046 or ibopamine. Control rats with MI and sham-operated rats were on control food. All animals were housed individually, under standard conditions. Food uptake and body weight were registered during the trial. Before the operation, 1 week after MI previous to active drug treatment, and after 6 weeks of treatment, tailcuff registrations were made from blood pressures and heart rates. Before starting the medication, groups were balanced for MI-induced reduction in blood pressure. Hence, groups were also balanced for infarct size, as reduction in blood pressure is linearly correlated with infarct size, as shown by Pfeffer et al. (17) and Fletcher et al. (18). Thus, rats with MI were randomized to two treatment groups of 12 animals each and one untreated group of 18 animals. The shamoperated group consisted of 18 animals. This study was performed according to the guidelines of the Ethical Committee for Animal Experiments of the University of Groningen.
Surgical Procedures In short, rats were anesthetized with a mixture of (2:1) and 1-1.5% fluothane, intubated, and mechanically ventilated. During the operation rats were placed on a homeothermic blanket. A left-side thoracotomy was made, and the left anterior descending artery was ligated with a 6-0 silk suture, 1 to 2 mm dorsal from its origin. Then the thorax was closed, and the rats were extubated. Thereafter, the right jugular vein was cannulated with a silicon rubber tube (16). The cannula was attached to an L-shaped steel tubing and fixed to the head with dental cement and a screw. Cannulas were filled with 500 IU/mL heparinized, 60% polyvinylpyrolidone and sealed with a polyethylene cap. Shamoperated rats underwent identical surgery, but did not sustain a MI. N20/O2
Table 1. Receptor Profiles of the Dopamine Agonists Ibopamine and Z1046 Receptor Subtype Drlike D2-like Alpha-1 Alpha-2 Beta-1 Beta-2
Ibopamine (Epinine) (pDa)
Z1046 (pD2)
6.2 8.4 5.4 NT 5.9 5.1
6.8 9.8 pA2 = 6.6 6.4 < 4.5 < 4.5
Data on each receptor subtype are based on comparable protocols. NT, not tested. Agonistic effect is expressed as pD2; antagonistic activity is expressed as pA2. Data are from Ferlenga et al. (14) and Ferrini and Miragoli (11).
Drugs and Dosages Both ibopamine and Z1046 were provided by the Zambon Group, (Milan, Italy). The actual dosage of Z1046 (7.7 mg/kg/d) was based on previous experiments that showed a reduction of blood pressure in SHR rats in this dosage range (19). The actual ibopamine dosage (16.1 mg/kg/d), was based on previous experiments in this MI model (4). At Che start and end of the trial, drug content of the food was determined by means of highperformance liquid chromatography, and average daily drug dosages per gram body weight were calculated.
Dopaminergic Agonists in Rats With MI
Plasma Catecholamines Blood samples were collected between 9 and 10 a.m., from the right atrium, by means of the permanent jugular vein cannula. After MI, average values of two samples collected (3 days apart) before and two samples collected (3 days apart) 1 week after active drug treatment were calculated. Blood samples were temporarily stored in ethylenediaminetetraacetate tubes on ice; thereafter, red blood cells were spun down by cooled centrifugation (2000 rpm, 10 minutes, -4°C), and plasma was collected and stored at -80°C before further analyses. The permanent cannulas were flushed with a 1 mL physiologic salt solution once a week, additionally to blood sampling. Norepinephrine (NE) was extracted from 100 BL plasma by a fluid-fluid extraction method and plasma concentrations were determined using highperformance liquid chromatography with electrochemical detection (20).
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were measured by means of a computerized planimeter. Infarct size was expressed as the percentage scar length at the circumference of total left ventricular circumference. Infarct volume and left ventricular cavity volume were expressed as the infarct area (cavity area) of each transverse slice multiplied by the distance between the transverse slices.
Statistics Reported values are means + SEM. One-way analysis of variance for multiple comparisons according to Duncan was used to evaluate differences between the groups, and post hoc within-group analysis were performed with paired Student's t-tests for differences in plasma NE levels. Differences with a P value less than .05 were considered statistically significant.
Results
Hemodynamic Registrations
Animals
Mean blood pressure and heart rate were recorded by means of a computerized tall-cuff method under anesthesia. Animals were sedated with a mixture of N20/O2(2:1) and 1-1.5% fluothane for 5 minutes; then three registrations were made, each 1 minute apart.
Overall mortality of rats with MI before randomization to the treatment groups was 24%. Mortality during surgery was 13 %, and mortality within 3 days of surgery was 11%. One week after surgery 42 rats with MI were divided into three groups. Care was taken to balance these three groups, as described. Thus, groups comparable at baseline for plasma NE level (Fig. 1), heart rate, and blood pressure were obtained (Table 2). After 6 weeks, 10 of 12 (83%) rats survived after Z1046, 8 of 22 (67%) after
Isolated Heart Preparation After 6 weeks of drug treatment the rats were anesthetized with ether and heparinized. The hearts were excised and immediately arrested in ice-cold 0.9% NaC1 (_+ 4°C). Retrograde perfusion of the aorta was started with a modified Tyrode buffer according to the method of Langendorff. The buffer was led through a 1.2-gmpore-sized filter before reaching the heart. The temperature, measured in the aorta cannula tip, was kept between 38.0 and 38.5°C. Coronary flow was registered with a microprocessor, which was maintained at a constant perfusion pressure of 60 mmHg. End-systolic pressure (left ventricular pressure [LVP]) was determined with a catheter inserted into the left ventricle, connected to a pressure transducer. Baseline LVR coronary flow, dP/dt+, dP/dt-, and heart rate were registered after 20 minutes of equilibration.
Fixation and Histology After perfusion, hearts were arrested in diastole in a 1M KC1 solution (4°C), and left ventricles were stored in Bouin's at 4°C. Hearts were dehydrated and embedded in paraffin. Transverse slices (10 gm) were cut off every millimeter, 4 to 7 mm from the apex. The sections were stained by a method coloring both collagen and protein, as described before (4). In all heart sections total left ventricular circumference, length of the scar at the circumference, left ventricular cavity area, and infarct area
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Fig. 1, Plasma norepinephrine level at baseline after myocardial infarction (MI) and after treatment. Data shown are means + SEM. #Significant by one-way analysis of variance versus sham-operated rats (P < .05). *Significant by one-way analysis of variance versus control rats with MI (P < .05). ^Significant by paired Student t-test versus baseline after MI (P < .05).
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Journal of Cardiac Failure Vol. 3 No. 3 September 1997
Table 2. In vivo Hemodynamic Profile at Baseline After Myocardial Infarction of All Experimental Groups (Before Treatment) Rats With Myocardial Infarction
Sham-operated Rats Control Treatment
Control Treatment
Ibopamine
Z1046
396 + 20
424 + 9
410 + 7
397 + 8
77 _+3
80 + 4
76 _+3
Heart rate (beats/min) NS Mean blood pressure (mm Hg) NS
79 + 4
Data are from tailcuff registration. NS, no significant differences between the groups at P < .05.
ibopamine, and 13 of 18 (72%) after control treatment, resulting in overall survival during the treatment trial of 74% after MI. All sham-operated rats survived. Neurohumoral Changes At baseline, that is, after surgery and before treatment, plasma NE was higher in all three MI groups when compared with sham-operated rats. During the treatment period, plasma NE increased significantly in control rats with MI (Fig. 1). This increase was not found in sham-operated rats or in rats with MI treated with either Z1046 or ibopamine. After treatment, plasma NE levels were significantly lower in Z1046treated (508 _+44 pg/mL) and ibopamine treated (561 + 28 pg/mL) rats, when compared with control animals with MI (736 + 66 pg/mL). In all rats with MI, however, plasma NE was significantly higher than in sham-operated rats (339 + 20 pg/mL). Hemodynamics Compared with control rats with MI, both heart rate and mean blood pressure were significantly lower after
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Z1046 treatment (Fig. 2). Ibopamine reduced only blood pressure (Fig. 2). Heart rate was significantly higher in control rats with MI than in sham-operated rats. Mean blood pressure was significantly reduced by ibopamine and Z1046, but not in control rats with MI. Isolated Heart Preparation Perfusion experiments showed a significantly higher LVP after Z1046, when compared with control rats with MI (Table 3). In this group, both LVP and dP/dt+ were comparable to those of sham-operated rats. After ibopamine and in control rats with MI, LVP was significantly lower than in sham-operated rats. In all rats with MI, coronary flow and dP/dt- were significantly lower than in sham-operated rats. Heart rates were not significantly different (Table 3). Histologic Parameters Left ventricular cavity volumes were significantly larger after MI than after sham operation (Fig. 3). Treatment with both ibopamine and Z1046 resulted in signifi-
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203
Table 3. Baseline Characteristics of Langendorff Heart Perfusion in All Experimental Groups (After Treatment) Sham-operated Rats
Left ventricular pressure (mmHg) dP/dt+ (mm Hg/s) dP/dt- (mm Hg/s) Heart rate (beats/min) Coronary flow (mL/min/g heart weight)
Rats With Myocardial Infarction
Control Treatment
Control Treatment
Ibopamine
Z1046
90-+4 3179 _+200 2597 _+ 139 270 _+20 8.1 _+0.7
64_+5* 2396 _+ 145" 1482 +_ 164" 304 _+ 14 6.4_+0.3*
67_+8* 2303 _+383* 1399 + 202* 259 -+ 7 6.0_+0.4*
84_+4** 2825 _+ 184 1711 _+ 118" 264 -+ 11 6.2_+0.4*
Data are means -+ SEM. * P < .05 versus sham-operated rats. ** P < .05 versus control rats with myocardial infarction.
candy smaller cavity volumes compared with control rats with MI. Volumes of infarcted tissue were not significantly different between control rats with MI (101 + 7 mm 3) and ibopamine-treated (91 + 7 mm 3) or Z1046treated (94 + 9 mm 3) animals. Infarct size, however, was significantly smaller after both Z1046 (30.7 + 1.0%) and ibopamine (34.2 + 2.4) treatment, when compared with control rats with MI (39.7 _+ 1.7%) (Fig. 3). Heart weights (corrected for body weight) were not significantly different between the rats with MI, but were significantly higher than those of sham-operated rats (Table 4).
Discussion The main finding of this study is that the new (relative selective) dopaminergic agonist Z1046 exerts beneficial effects on ventricular remodeling after experimental MI in rats. The effects on remodeling were comparable to those of ibopamine. After Z1046, however, the reduction in left ventricular cavity dilation and the concomitant
decrease in infarct size were accompanied by preservation of left ventricular function. This preservation of left ventricular function was found only after treatment with the primarily D2-selective agonist Z1046, but not after ibopamine treatment. In a previous experiment from our laboratory, in which treatment was started immediately after MI, ibopamine was found to favorably affect ventricular remodeling after MI (4). In that study, it was hypothesized that both a reduction in sympathetic drive and an improvement of hemodynamic status could contribute to the observed favorable effect on remodeling of the myocardium. In this study, Z1046 showed a more pronounced effect on remodeling than ibopamine. Protocol differences may account for these different results. Although treatment was started in the subacute phase after MI, Z1046 markedly reduced plasma NE levels. This reduction in plasma NE levels may be explained by the inhibitory effect of D2-1ike receptors on the release of NE from the sympathetic nerve endings, as shown in
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204
Journal of Cardiac Failure Vol. 3 No. 3 September 1997 Table 4. Left Ventricular Weight-to-Body Weight Ratios and Left and Right Ventricular Weights of the Experimental Groups (After Treatment) Sham-operated Rats
Left ventricular weight (g) Right ventricular weight (g) Left ventricular weight-to-bodyweight ratio (mg/g)
Rats With MyocardialInfarction
Control Treatment
Control Treatment
1.20+0.04 0.34 _+0.01 3.0 + 0.1
1.67_+0.07" 0.42 _+0.02* 4.5 _+0.2*
Ibopamine 1.76_+0.11" 0.45 _+0.03* 4.6 _+0.4*
Z 1046 1.73_+0.05" 0.44 + 0.01" 4.3 + 0.2*
Data are means + SEM. * P < .05 versus sham-operatedrats.
several species (21-23). The reduction of blood pressure in this study could be due to direct vasodilation D 1receptor stimulation, but it may also be secondary to the reduction in sympathetic drive (13,24). Furthermore, the alpha-i-antagonistic effect of Z1046 may play a role, although its importance is unclear. From this experiment no differentiation between these two factors can be made, as they are both influenced in the treated groups. Still, reduction in wall stress alone is probably not sufficient to affect remodeling beneficially, as treatment with direct-acting vasodilators demonstrated no effects on cavity volume (25). We did not actually assess infarct size at baseline; therefore, imbalance for infarct size before start of medication cannot be excluded. After MI but before randomization to treatment, however, the three groups with MI were comparable with respect hemodynamic and neurohumoral parameters. Also, volumes of infarcted tissue were comparable among the groups with MI after treatment. Therefore, it is not likely that rats in the active treated groups had smaller infarcts than control rats with MI at baseline. The effect on infarct size of Z1046, therefore, appears not to be related to salvation of myocytes, but more to reduced ventricular dilation. It is difficult to assess whether the present favorable effects of Z1046 will be observed in humans. Z1046 acts by receptor activation; therefore, eventual effects may be different between species because of different receptor profiles (24,26). Considering the receptor profile of Z1046, however, side effects due to nonselective receptor activation (which could occur especially in heart failure) will probably be less significant. A strict comparison between Z1046 and ibopamine in terms of importance of total receptor profiles is difficult from these data, as single dosages were used. This is a limitation of this study.
Conclusion The doparninergic agonist Z1046 has a beneficial influence on the process of ventricular remodeling after MI in
rats. The different receptor profile of Z1046 (ie, higher affinity for D2-1ike receptors and absence of beta-1-agonistic and alpha-l-antagonistic effects) is probably more useful in the treatment of heart failure, in comparison to the receptor profile of ibopamine; however, as plasma concentrations and half-lives of the drugs differed, a strict comparison is difficult to make from these data. Our results may be particularly useful in a discussion of the findings of the recently presented PRIME-2 trial, in which efficacy and safety of ibopamine, as an adjunct to angiotensin-converting enzyme inhibitors in patients with advanced heart failure, was investigated (7).
Acknowledgments We thank Katja Wolters-Keulemans and Alexander Horsch for their technical assistance. We are also indebted to Dr. Claudio Semeraro and Francesco Marchini (Zambon Group, Milan, Italy) for constructive remarks on the design of the protocol.
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