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Cardiovascular Research 1998 39(2):413-422; doi:10.1016/S0008-6363(98)00117-5
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Copyright © 1998, European Society of Cardiology

Combined effects of angiotensin converting enzyme inhibition and angiotensin II receptor antagonism in conscious pigs with congestive heart failure

You-Tang Shen*, R.T. Wiedmann, B.D. Greenland, J.J. Lynch and W. Grossman

Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA

* Corresponding author. Tel.: 001-215-652-2640; Fax: 001-215-652-4692.

Received 10 December 1997; accepted 4 March 1998


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: The goal of this study was to determine if the hemodynamic effects of the combined administration of an angiotensin converting enzyme (ACE) inhibitor and angiotensin II type 1 (AT1) receptor antagonist are greater than those produced by either of these agents administered individually during heart failure. Methods: Ten farm pigs were chronically instrumented with aortic, left atrial and right atrial catheters, a left ventricular (LV) pressure gauge, LV dimension crystals, coronary occluders, an ascending aortic flow probe and pacing leads. Heart failure was induced by serial myocardial infarctions followed by repeated rapid ventricular pacing. Results: Heart failure was manifested by significant (p<0.01) decreases in LV dP/dt (–38±5%, from 2943±107 mmHg/s) and cardiac output (–27±4%, from 4.1±0.2 l/min) and increases in left atrial pressure (+18±1 mmHg, from 4±1 mmHg) and total peripheral resistance (TPR)(+40±8%, from 23±2 mmHg/l/min). The effects of an ACE inhibitor (enalaprilat) and an AT1 receptor antagonist (L-158,809), administered in maximally effective doses, either individually or concomitantly, were examined on different days in conscious pigs with heart failure. There were no differences in any of the baseline hemodynamic measurements among the groups studied. Thirty minutes after administration, enalaprilat (4 mg/kg i.v.) increased (p<0.05) cardiac output by 8±2% and reduced (p<0.05) mean arterial pressure and TPR by 5±1 and 12±1%, respectively, while the changes in LV dP/dt (0±2%), LV fractional shortening (+4±3%) and heart rate (+1±1%) were not statistically significant. Similarly, L-158,809 (4 mg/kg, i.v.) increased cardiac output by 9±2% and reduced mean arterial pressure and TPR by 4±1 and 11±3%, respectively, while the changes in LV dP/dt (+3±3%), LV fractional shortening (+3±1%) and heart rate (0±1%) were not significant. However, enalaprilat (1 mg/kg, i.v.) and L-158,809 (1 mg/kg, i.v.), administered concomitantly, reduced TPR by 21±3%, an effect greater (p<0.05) than when either of these agents was administered individually at a dose of 4 mg/kg, i.v. The changes in mean arterial pressure (–9±2%), cardiac output (+15±4%) and LV fractional shortening (+11±3%) also tended to be greater with concomitant administration. In addition, in a sequential dosing protocol, when L-158,809 (1 mg/kg, i.v.) was administered 30 min after enalaprilat (1 mg/kg, i.v.), TPR was reduced by 20±4% compared to only a 6±3% reduction (p<0.05) when the enalaprilat was followed 30 min later by a second dose of enalaprilat (1 mg/kg, i.v.). The changes in mean arterial pressure and cardiac output for the combined treatment group also tended to be greater than those for the group given two sequential doses of enalaprilat. Conclusion: In conscious pigs with heart failure, the combined vasodilatory effects of an ACE inhibitor and AT1 receptor antagonist are greater than those produced when only one of these agents is administered, suggesting that independent mechanisms of ACE inhibition and AT1 receptor antagonism could be partly responsible for the improved vascular dynamics during heart failure.

KEYWORDS Cardiac function; Vascular resistance; Dose–response effects; Myocardial ischemia


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
One of the important hemodynamic abnormalities in congestive heart failure is a progressive inability of the left ventricle (LV) to provide sufficient blood for organ perfusion. As a consequence of LV dysfunction, neurohormonal pathways are activated in an attempt to maintain adequate perfusion pressure by causing vasoconstriction [1]. It is generally accepted that angiotensin converting enzyme (ACE) inhibitors effectively prevent an increase in peripheral vascular resistance by inhibiting the formation of angiotensin II, a potent vasoconstrictive hormone. However, recent studies suggest that angiotensin II can be generated via ACE-independent pathways, such as by the chymotrypsin-sensitive angiotensin II-generating enzyme [2–6]. On the other hand, in addition to attenuating the biosynthesis of angiotensin II, ACE inhibitors potentiate the activity of the kallikrein–kinin systems, leading to accumulation of endogenous bradykinin [7–9]. Increased levels of vascular bradykinin are thought to contribute vasodilatory support during heart failure [10–14], through the mediation of nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor [15, 16].

Accordingly, we hypothesized that the hemodynamic effects, particularly the vasodilatory action, of the combined administration of an angiotensin II receptor antagonist and an ACE inhibitor would be greater than the effects produced by either one of these agents administered individually during congestive heart failure. To test this hypothesis and to determine if the combined therapy has any detrimental hemodynamic effects in congestive heart failure, the cardiac and systemic dynamic effects of the ACE inhibitor, enalaprilat, and a selective angiotensin II type 1 (AT1) receptor antagonist, L-158,809 [17, 18], were examined in chronically instrumented, conscious pigs with stable advanced congestive heart failure. Heart failure was induced by serial myocardial infarctions followed by repeated rapid ventricular pacing [19]. After determining the individual dose–response effects of enalaprilat and L-158,809, two general experimental protocols were performed: (1) Enalaprilat and L-158,809 were administered individually or concomitantly at different doses and (2) in a sequential dosing protocol, enalaprilat was administered, followed 30 min later either by a dose of L-158,809 or by a second dose of enalaprilat. The unique aspect of these protocols was that the total doses administered in the combined treatment with enalaprilat and L-158,809 were less than or equal to the individually administered doses of either enalaprilat or L-158,809.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Implantation of instrumentation
Ten farm pigs of either sex and weighing 25–30 kg were sedated with ketamine hydrochloride (10 mg/kg, i.m.). After tracheal intubation, general anesthesia was maintained with isoflurane (1.5–2.0 vol% in oxygen). Using sterile surgical technique, a left thoracotomy was performed at the fifth intercostal space. Catheters made of Tygon tubing (Norton Performance Plastics, Akron, OH, USA) were implanted in the descending aorta and in both atria, to measure pressures, and in the right atrium, to administer drugs. A solid-state miniature pressure gauge (Konigsberg Instruments, Pasadena, CA, USA) was implanted in the LV chamber, to obtain LV pressure and the rate of change of LV pressure (LV dP/dt). A pacing lead (model 5069, Medtronic, Minneapolis, MN, USA) was attached to the right ventricular free wall, and stainless steel pacing leads were attached to the left atrial appendage. The left circumflex coronary artery was isolated, and two hydraulic occluders made of Tygon tubing were implanted proximally and distally to the first obtuse marginal branch. In nine pigs, a flow probe with a diameter of either 20 or 24 mm (Transonic Systems, Ithaca, NY, USA) was placed around the ascending aorta to measure cardiac output, and one pair of piezoelectric ultrasonic dimension crystals were implanted on opposing anterior and posterior endocardial regions of the left ventricle, to measure the short-axis internal diameter. Proper alignment of the endocardial crystals was achieved during surgical implantation by positioning the crystals to obtain a signal with the greatest amplitude and shortest transit time. The wires and catheters were externalized between the scapulae, the incision was closed in layers, and air was evacuated from the chest cavity. All of the surgical procedures and instrumentation implanted in this study were similar to those described in our previous studies [19–21]. The pigs used in this study were maintained in accordance with the Guide for the Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, the National Council [Department of Health and Human Services publication No (NIH) 85-23, revised 1985] and the studies were approved by the Merck Research Laboratories (West Point, PA, USA) Institutional Animal Care and Use Committee.

2.2 Experimental measurements
Hemodynamic recordings were made using a data tape recorder (Model RD-130TE, TEAC, Montebello, CA, USA) and a multiple-channel oscillograph (Model MT95K2, Astro-Med, West Warwick, RI, USA). Aortic and left atrial pressures were measured using strain gauge manometers (Statham Instruments, Oxnard, CA, USA), which were calibrated in vitro using a mercury manometer, connected to the fluid-filled catheters. The solid-state LV pressure gauge was cross-calibrated with aortic and left atrial pressure measurements. LV dP/dt was obtained by electronically differentiating the LV pressure signal. A triangular wave signal was substituted for the pressure signals, to directly calibrate the differentiator (Triton Technology, San Diego, CA, USA). Ascending aortic blood flow was measured using a volume flow meter (Model T208, Transonic Systems). Mean arterial pressure, mean left atrial pressure and mean aortic blood flow (cardiac output) were measured using an amplifier filter. Stroke volume was calculated as the quotient of cardiac output and heart rate. LV dimension was measured with an ultrasonic transit-time dimension gauge (Model 203, Triton Technology). Total peripheral resistance was calculated as the quotient of mean arterial pressure and cardiac output. LV short-axis end-diastolic dimension (EDD) was measured at the beginning of the upstroke of the LV dP/dt signal. LV end-systolic dimension (ESD) was measured at the time of minimum dP/dt. The percentage shortening of the LV internal diameter was calculated as (EDD–ESD)/EDD·100. The LV velocity of circumferential fiber shortening (Vcf) was calculated from the dimension measurements using the following formula: (EDD–ESD)/EDD/ejection time (s–1). Ejection time was measured as the interval between the maximum and minimum LV dP/dt. A cardiotachometer triggered by the LV pressure signal provided instantaneous and continuous records of heart rate.

2.3 Congestive heart failure model
After the pigs had fully recovered from the surgery, i.e., ten–fourteen days after surgery, heart failure was induced by two coronary artery occlusions and subsequent intermittent tachycardiac pacing [19]. Briefly, after post-surgical hemodynamic control monitoring, the left circumflex coronary artery was occluded distal to the origin of the first marginal branch, by inflating the distally implanted hydraulic occluder. Approximately 48 h after the first occlusion, the proximal circumflex coronary artery occluder was inflated. The right ventricle was then paced at a rate of 210–220 beats/min using a programmable external cardiac pacemaker (model EV4543, Pace Medical, Waltham, MA, USA) beginning one to four days (2.6±0.5 days), depending on the condition of the animal, after the second myocardial infarction. This pacing was continued for one week and then terminated for three days. This procedure was repeated for another one–two cycles, until hemodynamic parameters were stable. In addition to the hemodynamic changes, heart failure was also characterized by anorexia, peripheral and pulmonary edema, and reduced physical activity.

2.4 Experimental protocols
Baseline hemodynamic recordings were made before inducing heart failure. Experiments were performed after the pigs had achieved stable heart failure, i.e., during the second and third pacing cycles, while they were conscious and quietly restrained in a sling. Experimental protocols consisted of eight treatment regimens with the ACE inhibitor, enalaprilat, and/or the AT1 receptor antagonist, L-158,809, tested on different days. The treatment regimens were (1) vehicle (n=7); (2) 1 mg/kg enalaprilat (n=5); (3) 4 mg/kg enalaprilat (n=8); (4) 1 mg/kg L-158,809 (n=5); (5) 4 mg/kg L-158,809 (n=7); (6) 1 mg/kg enalaprilat and 1 mg/kg L-158,809, administered concomitantly (n=8); (7) 1 mg/kg enalaprilat followed 30 min later by 1 mg/kg L-158,809 (n=7) and (8) 1 mg/kg enalaprilat followed 30 min later by a second dose of 1 mg/kg enalaprilat (n=5). Hemodynamic measurements were continuously recorded before and for 90 min after intravenously injecting each of the agents or the vehicle during a 2-min period. Treatment dosages and timing in these eight treatment regimens were determined in pilot studies. Enalaprilat was dissolved in 0.9% saline, and L-158,809 was dissolved in saturated NaHCO3 and 0.9% saline (10:90, v/v), at a concentration of 2 mg/ml.

2.5 Data analysis
Data before and after development of heart failure were compared using Student's t-test for paired data. Comparisons between the groups were performed using Student's grouped t-test when only two groups were compared and analysis of variance when more than two groups were compared. Data between the baseline and multiple responses to treatment over time were performed using Student's t-test for paired data with a Bonferroni correction. All values were expressed as the mean±S.E. Statistical significance was accepted at the p<0.05 level.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Baseline hemodynamics before and after development of heart failure
Table 1 summarizes the baseline LV function and systemic vascular dynamics before and after heart failure in conscious pigs. Heart failure resulting from two cycles of tachycardiac pacing in the presence of myocardial injury was manifested by significant (p<0.01) decreases in LV dP/dt, LV fractional shortening, Vcf, stroke volume and cardiac output, by 38±5, 52±6, 49±5, 29±5 and 27±4% from their respective baseline values, i.e., before heart failure. Total peripheral resistance increased significantly (p<0.01), by 40±8% from baseline. LV end-diastolic (+30±6%) and LV end-systolic diameters (+51±9%), and mean left atrial pressure (+18±1 mmHg) were significantly (p<0.01) increased, while mean arterial pressure was unchanged and heart rate was slightly increased.


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  		Table 1 Baseline left ventricular function and systemic hemodynamics before (control) and after development of heart failure in conscious pigs

 
3.2 Effects of ACE inhibitor and AT1 receptor antagonist administered individually or concomitantly during heart failure
Fig. 1 shows the individual peak effects of the ACE inhibitor, enalaprilat, and the AT1 receptor antagonist, L-158,809, administered i.v. either individually, concomitantly or sequentially on mean arterial pressure, LV dP/dt, LV fractional shortening, cardiac output, total peripheral resistance and heart rate in conscious pigs with heart failure. Peak effects occurred approximately 15 min following drug administration. Enalaprilat and L-158,809, at doses of 1 or 4 mg/kg, each induced a small but significant decrease (p<0.05) in mean arterial pressure, an approximately 15% reduction (p<0.05) in total peripheral resistance and a moderate increase (p<0.05) in cardiac output, without inducing a significant change in LV dP/dt, LV fractional shortening or heart rate. However, enalaprilat (1 mg/kg, i.v.) and L-158,809 (1 mg/kg, i.v.) administered concomitantly or sequentially, i.e., a 1 mg/kg i.v. dose of enalaprilat followed 30 min later by a 1 mg/kg i.v. dose of L-158,809, elicited greater hemodynamic effects.


Figure 1
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  		Fig. 1 Peak effects of the ACE inhibitor enalaprilat and the AT1 receptor antagonist L-158,809 on mean arterial pressure (MAP), LV dP/dt, LV fractional shortening (FS), cardiac output (CO), total peripheral resistance (TPR) and heart rate (HR) 15 min after intravenous administration either individually, concomitantly or sequentially in conscious pigs with heart failure. Values are expressed as the percent change from baseline. Each of these agents when administered individually at 1 or 4 mg/kg induced similar (p<0.05) changes in MAP, CO and TPR, while LV dP/dt, FS and HR were slightly (p>0.05) affected. However, the combined treatments, either concomitantly or sequentially, had greater (p<0.05) effects than did the individual treatments.

 
The effects of enalaprilat at a dose of 4 mg/kg i.v., of L-158,809 at a dose of 4 mg/kg i.v., and of both agents administered concomitantly, each at a dose of 1 mg/kg i.v., on cardiac and systemic hemodynamics in conscious pigs with heart failure are shown in Table 2. There were no differences in any of the measurements among the groups before treatment. When administered concomitantly, enalaprilat and L-158,809, each at a dose of 1 mg/kg i.v., decreased mean arterial pressure and increased cardiac output more than when either enalaprilat or L-158,809 was administered individually at a dose of 4 mg/kg i.v. Also, the increase in LV fractional shortening and the decrease in left atrial pressure also tended to be greater following the combined treatment compared to the individual treatments, although these differences were not statistically significant. However, total peripheral resistance was reduced significantly (p<0.05) more 30 min after concomitant administration of the agents compared to when only enalaprilat or L-158,809 was administered. The 90 min time courses of the changes in mean arterial pressure, cardiac output, total peripheral resistance and heart rate after administering the agents individually or concomitantly are shown in Fig. 2.


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  		Table 2 Effects of the ACE inhibitor enalaprilat and the AT1 antagonist L-158,809, administered individually or concomitantly, in conscious pigs with congestive heart failure

 

Figure 2
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  		Fig. 2 Effects of the ACE inhibitor enalaprilat and the AT1 receptor antagonist L-158,809, administered on the mean arterial pressure, cardiac output, heart rate and total peripheral resistance in conscious pigs with heart failure for the 90 min period following individual or concomitant administration. Values are expressed as the percent change from baseline. Enalaprilat (4 mg/kg i.v.) and L-158,809 (4 mg/kg i.v.), when administered individually, each induced a similar increase in cardiac output and a decrease in total peripheral resistance without affecting the heart rate. These changes were enhanced when enalaprilat (1 mg/kg i.v.) and L-158,809 (1 mg/kg i.v.) were administered concomitantly.

 
Fig. 3 shows a comparison of the absolute values of LV dP/dt, mean arterial pressure, mean left atrial pressure and total peripheral resistance before heart failure and during heart failure both before and 30 min after individual or combined treatment with enalaprilat and L-158,809. Although the individual administrations of enalaprilat or L-158,809 reduced the total peripheral resistance, the absolute values were still significantly (p<0.05) elevated compared to values before heart failure. In contrast, there was no difference in total peripheral resistance between the group with heart failure that was treated with combined ACE inhibitor and AT1 receptor antagonist vs. the control group (i.e., before heart failure). That is, in this heart failure model, combined ACE inhibitor and AT1 receptor antagonist treatment normalized total peripheral resistance to pre-heart failure values.


Figure 3
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  		Fig. 3 LV dP/dt, mean left atrial pressure, mean arterial pressure and total peripheral resistance measured in conscious pigs before (n=9) and after (n=9) heart failure development, and 30 min after administering the ACE inhibitor enalaprilat at a dose of 4 mg/kg i.v. (n=8), the AT1 receptor antagonist L-158,809 at a dose of 4 mg/kg i.v. (n=7), and enalaprilat combined with L-158,809, each at a dose of 1 mg/kg i.v. (n=7), during heart failure. Note that the combined enalaprilat and L-158,809 treatment reduced the elevated total peripheral resistance closer to the pre-heart failure value than did either enalaprilat or L-158,809 when administered individually. *p<0.05 vs. before heart failure.

 
3.3 Effects of ACE inhibitor followed by AT1 receptor antagonist during heart failure
In a sequential dosing protocol, an initial 1 mg/kg i.v. dose of enalaprilat was followed 30 min later by a 1 mg/kg i.v. dose of either L-158,809 or a second dose of enalaprilat. Table 3 compares the effects of the sequential administration of enalaprilat and L-158,809 to that of two doses of enalaprilat. Fig. 4 shows the time course of the percent changes in mean arterial pressure, cardiac output, total peripheral resistance and heart rate during both protocols. In the presence of enalaprilat, there was a significantly greater (p<0.05) decrease in total peripheral resistance 15 and 30 min after administering L-158,809 compared to that found after administering a second dose of enalaprilat. Administering L-158,809 after enalaprilat also increased cardiac output more than did a second dose of enalaprilat, but the difference was only significant (p<0.05) 45 min after administering the initial dose of enalaprilat. The decrease in mean arterial pressure was slightly (p>0.05) enhanced by the dose of L-158,809 compared to the second dose of enalaprilat, while heart rate was unchanged in either protocol.


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  		Table 3 Effects of the ACE inhibitor enalaprilat followed 30 min later by the AT1 antagonist L-158,809 or additional enalaprilat in conscious pigs with heart failure

 

Figure 4
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  		Fig. 4 Effects of the AT1 receptor antagonist L-158,809 (1 mg/kg i.v.) or the ACE inhibitor enalaprilat (1 mg/kg, i.v.) when administered 30 min after an initial dose of enalaprilat (1 mg/kg i.v.) on mean arterial pressure, cardiac output, total peripheral resistance and heart rate in conscious pigs with heart failure (n=7). Values are expressed as the percentage change from baseline. Note that the addition of L-158,809 (1 mg/kg i.v.) increased cardiac output and decreased the mean arterial pressure and total peripheral resistance more than did the addition of a second dose of enalaprilat (1 mg/kg, i.v.). The arrow denotes the time of administration of the second agent in this protocol.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
We hypothesized that the combined administration of an ACE inhibitor and angiotensin II receptor antagonist would produce greater hemodynamic effects than either of these agents administered individually during congestive heart failure. To test this hypothesis, we used chronically instrumented, conscious pigs in which congestive heart failure had been induced by intermittent, rapid ventricular pacing in the presence of previous myocardial infarction. This unique model was recently developed in our laboratory [19]and has the following characteristics: (1) The etiology of heart failure is similar to that in humans, where it is commonly initiated from multiple myocardial infarcts caused by coronary artery disease, (2) once heart failure (i.e., severe LV contractile dysfunction) has developed, it is relatively stable, so multiple protocols performed on different days can be compared, (3) unlike the canine rapid pacing-induced heart failure model [22], LV dysfunction is associated with elevated peripheral vascular resistance and (4) the data are not influenced by recent surgical trauma and anesthesia, which can significantly affect neurohumoral systems [23–26]. The latter is particularly important in the present study, since the renin–angiotensin system interacts closely with the baroreflex and autonomic nervous systems [27–29].

We selected enalaprilat as the ACE inhibitor and L-158,809 as a potent and selective AT1 receptor antagonist [17, 18]. The results show that the ACE inhibitor enalaprilat and the AT1 receptor antagonist L-158,809 induced similar hemodynamic profiles in terms of potency and duration of action in this preparation. In addition, the hemodynamic effects of a 4 mg/kg dose of enalaprilat or L-158,809 were not significantly different from those observed with a 1 mg/kg dose of either of these two agents, suggesting that the maximal hemodynamic responses were elicited. Therefore, it is unlikely that increased doses of either agent in any of the protocols would have resulted in any increased or detrimental hemodynamic responses.

The results from two different experimental protocols, in which both the ACE inhibitor and the AT1 receptor antagonist were administered, support our hypothesis. First, the elevated vascular resistance in heart failure was reduced significantly more when the ACE inhibitor and AT1 receptor antagonist were administered concomitantly compared to when only one of these agents was administered, even though the doses of the ACE inhibitor and AT1 receptor antagonist were each 4 mg/kg when administered individually, compared to 1 mg/kg each in the combined treatment. Second, when the AT1 receptor antagonist (1 mg/kg) was administered 30 min after administering the ACE inhibitor (1 mg/kg) in the sequential dosing protocol, it clearly enhanced the vasodilatory response. In contrast, when a second dose of the ACE inhibitor (1 mg/kg) was administered instead of the AT1 receptor antagonist, to exclude the possibility that the additive effect was due to multiple dosing, the second dose of ACE inhibitor did not induce any additional change in vascular resistance, which also supports the results from the first set of experiments. These data are consistent with preliminary studies by Spinale et al. [30, 31]in which chronic treatment with the ACE inhibitor, benazepril, combined with the AT1 receptor antagonist, valsartan, reduced pulmonary and peripheral vascular resistance more than individual treatment in a porcine pacing-induced heart failure model.

Although the mechanism by which the combined treatment enhances the individual vasoactive effects of the ACE inhibitor and the AT1 receptor antagonist is not quite understood, one can speculate based on existing knowledge. It is known that a significant amount of angiotensin II can be formed despite ACE inhibition [4, 6]. Alternative ACE-independent pathways, such as the chymotrypsin-sensitive angiotensin II-generating enzyme, have been reported to be largely involved in angiotensin II formation [2–6]. Therefore, we would expect that using an AT1 receptor antagonist to block the angiotensin II pathway at a more distal level would result in additional vasodilation, even in the presence of ACE inhibition. Also, ACE interacts with the kininase-II of the kallikrein–kinin systems in such a way that inhibition of ACE potentiates the activity of these systems, leading to an accumulation of endogenous bradykinin [7–9]. It is believed that bradykinin causes vascular endothelium-dependent relaxation that is mediated by release of nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor [15, 16]. Because of these unique dual-actions of ACE, it is conceivable that ACE inhibitors would augment the vasodilatory effects of angiotensin II receptor antagonists. Our results support the existence of these independent pathways of the renin–angiotensin systems.

In the present study, we also observed that LV performance, as reflected by LV fractional shortening and the velocity of circumferential fiber shortening (Vcf), tended to be slightly enhanced in the combined treatment group compared to the individual treatment groups. However, this additive effect was most likely a consequence of LV unloading rather than an increase in LV contractile function, since the patterns of LV fractional shortening and Vcf were associated with changes in total peripheral resistance but not of myocardial isovolumic contractile indices, such as LV dP/dt. Spinale et al. [30, 31]have shown that chronic treatment with an ACE inhibitor and AT1 receptor antagonist enhances the velocity of shortening of LV myocytes, effectively normalizes excitation contraction coupling and improves LV systolic function more than treatment with either an ACE inhibitor or an AT1 receptor antagonist. In contrast, a recent preliminary study by Tanimura et al. [32]found that, in dogs with moderate heart failure induced by intracoronary microembolizations, treatment with an ACE inhibitor and AT1 receptor antagonist did not improve the LV ejection fraction beyond that produced by the ACE inhibitor alone.

Since the characteristics of the heart failure models, the severity of the heart failure induced and treatment protocols were quite different in each of these previous studies, it is difficult to reconcile the conflicting findings. Since previous studies have demonstrated that some vasodilatory agents, such as {alpha}1-adrenergic receptor antagonists and calcium channel blockers, fail to improve exercise tolerance and mortality in patients with congestive heart failure [10, 33], our results do not necessarily indicate long-term beneficial effects. However, it is possible that, unlike other vasodilator treatment strategies, the combined administration of an ACE inhibitor and an AT1 receptor antagonist might have greater long-term efficacy than that provided by either agent alone, since both ACE inhibitors and angiotensin II receptor antagonists have tissue growth-inhibiting properties via different pathways, i.e., the nitric oxide- and protein kinase C-mediated pathways, respectively [10]. In addition, angiotensin II interacts uniquely with the enhanced central gain of the cardiac sympathetic afferent reflex [34].

In summary, in conscious pigs with congestive heart failure induced by myocardial infarction and repeated tachycardiac stress, the acute, combined administration of an ACE inhibitor and an AT1 receptor antagonist had a greater vasodilatory effect than did either of these agents when administered individually, even when administered at a dose that was twice as great as that of the combined treatment. Neither the combined nor the individual treatments significantly affected myocardial contractility. Whether or not the combined treatment has long-term beneficial effects during the development of congestive heart failure requires further study.

Timre for primary review 21 days


   Acknowledgements
 
This study was presented at the American College of Cardiology 46th Annual Scientific Session, 1997.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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