Activation of the renin-angiotensin-aldosterone system (RAAS) after myocardial infarction (MI) has important hemodynamic and prognostic effects, as evidenced by observations that angiotensin-converting enzyme (ACE) inhibition improves cardiac performance and survival in patients with left ventricular (LV) dysfunction (1-5). The mechanisms by which ACE inhibitors exert these beneficial effects have not been precisely identified but could include, in addition to decreased production of angiotensin II (AII) increased bioavailability of bradykinin (BK) and vasodilatory prostaglandins (6-8).
The kidney is an important organ of AII, BK, and prostaglandins and plays a crucial role in salt and water homeostasis after MI (9-13). Although renal perfusion might be impaired, sodium and water balances are improved after ACE inhibition, even in mild, compensated heart failure, when the circulating RAAS is not activated (11,14,15). BK and prostaglandins may mediate some of these beneficial effects, as evidenced by the clinical deterioration of patients concomitantly exposed to cyclooxygenase inhibitors (7,16). With the development of specific renin inhibitors and nonpeptide antagonists of AII, more precise analysis of the individual components of the renin-angiotensin-aldosterone axis has become feasible, since these agents do not affect metabolism of BK and prostaglandins.
The purpose of the present investigation was twofold: (a) to compare the chronic effects of specific blockade of AII with ACE inhibition on renal function after MI, and (b) to determine whether any differences in these effects are due to the actions of BK and prostaglandins. To accomplish these objectives, we examined renal hemodynamics and salt handling in conscious rats with ischemic LV dysfunction chronically treated with the specific AII blocker losartan, or the ACE-inhibitor captopril. These studies were performed before and after acute sequential blockade of BK and prostaglandins.
METHODS
General
We performed studies in 59 male Sprague-Dawley rats weighing 175-275 g using techniques similar to those described previously (17-21). MI was produced by coronary artery ligation. The rats were anesthetized with a mixture of acepromazine (2 mg/kg), ketamine (50 mg/kg), and xylazine (5 mg/kg) given by intraperitoneal (i.p.) injection. A left thoracotomy was performed, the heart was expressed from the thorax, and a ligature was placed around the proximal left coronary artery. The heart was returned to the chest, and the thorax was closed. The rats were maintained on standard rat chow with water ad libitum. After 3 weeks, rats were anesthetized with methoxyflurane and a nine-lead ECG with six limb leads and three chest leads was performed. Using criteria described previously (19), we selected rats with evidence of large MI for study. The presence of Q waves (>1 mV) in the limb leads (I or a VL) and the sum of the R waves in the precordial leads (<10 mV) were used as criteria for a large MI. Rats with no ECG abnormalities constituted the sham-operated group. We previously showed that rats selected in this fashion have large MI averaging 48 ± 2% of the left ventricle (19,22). In addition, in infarcted rats, the size of the infarcts were determined visually postmortem at the conclusion of the studies.
Experimental protocol
Seven groups of rats were studied. There were 9 normal, 11 sham-operated, 8 captopril-treated sham-operated, 5 losartan-treated sham-operated, 8 untreated infarcted, 10 captopril-treated infarcted, and 8 losartan-treated infarcted rats. Sham-operated rats were rats that underwent the ligation but did not have MI on ECG and visual examination. Captopril or losartan treatment (2 g/L drinking water) was initiated 3 weeks after infarction, and the rats were studied after 3 weeks of treatment. The details of the procedure were described previously (19-21). The animals were anesthetized on the day before the study with methoxyflurane. A femoral artery and vein were cannulated with heparinized PE-50 tubing (0.58 mm ID). The urinary bladder was cannulated by transabdominal approach with flanged PE-90 tubing (0.86 mm ID). The proximal urethra was tied with silk sutures. All catheters were tunneled subcutaneously to exit the skin between the scapulas. After an overnight recovery period, the unrestrained rat was placed in a 25 Ă— 10 Ă— 10-cm3 box. On the day of the study, the fluid-filled arterial catheter was connected to a to a solid-state pressure transducer (Millar Instruments, Houston, TX, U.S.A.). Mean arterial pressure (MAP) was electronically derived from the phasic blood pressure (BP) signal (low and high cutoff frequencies were direct current (DC) and 100 Hz, respectively), as was heart rate (HR) with a biotachometer. Recordings were made on a physiologic recorder (model 2400, Gould Instrument, Cleveland, OH, U.S.A.).
Renal function studies
[3H]inulin (NET 086 L inulin-methoxy) and [14C]PAH (NEC 563- aminohyppuric acid) isotopes (DuPont, NEN Research Products, Boston, MA, U.S.A.) were used in all clearance studies. An intravenous (i.v.) loading dose of 40 μCi/kg body weight followed by infusion of 12 μCi/kg body weight/h of each isotope in a volume of 1.5 ml normal saline/h/100 g body weight was given (model 355, Sage Instruments infusion pump). After 1 h was allowed for equilibrium, four timed (10 min) urine samples were collected in preweighed plastic vials, averaged, and reported as urine flow (UF, ml/kg/min). Duplicate blood samples were obtained in capillary tubes at the midpoint of alternate collection periods, as were BP and HR measurements. After completion of baseline studies, a BK inhibitor (BKI, NPC 567 {D-Arg[Hyp3, D-Phe7]-BK}, Sigma Chemical, St. Louis, MO, U.S.A.) in normal saline was infused at 0.02 ng/kg body weight/min, in parallel with the isotope infusion (Sage Instruments infusion pump model 341). After 30-min equilibration, the hemodynamic and renal function studies were repeated. To document the efficacy of BK inhibition, a bolus of 200 μg BK (Peninsula Laboratories, Belmont, CA, U.S.A.) was given intraarterially before and at the end of the BKI infusion. We previously showed that this dose of BKI will block at least 50% of the decrease in MAP after BK injection as compared with baseline in untreated animals. The infusion of BKI was then discontinued, and the effects of BK and BKI were allowed to dissipate. After 20 min, prostaglandin synthesis was blocked with indomethacin (Merck, Sharp & Dohme) given as an intravenous bolus of 1 mg/kg body weight in normal saline. This sequential order was chosen because the long-lasting effects of indomethacin would preclude random administration of BKI and indomethacin in the same animal. After 40 min, the hemodynamic and renal function studies were repeated. An arterial blood sample was taken for determination of plasma sodium. The rat was then killed under methoxyflurane anesthesia with intravenous KCl. A necropsy study was performed.
Ten microliters urine and 20 μl serum were pipetted into vials containing 3.3 ml scintillation cocktail (Aquasol) and 1 ml distilled water. The counts per minute (cpm) were measured with a liquid scintillation counter (Beckman LS 1801). Glomerular filtration rate (GFR, ml/kg/min) and renal blood flow (RBF, ml/kg/min) were calculated using the standard formula [CI = (U Ă— V)/P], where U and P represent cpm of isotope ([3H]inulin for GFR and [14C]PAH for RBF) in urine and plasma, respectively. Renal vascular resistance (RVR) and filtration fraction (FF) were calculated as follows: RVR = (MAP/RBF), and FF = (GFR/RBF). Urine and plasma samples were kept refrigerated at -80°C for later analysis. For determination of urinary sodium excretion (UNa, mEq/L), samples of the four urine specimens obtained during the clearance studies were pooled, and electrolyte concentration was measured by flame photometric technique (Flame photometer no. 143, Inst. Laboratory, Lexington, MA, U.S.A.). Plasma sodium (PNa, mEq/L) was measured from the final blood sample by the same flame photometric technique. Fractional excretion of sodium (FENa,%) was calculated as follows: FENa = [(UNa/PNa)/(Uinulin/Pinulin)] Ă— 100.
Statistical analysis
Values are mean ± SD. The measured and generated parameters for each group were screened for normality of their distribution and the presence of outliers by the Wilk-Shapiro test in a commercially available standard statistical package for PC (23). If a variable was not normally distributed, a transformation was made with standard procedures (BMDP-2D). Values derived from the measured and generated parameters were treated as independent variables. Because a multivariate repeated measures analysis of variance (ANOVA, BMDP-4V) failed to show significant interactions between disease, treatment and intervention, two-way ANOVA (BMDP-7D) was used to evaluate the effects of heart failure or treatment with captopril or losartan. On selected parameters, an unpaired t test was used to analyze the effects of MI and treatment with captopril or losartan. Because measurements at baseline and after intervention with BKI and indomethacin were performed serially in the same animals, repeated-measures ANOVA (BDMP-2V) was used to determine the effects of these interventions in sham and infarcted rats. The same analysis was also performed to determine whether there was an effect of time in sham rats. Contrasts performed included BKI versus baseline, indomethacin versus baseline, and BKI versus indomethacin. Differences were significant at p < 0.05.
RESULTS
Baseline data
Baseline values are shown in Tables 1 and 2. The presence of large MI was documented by increased (p < 0.05) right ventricle (RV) weight in untreated infarcted rats as compared with sham-operated rats. However, there were no differences in body weight, left ventricle (LV) weight or LV/body weight ratio between sham-operated and infarcted rats. Treatment with captopril decreased (p < 0.05) LV weight 20% and LV/body weight ratio by 14%. Losartan decreased (p < 0.05) LV weight 14% and LV/body weight ratio by 19%. Neither treatment significantly altered RV weight in infarcted rats. Statistical analysis for the data in Tables 1 and 2 was performed with two-way ANOVA; disease and treatment were grouping factors. There were no significant interactions for any parameter between disease and treatment.
Hemodynamic and renal function indexes are shown in Tables 3 and 4. In untreated rats, MI increased (p < 0.05) FF 20% and did not change resting HR, MAP, UF, GFR, RBF, RVR, UNa, or FENa. Captopril treatment increased (p < 0.05) GFR 22% and RBF 34%, decreased (p < 0.05) MAP, 25%, UF 66%, RVR 42%, and FENa 75%, but did not change HR, UNa, or FF (p < 0.05). There was no specific interaction with respect to treatment with captopril for these parameters. Losartan treatment decreased (p < 0.05) MAP 27%, UF 52%, RVR 21%, and FENa 44% but did not change HR, GFR, RBF, UNa, or FF. Statistical analysis for the data in Tables 3 and 4 was performed with two-way ANOVA, with disease and treatment as grouping factors. There was no specific interaction between disease and losartan treatment for these parameters.
Intervention with BKI
The effects of the BKI are shown in Tables 5-7. In infarcted rats (Table 5), the BKI increased (p < 0.05) HR 4% and UNa 53%, decreased (p < 0.05) MAP 6% and GFR 19%, but did not change UF, RBF, RVR, FENa, or FF. In infarcted rats treated with captopril (Table 6), the BKI increased (p < 0.05) HR 4%, RVR 32%, UNa 43%, and FENa 28% and decreased (p < 0.05) GFR 22% and RBF 25% but did not significantly alter MAP, UF, or FF. In infarcted rats treated with losartan (Table 7), the BKI increased (p < 0.05) UNa 42% and FENa 60% but did not alter any other parameter.
Intervention with indomethacin
The effects of prostaglandin inhibition with indomethacin is shown in Tables 5-7. In infarcted rats (Table 5), indomethacin increased (p < 0.05) UNa 99% and decreased (p < 0.05) MAP 15% and UF 39% but did not alter HR, GFR, RBF, RVR, FENa, or FF. In infarcted rats treated with captopril (Table 6) prostaglandin inhibition with indomethacin increased (p < 0.05) HR 10%, UNa 86%, and FENa 112% and decreased (p < 0.05) MAP 9% and GFR 24% but did not change UF, RBF, RVR, or FF. In infarcted rats treated with losartan (Table 7), indomethacin increased (p < 0.05) UNa 79% and FENa 80% but did not significantly alter any other parameter. Because measurements at baseline and after BKI and prostaglandin inhibition were performed in the same animals at different timepoints, the statistical analysis for the data in Tables 5-7 was performed with repeated-measures ANOVA. This analysis resulted in significant differences in the studied parameters that might not have been achieved with Student's t test. Standard Student's t test is not valid for this type of experiments.
BKI versus indomethacin
Comparison of the effects of indomethacin with those of BKI in untreated infarcted rats (Table 5) showed a greater increase with indomethacin in UNa by 30% and in FF by 13% and a larger decrease in MAP by 10% and in UF by 26%. There were no differences in the other parameters. Comparison of the effects of indomethacin with those of BKI in infarcted rats treated with captopril (Table 6) showed a greater increase with indomethacin in HR by 6% and in UNa by 31% and a larger decrease in MAP by 7%. The effects on the other parameters were not different. Comparison of the effects of indomethacin with those of BKI in infarcted rats treated with losartan (Table 7) showed a greater increase with indomethacin in UNa by 27% but no appreciable differences in any other parameter.
To assess the effect of time on renal function parameters, we evaluated 9 normal rats infused with normal saline for 6 h. Again, repeated-measures ANOVA, similar to that used to compare the effects of BK and prostaglandin inhibitors on renal function, showed no changes in UF, GFR, RBF, RVR, FF, and FENa. However, over time, there was a 33% increase in UNa, most probably related to the increase in salt loading.
DISCUSSION
In experimental and clinical heart failure, the hemodynamic effects of ACE inhibitors are believed to be due to decreased formation of AII. However, ACE inhibitors, by virtue of their antagonism of kininase II, also potentiate the actions of BK, a peptide with potent vasodilating effects (8,24,25). Furthermore, ACE inhibition may enhance prostaglandin formation, either by amplification of the effects of BK and/or by accumulation of AI (7,8,26). Elucidation of the precise contribution of AII withdrawal to the hemodynamic effects of ACE inhibition has been advanced by the development of specific AII receptor antagonists, such as losartan, as well as by the synthesis of specific BK antagonists (20,25). The present investigation is the first to define the relative contributions of AII blockade versus potentiation of BK and prostaglandin to the chronic effects of ACE inhibition in a clinically relevant model of chronic MI.
Renal function after MI
Our results in the present study, the first of its kind in conscious, unrestrained rats, show that baseline renal function is minimally altered after MI. Although a close association is generally believed to exist between clinical stage of heart failure and magnitude of renal dysfunction, this correlation is probably true only late in the course of the disease (2,12,27). In advanced heart failure, there is a decrease in GFR, RBF, and sodium excretion, and an increase in RVR and FF (9,11). In patients and in animal models of compensated heart failure, there are minimal changes in basal renal function (1,3,4,5,11). Our data support this observation, since we showed that chronic MI had little effect on renal function other than to increase FF (Table 3). In rats with compensated heart failure due to ischemic LV dysfunction, other investigators have documented that early in the course of heart failure excretion of a saline load is impaired at a time when systemic and renal hemodynamics are well preserved (11). This alteration is proportional to the severity of heart failure and is mediated by the sympathetic system and the renin-angiotensin system (RAS) (9,10-12,14,15). Using the same model, we showed that chronic MI increases FF, RVR, and salt and water retention while decreasing GFR, RBF, and UF rate (21). However, these parameters were measured in anesthetized and ventilated rats, conditions that significantly alter hemodynamic parameters.
Renal function after MI: Effects of captopril
As have other ACE inhibitors, captopril has been shown to improve symptoms and survival in animal models and patients with heart failure. These effects are independent of the clinical stage or the etiology of the disease (1-4). The precise mechanisms of these beneficial effects are still unclear. Because the kidney plays a key role in circulatory and salt and water homeostasis, it is important to evaluate the contribution of the renal effects of chronic blockade of the RAS after MI. Recent studies of the coronary artery ligation rat model have documented the persistent and selective activation of the intrarenal RAS occurring when circulating neurohormones have returned to baseline (14,15). However, previous reports on the effects of ACE inhibitors on renal function after MI have shown conflicting results, probably reflecting the diverse populations studied, the various MI models used, the concomitant treatments and different experimental protocols followed, as well as the confounding effects of anesthesia (9,14,21,28-32). Most previous studies assessing the role of the RAS on renal function in rats with MI have involved acute interventions with converting enzyme inhibitors in anesthetized rats (9,33). These studies have suggested that AII has a central role in renal function abnormalities after MI. In single nephron preparations of rats under anesthesia, the acute infusion of teprotide, an AI-converting enzyme inhibitor, reverses the abnormalities induced by chronic MI in renal hemodynamics and sodium excretion (9). Chronic oral administration of captopril to anesthetized rats with large MI caused an increase in UF rate and RBF with a concomitant decrease in RVR without altering GFR or sodium excretion (21).
We studied conscious rats with compensated MI after chronic blockade with either captopril or losartan. Captopril increased RBF by decreasing RVR, even when perfusion pressure was decreased (Table 3). The decrease in RVR and the increase in RBF and GFR were consistent with previous reports (9,21). Furthermore, captopril significantly decreased UF rate and FeNa. The latter findings have not been previously reported. One explanation for these differences is that the previous studies were performed in anesthetized animals, which may have altered the intrarenal distribution of BF. To our knowledge, ours is the first description of conscious renal hemodynamics and sodium balance in infarcted rats chronically treated with captopril. Table 8
Renal function after MI: Effects of losartan
ACE inhibitors potentiate the effects of BK and vasodilatory prostaglandins (6-8). A significant portion of the effects of ACE inhibitors has been suggested to be mediated by these non-angiotensin-blocking mechanisms (26,34,35).
Earlier studies in experimental MI models have not supported this contention (20,33). Therefore, to evaluate selectively the effects of AII on renal function after MI, we studied infarcted rats chronically treated with the specific AII receptor blocker losartan (20). In the present study, we showed that losartan, at doses that decreased MAP to degree comparable to that produced by captopril, decreased UF rate, RVR, and FeNa. Nevertheless, the extent of these changes were less than those produced by captopril. Losartan did not affect GFR or RBF (Table 4).
The explanation for the changes in sodium and water excretion induced by either agent is not clear. In previous studies in normal anesthetized rats, acute infusion of losartan decreased BP, UF rate, FeNa, and RVR, without altering RBF, GFR, or FeNa (35). Losartan increased cortical RBF but did not affect papillary flow. In another study using the same model, infusion of the AII antagonist saralasin increased GFR and RBF and increased UF rate and sodium excretion as well (34). These results suggest that AII regulates the intrarenal distribution of BF and sodium excretion. However, in a conscious ovine model of pacing-induced heart failure, acute inhibition of AII with losartan did not change GFR or sodium excretion (30).
Renal function after MI: Effects of BK and prostaglandin inhibition
To explore further the role of BK and prostaglandins on the renal effects of ACE inhibitors after MI, we compared renal hemodynamics and sodium excretion after acute blockade with a specific BKI or indomethacin (Tables 5-7). In untreated infarcted rats, the BKI decreased MAP and GFR and increased sodium excretion (Table 5). In captopril-treated infarcted rats, the BKI reversed the changes in GFR, RBF, and RVR (Table 6). The BKI also reversed the captopril-induced changes in sodium excretion, suggesting that a portion of the renal changes observed after chronic captopril treatment are due to the potentiation of the BK and prostaglandin system. Further supporting this argument, in losartan-treated rats, BK inhibition exerted little if any effect on the hemodynamic parameters but significantly improved sodium excretion (Table 7). Blockade of prostaglandin generation by indomethacin did not affect renal hemodynamics in either captopril- or losartan-treated rats, but it improved sodium excretion in both treated groups (Tables 6 and 7). Therefore, our present results indicate, with respect to renal function, that potentiation of BK is an important corollary effect of ACE inhibition in this model of LV dysfunction. Furthermore, this effect is mainly exerted through renovasodilation and is not further potentiated by prostaglandins.
Previous studies have suggested that the BK system may play a role in regulating papillary BF in normal anesthetized rats. Furthermore, it may mediate some of the effects of captopril in sodium and water excretion in normal, anesthetized rats (34,35). In a study of anesthetized dogs in which renal perfusion pressure was maintained constant, acute infusion of BK had no significant effect on GFR, but significantly increased RBF, UF rate, and urinary sodium excretion. During chronic (7-day) infusion, BK had no effect on GFR, UF rate, and sodium excretion but persistently increased RBF and decreased RVR, suggesting that chronic increases in intrarenal BK do not alter sodium and water excretion (24). We postulate, based on our results, that BK and vasodilatory prostaglandins influence both renal hemodynamics and sodium balance after MI under chronic suppression of the RAS.
Acknowledgment: This work was supported by grants from the Veterans Administration, Grant No. HL-4816302 from the National Institutes of Health, Arizona Disease Control Research Commission, the National American Heart Association, and the Arizona Affiliate of the American Heart Association. We thank Sherry Dougherty, Michelle Timmons, Jennifer Lowell, Ted Meeks, and Howard Byrne for technical assistance and Dr. Steven Goldman for reviewing the manuscript. We also thank DuPont Merck for supplying losartan.
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