Infusion Of Enalaprilat Research Articles

Roles of ANG II and bradykinin in the renal regional blood flow responses to ACE inhibition in sodium-depleted dogs.

The relative contributions of ANG II and bradykinin (BK) to the renal regional blood flow responses during angiotensin-converting enzyme (ACE) inhibition remain unclear. This study was performed to evaluate renal cortical (CBF) and medullary blood flow (MBF) responses to intrarterial administration of enalaprilat (33 microg. kg(-1). min (-1)) after blockade of the ANG II AT(1 )receptors with candesartan (100 microg) in 7 dogs fed a low-salt diet (0.01%) for 5 days. Laser-Doppler flowmetry was used to measure relative changes in CBF and MBF. Candesartan alone increased CBF (+20 +/- 2%) and MBF (+22 +/- 7%). Enalaprilat infusion after candesartan administration resulted in further increases in both CBF (+21 +/- 5%) and MBF (+41 +/- 8%). However, the relative changes in MBF were significantly greater (P < 0.01) than those in CBF. Administration of the BK B(2) receptor blocker icatibant (300 microg) after enalaprilat returned CBF and MBF to values seen with candesartan alone. These data support a substantive role for BK potentiation during ACE inhibitor-induced renal vasodilation in dogs maintained on a low-sodium diet, with a relatively greater effect on MBF compared to CBF.

Dissociation between ACE activity and autonomic response to ACE inhibition in patients with heart failure

Background Administration of angiotensin-converting enzyme (ACE) inhibitors to patients with congestive heart failure has been shown to increase parasympathetic tone as indicated by increases in high-frequency heart rate variability. The mechanism for this effect, including its relation to changes in baroreflex activity, blood pressure variability, and suppression of ACE activity, remains undefined. This study was designed to test the relation of these variables, which may govern changes in autonomic activity, to the previously described increase in parasympathetic tone. Methods Seven patients with heart failure received a 3-hour infusion of the ACE inhibitor enalaprilat. Hemodynamic variables and parameters of heart rate and blood pressure variability, baroreflex gain derived from the interaction of heart rate and blood pressure variability, and serum ACE activity were measured during and after the infusion. Measures of heart rate and blood pressure variability were also compared against a historic control group. Results Serum ACE activity was significantly suppressed throughout and after enalaprilat infusion. Hemodynamic measures did not change other than a small decline in right atrial and pulmonary capillary wedge pressures. Parasympathetic tone showed an initial significant increase with a peak at 2 hours but then declined below baseline 8 hours after initiation of enalaprilat infusion. Sympathetically influenced low-frequency heart rate variability was significantly increased above baseline in the enalaprilat treatment group 8 hours after initiation of the infusion. Baroreflex gain showed a significant trend to an increase with the maximum value coinciding with the peak in parasympathetic tone. There was no change in blood pressure variability in the enalaprilat group and no change in baroreflex gain, heart rate variability, or blood pressure variability in the control group. Conclusions Parasympathetic tone and baroreflex gain increased with parenteral administration of an ACE inhibitor but subsequently decreased below baseline values despite continued suppression of serum ACE activity. The dissociation between ACE suppression and autonomic response to ACE inhibition indicates that enzyme systems not reflected by plasma ACE activity or independent from the classic pathways of angiotensin formation contribute to the regulation of the autonomic response to ACE inhibition in patients with heart failure. The absence of significant change in hemodynamic variables or in blood pressure variability indicates that these autonomic changes are not an indirect reflex response to ACE inhibitor-induced vasodilation or hemodynamic baroreceptor stimulation. (Am Heart J 2000;140:34-42.)

Interaction between norepinephrine release and intrarenal angiotensin II formation during renal nerve stimulation in dogs.

We examined possible interactions between intrarenal angiotensin II (ANG II) formation and norepinephrine (NE) release during renal sympathetic nerve stimulation (RNS) in anesthetized dogs. During 10 min of continuous RNS (1.5-2 Hz), the ANG II formation rates (ANG II-FR) and NE secretion rates (NE-SR) were determined at 1 and 10 min. Under control conditions, almost the same extent of increase in the NE-SR was observed at 1 and 10 min of RNS, whereas a significant increase in ANG II-FR was observed at 10 min but not at 1 min. During intrarenal arterial infusion of enalaprilat or losartan, the increase in NE-SR and reduction in renal blood flow at 10 min of RNS were suppressed, whereas the NE release and vasoconstriction responses at 1 min remained unaffected. The RNS-induced increases in ANG II-FR were completely abolished during infusion of enalaprilat. These results suggest that NE release on continuous RNS is enhanced by concomitantly formed ANG II, and this interaction depends on the time-related changes in intrarenal ANG II formation during RNS in the canine kidney.

Intrarenal angiotensin converting enzyme inhibition in spontaneously hypertensive rats

We examined the hypotensive effect of enalapril in relation to the local renin–angiotensin system of the kidney in spontaneously hypertensive rats (SHR). Oral administration of enalapril for 7 days decreased mean arterial blood pressure and renal tissue angiotensin II concentration without affecting plasma angiotensin II concentration in SHR. The enalapril treatment did not affect maximum binding of angiotensin II to renal tubules and glomeruli in SHR. In normotensive Wistar–Kyoto rats, no significant changes in mean arterial blood pressure, renal and plasma angiotensin levels were observed with enalapril treatment. Direct infusion of enalapril into the renal medullary interstitium decreased mean arterial blood pressure in association with the reduction of renal tissue angiotensin II concentration without changes in plasma angiotensin II concentration in SHR. These observations suggest that the inhibition of angiotensin conversion in the kidney is important for the hypotensive action of enalapril.

Abnormal flow-mediated epicardial vasomotion in human coronary arteries is improved by angiotensin-converting enzyme inhibition: A potential role of bradykinin

OBJECTIVESThis study was performed to determine whether angiotensin converting enzyme (ACE) inhibition improves endothelium-dependent flow-mediated vasodilation in patients with atherosclerosis or its risk factors and whether this is mediated by enhanced bradykinin activity.BACKGROUNDAbnormal coronary vasomotion due to endothelial dysfunction contributes to myocardial ischemia in patients with atherosclerosis, and its reversal may have an antiischemic action. Previous studies have shown that ACE inhibition improves coronary endothelial responses to acetylcholine, but whether this is accompanied by improved responses to shear stress remains unknown.METHODSIn 19 patients with mild atherosclerosis, metabolic vasodilation was assessed during cardiac pacing. Pacing was repeated during separate intracoronary infusions of low-dose bradykinin (BK) and enalaprilat. Endothelium-dependent and -independent vasodilation was estimated with intracoronary BK and sodium nitroprusside respectively.RESULTSEnalaprilat did not alter either resting coronary vascular tone or dilation with sodium nitroprusside, but potentiated BK-mediated dilation. Epicardial segments that constricted abnormally with pacing (−5 ± 1%) dilated (3 ± 2%) with pacing in the presence of enalaprilat (p = 0.002). Similarly, BK at a concentration (62.5 ng/min) that did not alter resting diameter in the constricting segments also improved the abnormal response to a 6 ± 1% dilation (p < 0.001). Cardiac pacing-induced reduction in coronary vascular resistance of 27 ± 4% (p < 0.001) remained unchanged after enalaprilat.CONCLUSIONSThus ACE inhibition: A) selectively improved endothelium-dependent but not -independent dilation, and B) abolished abnormal flow-mediated epicardial vasomotion in patients with endothelial dysfunction, in part, by increasing endogenous BK activity.

Angiotensin converting enzyme inhibition has no effect on blood pressure and splanchnic perfusion after cardiac surgery

The purpose of this study was to study the effect of the angiotensin-converting enzyme inhibitor, enalaprilat, on blood pressure and splanchnic perfusion after cardiac surgery. Sixteen patients were studied after coronary artery bypass grafting. After admission to the intensive care unit, a 30-minute baseline measurement of systemic hemodynamics, oxygen transport, and gastric tonometry was performed. In 6 of 10 patients receiving enalaprilat and in each of 6 control patients, regional (splanchnic and leg) blood flows were measured also. After the baseline measurement period, 10 patients received a 0.5 mg bolus of enalaprilat and thereafter an incremental infusion of enalaprilat up to a total dose of 10 mg (mean 8.3; range 4 to 10 mg) was continued to reduce the mean arterial pressure (MAP) to 70 to 80 mm Hg. A 30-minute measurement period was repeated 2 to 3 hours after the first measurement period. In the control group, the second measurement was performed at corresponding time points. Though MAP decreased in the enalaprilat group (enalaprilat 99 +/- 14 mm Hg v 89 +/- 21 mm Hg, P < .05; control 95 +/- 13 mm Hg v82 +/- 10 mm Hg, P = NS) in only 4 of 10 patients was the targeted MAP reduction achieved. No significant changes were observed either in systemic or regional blood flows. Systemic, pulmonary, and femoral vascular resistance indices decreased significantly in both groups. Gastric-arterial PCO2 difference did not change in either groups. Angiotensin-converting enzyme activity decreased in the enalaprilat group (10.0 +/- 2.3 v 1.3 +/- 0.3 U x l(-1), P < .01), but plasma renin and endothelin-1 concentrations did not change in either group. The effect of enalaprilat on blood pressure was poor and it had no beneficial effects on splanchnic circulation. Renin-angiotensin activation is not a major factor in hypertension and splanchnic perfusion after cardiac surgery.

Angiotensin converting enzyme inhibition improves baroreflex-induced noradrenaline spillover responses in rabbits with heart failure

Impaired baroreflex function is a characteristic feature of congestive heart failure (CHF), although the mechanism is obscure. This study examined the hypothesis that activation of the renin–angiotensin system contributes to baroreflex dysfunction in CHF. The acute effects of an angiotensin converting enzyme inhibitor, enalaprilat, on baroreflex-mediated changes in heart rate (HR), total and renal noradrenaline (NA) spillover rates were examined in conscious rabbits with doxorubicin-induced cardiomyopathic CHF. Studies were performed under resting conditions and in response to changes in mean arterial pressure (MAP) induced by sodium nitroprusside and phenylephrine infusions. Seven saline-treated (normal group) and 11 doxorubicin-treated rabbits (1 mg/kg administered intravenously twice weekly) were studied after 4 and 6 weeks' treatment. Five CHF rabbits received saline (C group) and 6 enalaprilat infusion (ACEI group) during each study period. After 4 weeks of doxorubicin, baroreflex-HR responses were normal, whereas baroreflex-NA spillover responses were enhanced. Enalaprilat infusion shifted the HR–MAP curve downwards to the left but had no effect on the NA spillover–MAP curves. After 6 weeks of doxorubicin, when CHF was established, baroreflex-HR and NA spillover curves were depressed. At this stage, enalaprilat had little effect on the HR–MAP curve but restored towards normal the NA spillover–MAP curves. The results suggest that the endogenous renin–angiotensin system contributes to attenuated baroreflex responses when CHF is established.

Enalaprilat decreases plasma endothelin and atrial natriuretic peptide levels and preload in patients with left ventricular dysfunction after cardiac surgery

Objective: To study the acute effects of angiotensinconverting enzyme inhibition by intravenous enalaprilat infusion in patients with left ventricular dysfunction after cardiac surgery. Design: Prospective, consecutive sample, before-after trial. Setting: Surgical intensive care unit in a tertiary care university hospital. Participants: Eight patients with left ventricular dysfunction after cardiac surgery. Patients were defined as having left ventricular dysfunction if the pulmonary capillary wedge pressure persisted above 18 mmHg in spite of conventional vasoactive medication (inotropic or vasodilating and diuretic drugs) and intermittent mandatory ventilation during the first postoperative week. Interventions: Enalaprilat was infused initially at 1 mg/hour. The rate was doubled every 30 minutes until pulmonary capillary wedge pressure decreased at least 20% or until a maximum total dose of 10 mg was achieved. Measurements and Results: Central hemodynamics, systemic oxygenation, and hormonal regulation of circulation (plasma renin activity, plasma endothelin, atrial natriuretic peptide, norepinephrine, epinephrine, and vasopressin concentrations, serum angiotensin-converting enzyme activity, and serum levels of aldosterone) were assessed at baseline before enalaprilat infusion, and repeatedly over 2 hours after the infusion. Enalaprilat infusion (median dose, 2.0 mg; infusion time, 48 minutes) caused a significant decrease in pulmonary capillary wedge pressure ( p = 0.004), lasting until, the end of the 2 hours' follow-up. This coincided with inhibition of serum angiotensin-converting enzyme activity ( p < 0.001), an increase in plasma renin activity ( p = 0.022), and decreases in plasma endothelin ( p = 0.035), atrial natriuretic peptide ( p = 0.005), and serum aldosterone ( p = 0,001) concentrations. Cardiac output, venous admixture, and oxygen delivery and consumption remained unchanged. Conclusions: Adding enalaprilat to conventional therapy makes it possible to unload the left ventricle and to relieve overt neurohormonal activation temporarily while maintaining cardiac function and systemic oxygenation.

Intracoronary blockade of angiotensin-converting enzyme in humans: interaction with cardiac sympathetic neurotransmission?

The present study was designed to identify an interaction between the renin-angiotensin system and noradrenergic transmission in the human heart. It is still under debate whether angiotensin II facilitates noradrenaline release in the heart. Clinical studies of congestive heart failure, involving systemic angiotensin-converting enzyme (ACE) inhibitor administration, have indicated anti-adrenergic effects, without giving a clear mechanistic picture. The influence on cardiac sympathetic transmission by local intracardiac administration of an ACE inhibitor has not been determined. Seven angina patients with normal left ventricular function, who underwent control coronary angiography after successful percutaneous transluminal coronary angioplasty were studied. Baseline measurements of haemodynamics and total and cardiac noradrenaline spillover were followed by handgrip exercise in the absence and presence of intracoronary enalaprilat infusion (0.05 mg min-1, 1 mL min-1). Baseline total body and cardiac noradrenaline spillover remained unchanged following intracoronary enalaprilat infusion, being 3745 +/- 349 and 3896 +/- 257 pmol min-1, and 148 +/- 56 and 149 +/- 55 pmol min-1, before and after drug administration, respectively. Mean arterial pressure, peripheral plasma renin activity and angiotensin II levels were also unaffected by enalaprilat infusion. During handgrip exercise procedures, both total body and cardiac noradrenaline spillover increased substantially, showing no reduction in the presence of intracardiac enalaprilat. Direct administration of the ACE inhibitor enalaprilat to the human heart failed to attenuate cardiac sympathetic drive during baseline conditions or following cardiac adrenergic activation by handgrip exercise. Thus, in the non-failing heart, without chronic adrenergic activation, no angiotensin II-facilitated effect on cardiac noradrenaline spillover could be detected.

Angiotensin-converting enzyme inhibition by enalapril: a novel approach to reduce ischemia/reperfusion damage after experimental liver transplantation.

Angiotensin-converting enzyme (ACE) inhibitors have proven to be effective in the reduction of ischemia/reperfusion damage after myocardial ischemia. Whether this favorable effect can be related to other models of ischemia and reperfusion has not yet been investigated. Therefore, we studied in a model of syngeneic liver transplantation in the rat the effect of recipient enalapril treatment on postischemic liver injury. Untreated animals served as the control group. Treatment with enalapril was started 5 minutes before reperfusion by intravenous infusion of enalapril at a dosage of 5 mg/kg/h. By means of in vivo microscopy, the sinusoidal perfusion rate and leukocyte adherence in sinusoids and postsinusoidal venules were analyzed during 45 to 60 minutes of reperfusion. Liver function was monitored by measuring bile output over a period of 60 minutes. Analysis of coagulation factors (prothrombin time, factor V, fibrinogen) and liver enzymes (alanine transaminase [ALT], aspartate transaminase [AST]) served for the evaluation of organ dysfunction and damage secondary to ischemia/reperfusion injury. The sinusoidal perfusion rate was significantly improved by enalapril treatment (94.7% [1.0] vs. 75.3% [3.8]; mean [SEM]; P = .005). In addition, leukocyte-sticking in both liver sinusoids and postsinusoidal venules was remarkably reduced in enalapril-treated animals as compared with controls (stickers/lobule: 21.0 [3.3] vs. 59.2 [2.1]; P = .0004; stickers/mm2 venular surface: 20.5 [4.7] vs. 110.3 [18.1]; P = .0004). Moreover, bile output was increased (1.13 [0.35] vs. 0.43 [0.18] g bile/60 min x 100 g liver; P = .06). Values for PT (22.5% [2.1] vs. 9.7% [1.8]; P = .005), factor V 99.4% [9.5] vs. 49.5% [8.5]; P = .007), and fibrinogen (64.1% [7.7] vs. 12.8% [3.2]; P = .001) were significantly improved, paralleled by a remarkable reduction in serum ALT (1,428 U/L [190] vs. 2,315 [248]; P = .02). Our data show for the first time that ACE inhibition in the liver recipient by enalapril attenuates hepatic ischemia/reperfusion damage after experimental liver transplantation. Our results may offer a novel approach to reduce ischemia/reperfusion injury in clinical liver transplantation.

Effects of angiotensin-converting enzyme inhibition on arterial, venous and capillary functions in cat skeletal muscle in vivo.

The aim of the present study was to analyse quantitatively, on a cat gastrocnemius muscle preparation in vivo, the effects of local angiotensin-converting enzyme (ACE) inhibition by enalaprilat on total regional vascular resistance (tone) and its distribution to the large-bore arterial resistance vessels (> 25 microns), the small arterioles (< 25 microns) and the veins. Associated effects on capillary pressure and fluid exchange were also studied. Close-arterial infusion of enalaprilat (0.05-0.20 mg kg muscle tissue min-1) elicited a moderate dilator response in all three consecutive sections of the muscle vascular bed, an increase in capillary pressure and transcapillary fluid filtration. This dilation could be abolished by the selective bradykinin B2-receptor antagonist Hoe 140 (2 mg kg-1 min-1, i.a.), indicating that the dilator mechanism of ACE inhibition was an increased local concentration of bradykinin, and hardly at all a decreased concentration of angiotensin (AT) II. The generalized dilator response to ACE inhibition along the vascular bed suggested a relatively uniform distribution of ACE from artery to vein and this was further supported by the finding that a close-arterial infusion of AT I (0.04-0.32 microgram kg-1 min-1), which was vasoactive only after conversion to AT II by local ACE, elicited a generalized constrictor response in all three vascular sections. In contrast, infused AT II (0.01-0.16 microgram kg-1 min-1) constricted almost selectively the large-bore arterial vessels. The specific angiotensin AT1-receptor antagonist losartan (2 mg kg-1 min-1, i.a.) abolished the constrictor response to AT II but did not affect vascular tone under control conditions, indicating that AT II is not involved in the initiation of basal vascular tone in muscle. These results, taken together, indicate that under basal conditions vascular ACE contributes to the local control of vascular tone in skeletal muscle by degrading the endogenous dilator bradykinin, and not by converting AT I into vasoconstrictor AT II.

Pharmacokinetic and fetal cardiovascular effects of enalaprilat administration to maternal rhesus macaques

OBJECTIVE: The purpose of this study was to determine the extent of placental transfer of the angiotensin-converting enzyme inhibitor enalaprilat and the effects on maternal and fetal cardiovascular parameters. STUDY DESIGN: Between gestational days 122 and 126 (term 167 days) five rhesus macaques underwent surgery for implantation of maternal and fetal vascular catheters. At least 4 days after surgery maternal and fetal blood pressures and heart rates were recorded for 1 hour. This was followed by a 5-minute maternal venous infusion of saline solution vehicle and recording for an additional hour. Enalaprilat was then infused over 5 minutes through the maternal femoral artery at doses of 0.05, 0.1, or 0.2 mg/kg. Maternal and fetal arterial blood samples were collected for determination of blood gas status and plasma enalaprilat concentrations. RESULTS: Enalaprilat rapidly crossed the placenta, and fetal values for areas under the concentration time curve were 50% to 65% of maternal values across dose groups. Drug was retained in the fetal plasma approximately threefold to fourfold longer than in maternal plasma. Maternal heart rate, blood pressure, arterial Po 2 and pH were unchanged after enalaprilat infusion, as were fetal heart rate and blood gases. In contrast, fetal arterial pressure decreased significantly (19% to 23%, p < 0.01) after maternal treatment with 0.1 and 0.2 mg/kg and remained depressed throughout the 6-hour study interval. At 0.05 mg/kg fetal arterial pressure was decreased by 13% from baseline; differences were not significantly different ( p > 0.05). CONCLUSIONS: Results from this study indicate that enalaprilat rapidly crosses the primate placenta with a single intravenous administration to the mother, resulting in significant and prolonged reduction of fetal arterial pressure. Because maternal cardiovascular parameters were unaffected, enalaprilat appears to have a direct effect on fetal arterial pressure. (Am J Obstet Gynecol 1996;175:50-5.)

Role of angiotensin II in dietary modulation of rat late distal tubule bicarbonate flux in vivo.

We have reported that overnight fasting stimulates bicarbonate reabsorption (JtCo2) in rat distal tubules. The present in vivo microperfusion studies evaluated the hypothesis that endogenous angiotensin II (AII) mediates this response. Rat late distal (LD) tubules were perfused at 8 nl/min in vivo with a hypotonic solution containing 28 mM bicarbonate. In overnight-fasted rats, LD JtCO2 was significantly higher than in normally fed rats (50 +/- 4 vs. 16 +/- 6 pmol/min.mm, P < 0.05). When overnight-fasted rats were salt-loaded, JtCO2 fell significantly (38 +/- 3 pmol/min.mm, P < 0.05). Conversely, in fed rats ingesting a zero-salt diet, JtCO2 increased three-fold (45 +/- 5 pmol/min.mm, P < 0.05). Enalaprilat infusion (0.25 micrograms/kg body wt, intravenously), in these zero-salt and overnight-fasted rats, reduced LD JtCO2 values to normal. Further, infusion of losartan (5 mg/kg body wt, intravenously), the specific AII AT1 receptor blocker, reduced JtCO2 in overnight-fasted rats by two-thirds (16 +/- 4 pmol/min.mm, P < 0.05). Finally, we perfused 10(-11) M AII intraluminally with and without 10(-6) M losartan: AII increased JtCO2 to 45 +/- 6 pmol/min.mm, equal to the zero-salt flux. This was completely abrogated by simultaneous losartan perfusion. Therefore, these results suggest that AII is an in vivo stimulator of late distal tubule bicarbonate reabsorption.

Cardiorespiratory effects of continuous i.v. administration of the ACE inhibitor enalaprilat in the critically ill.

1. Cardiorespiratory effects of long-term, continuous i.v. administration of the ACE inhibitor enalaprilat were studied. 2. Forty-five consecutive critically patients suffering from trauma or postoperative complications were randomly separated into three groups (15 patients in each group) receiving either 0.25 mg h-1 or 0.50 mg h-1 enalaprilat, respectively, or saline solution as placebo (= control group). The infusion was continued for 5 days. 3. Haemodynamic and respiratory parameters were intensively monitored on admission to the intensive care unit (= 'baseline' values) and daily during the next 5 days. 4. Mean arterial blood pressure (MAP) decreased significantly only in the enalaprilat-treated patients, whereas heart rate (HR) remained unchanged in these patients. 5. Pulmonary capillary wedge pressure (PCWP) and pulmonary artery pressure (PAP) were decreased by enalaprilat (0.50 mg h-1: PAP (mean +/- s.d.) decreased from 28.0 +/- 4.1 to 24.0 +/- 3.0 mm Hg) and remained significantly lower than in the control group. In the untreated control group, cardiac index (CI), oxygen consumption (VO2I) and oxygen delivery (DO2I) significantly decreased, which was blunted by enalaprilat infusion. Oxygen extraction (O2-extr) increased in both enalaprilat groups (0.25 mg h-1: from 26.1 +/- 5.5 to 30.4 +/- 4.0%; 0.50 mg h-1: 25.2 +/- 5.6 to 30.9 +/- 4.4%) and decreased in the control patients. 6. Right ventricular haemodynamics improved by enalaprilat infusion (0.50 mg h-1: RVEF increased from 40.0 +/- 3.5 to 45.5 +/- 4.0%). Lactate plasma concentrations decreased in the group with 0.50 mg h-1 enalaprilat (from 1.9 +/- 1.0 to 1.3 +/- 0.3 mg dl-1) and increased in the control patients. 7. Continuous infusion of the ACE inhibitor enalaprilat exerted beneficial cardiorespiratory effects in the critically ill. The widespread common risk of altered perfusion with decreased CI, DO2, VO2, O2-extr and increased lactate concentration was blunted by enalaprilat infusion. 8. Although 0.5 mg h-1 enalaprilat was most effective, a dose of 0.25 mg h-1 also showed beneficial haemodynamic effects in the critically ill.

Ureteral obstruction in the neonatal guinea pig: Interaction of sympathetic nerves and angiotensin

The contribution of sympathetic nerves to the hemodynamic effects of unilateral ureteral obstruction (UUO) was investigated in the neonatal guinea pig. The left ureter was partially constricted (or sham-operated) at birth, and sympathetic innervation was inhibited by guanethidine and compared with saline vehicle-treated animals. At 15-20 days of age, blood pressure, cardiac output, total vascular resistance (TVR), renal blood flow, and renal vascular resistance (RVR) were determined before and after infusion of enalapril. UUO reduced cardiac output, increased TVR, and increased RVR of the ipsilateral kidney, whereas guanethidine treatment had no additional effects. Enalapril decreased RVR only in obstructed kidneys and not in intact opposite kidneys of animals with UUO. This was not affected by guanethidine administration. In contrast, enalapril decreased RVR only in guanethidine-treated (but not saline-treated) sham-operated guinea pigs. Therefore, UUO increases angiotensin-dependent vascular tone of the ipsilateral kidney independent of renal innervation. However, UUO decreases angiotensin-mediated vascular tone of the contralateral kidney, an effect unmasked by sympathectomy.

Continuous I.V. Administration of the Angiotensin-Converting Enzyme Inhibitor Enalaprilat in the Critically Ill

Several components are responsible for circulatory control at the central, regional, and microcirculatory level. Angiotensin-converting enzyme (ACE) inhibitors are known to act beneficially on circulation by various mechanisms. The influence of continuous i.v. administration of the ACE inhibitor enalaprilat on regulators of circulation was studied in 45 critically ill patients. According to a prospective randomized sequence, either 0.25 mg/h (group 1, n = 15) or 0.5 mg/h (group 2, n = 15) of enalaprilat or saline solution as placebo (control group, n = 15) were continuously given. Infusion was started on the day of admission to the intensive care unit (ICU) and continued for the next 5 days. From arterial blood samples, plasma levels of endothelin-1 (ET), atrial natriuretic peptide (ANP), renin, vasopressin, angiotensin-II, and catecholamines (epinephrine, norepinephrine) were measured. All measurements were carried out before infusion (= baseline values) and during the next 5 days. In both enalaprilat groups, mean arterial blood pressure (MAP) decreased similarly; heart rate (HR) and central venous pressure (CVP) did not change, and were without differences in comparison to the untreated control. Except for ET, plasma levels of all vasoactive substances exceeded normal range at baseline. Angiotensin-II plasma concentrations significantly decreased during enalaprilat infusion (0.25 mg/h: from 53.1 +/- 11.3 to 22.1 +/- 9.3 pg/ml; 0.50 mg/h: 62.1 +/- 14.4 to 17.9 +/- 7.9 pg/ml), but they remained significantly elevated in the untreated control patients. Vasopressin plasma level increased only in the control group (p < 0.01) and decreased in the patients in whom 0.50 mg/h of enalaprilat was infused.(ABSTRACT TRUNCATED AT 250 WORDS)

757-2 Angiotensin II Formation in the Intact Human Heart: Predominance of the Angiotensin Converting Enzyme Pathway

It has been proposed that the contribution of myocardial tissue angiotensin converting enzyme (ACE) to angiotensin II (Ang II) formation in the heart is low compared to non-ACE pathways. However, little is known about the actual in vivo contribution of these pathways to Ang II formation in the human heart. Accordingly, we developed a method to quantify ACE and non-ACEmediated conversion of angiotensin I (Ang I) to Ang II across the myocardial circulation in human subjects. Using an intracoronary(lC) infusion of 123|-Ang I before and during an IC infusion of enalaprilat, we measured the fractional conversion of Ang I to Ang II in coronary sinus blood samples by taking the ratio of the labeled Ang II activity to the sum of activity corresponding to labeled Ang I and Ang II after peptide extraction and separation by HPLC (activity ratio method). Results obtained from this method were confirmed by combined HPLC/RIA of both labeled and unlabeled Ang I and Ang II (RIA method). The initial experience has been obtained in orthotopic heart transplant recipients with normal cardiac function and coronary anatomy. After a six minute IC infusion of 123|Ang I, fractional conversion of Ang I to Ang II was 0.44 ± 0.141, and 0.43 ± 0.084 (n = 4, mean ± SD) as determined, respectively, by the activity ratio and RIA methods. IC enalaprilat (0.01 mg/min for five minutes) reduced fractional conversion to 0.046 ± 0.065 (activity ratio method) or 0.033 ± 0.012 (RIA method) (n = 3, P = 0.014).Download : Download high-res image (61KB)Download : Download full-size image 1) Ang II formation can be measured in the intact human heart; 2) ACE mediates 90% of Ang I to Ang II conversion across the myocardial circulation.

Effect of angiotensin-converting enzyme inhibitors on endothelium-dependent peripheral vasodilation in patients with chronic heart failure

Objectives. This study was performed to determine whether acute inhibition of angiotensin-converting enzyme restores impaired endothelium-dependent vasorelaxation in patients with chronic heart failure.Background. Recent reports have demonstrated that endothelium-dependent vasodilation induced by cholinergic stimuli is attenuated in the peripheral vascular bed of patients with chronic heart failure.Methods. We examined the effects of local intraarterial infusion of enalaprilat (0.6 μg/min per 100 ml tissue volume) on responses inflated by acetylcholine or sodium nitroprusside in the forearm vascular bed in 8 normal subjects, 12 patients with mild heart failure (New York Heart Association functional classes I and II) and 10 patients with more advanced heart failure (functional classes III and IV). Forearm blood flow was measured by means of venous occlusion plethysmography.Results. Although enalaprilat alone did not affect basal forearm blood flow, it significantly augmented the increase in forearm blood flow induced by acetylcholine in normal subjects (p < 0.01) and in those with mild heart failure (p < 0.05). However, the effect was not found in patients with more advanced heart failure. Coinfusion of enalaprilat did not enhance sodium nitroprussideinduced vasodilation in any of the groups. To explore the mechanism of the inhibitor's effect, an additional 20 patients with mild heart failure (functional class II) were pretreated with a cyclooxygenase inhibitor, acetylsalicylic acid (n = 10) or an inhibitor of nitric oxide synthesis, NG-monomethyl-l-arginine (n = 10), followed by administration of acetylcholine with or without enalaprilat. Acetylsalicylic acid reduced the converting enzyme inhibitor's effect, whereas NG-monomethyl-l-arginine failed to block tie augmentation of blood flow.Conclusions. These results suggest that inhibition of angiotensinconverting enzyme potentiates endothelium-dependent vasodilation induced by cholinergic stimuli, presumably through modulation of prostaglandin metabolism, in the peripheral vasculature of patients with mild chronic heart failure.

Electrophysiologic Changes in the Human Heart Produced by Enalaprilat (Angiotensin-Converting Enzyme Inhibitor).

Several trials have showed that angiotensin-converting enzyme inhibitors possess some extent of antiarrhythmic properties. To evaluate the effects of Enalaprilat on His bundle recording, patients undergoing diagnostic coronary angiogram due to angina pectoris and a positive thallium exercise test subsequently underwent His bundle electrogram. A double-blind crossover protocol was used with conduction velocity measurements at baseline and after saline (placebo) and Enalaprilat 2.5 mg intravenously. There were no significant changes in heart rate (64 plus minus 9 versus 65 plus minus 11 versus 65 plus minus to beats min(minus sign1)) at baseline, after saline and enalaprilat infusion, respectively, mean blood pressure (97 plus minus 11 versus 94 plus minus 10 versus 94 plus minus 7 mm Hg, respectively), atrioventricular conduction time (100 plus minus 20 versus 100 plus minus versus 100 plus minus 20 versus 100 plus minus ms), and His--Purkinje (HV) conduction time (40 plus minus 12 versus 40 plus minus 13 versus 40 plus minus 12 ms). Ventricular activity duration was 110 plus minus 11 ms at baseline, 110 plus minus 10 ms after saline infusion (p = NS), and 88 plus minus 13 ms after Enalaprilat administration (p < 0.001). Angiotensin-converting enzyme inhibition appears to produce significant reduction in ventricular activity duration (increase in intraventricular conduction velocity).

Haemodynamic effects of enalaprilat and preload in acute severe heart failure complicating myocardial infarction.

In this study, the acute haemodynamic effects of angiotensin converting enzyme (ACE) inhibition with intravenous enalaprilat alone or in combination with preload restoration were determined in patients with severe heart failure complicating acute myocardial infarction. Ten patients with raised pulmonary arterial wedge pressure (PAWP > or = 18 mmHg) were first studied during constant conventional vasodilation with diuretic and inotropic medication, by monitoring central haemodynamics and arterial blood gases. The same variables were measured before enalaprilat infusion, after preload reduction with enalaprilat (1 mg.h-1, rate doubled every 30 min until PAWP decreased > or = 25% or up to total cumulative dose of 10 mg) and after preload restoration with fluid loading (4% albumin given 15 ml.min-1 to restore PAWP to baseline) during continuous low dose enalaprilat infusion. Enalaprilat alone (median dose 0.9 mg) reduced significantly the PAWP (from 25 to 17 mmHg; P = 0.004), the mean arterial pressure (from 87 to 83 mmHg; P = 0.008), the mean pulmonary arterial pressure and the right atrial pressure. The cardiac index, stroke volume index and systemic vascular resistance index remained unchanged. Preload restoration during continuous enalaprilat infusion (median dose of 4% albumin 230 ml, and enalaprilat 0.2 mg) did not further enhance left ventricular function; rather, there was a nearly significant decrease in myocardial perfusion pressure. Arterial oxygenation remained unchanged throughout the study. In conclusion, adding intravenous enalaprilat to conventional therapy makes it possible to relieve pulmonary congestion while maintaining the cardiac function and arterial oxygenation. Preload restoration during continuous ACE inhibition offers no further advantages, and may have adverse effects, since the myocardial perfusion pressure may fall.