Repurposed drugs in combinations exert additive anti-chikungunya virus activity: an in-vitro study.

Chikungunya virus (CHIKV) infection causes chikungunya, a viral disease that currently has no specific antiviral treatment. Several repurposed drug candidates have been investigated for the treatment of the disease. In order to improve the efficacy of the known drugs, combining drugs for treatment is a promising approach. The current study was undertaken to explore the antiviral activity of a combination of repurposed drugs that were reported to have anti-CHIKV activity. We explored the effect of different combinations of six effective drugs (2-fluoroadenine, emetine, lomibuvir, enalaprilat, metyrapone and resveratrol) at their non-toxic concentrations against CHIKV under post infection treatment conditions in Vero cells. Focus-forming unit assay, real time RT-PCR, immunofluorescence assay, and western blot were used to determine the virus titre. The results revealed that the combination of 2-fluoroadenine with either metyrapone or emetine or enalaprilat exerted inhibitory activity against CHIKV under post-infection treatment conditions. The effect of these drug combinations was additive in nature compared to the effect of the individual drugs. The results suggest an additive anti-viral effect of these drug combinations against CHIKV. The findings could serve as an outline for the development of an innovative therapeutic approach in the future to treat CHIKV-infected patients.

Focused Update on Pharmacologic Management of Hypertensive Emergencies.

PURPOSE OF REVIEW: Hypertensive emergency is defined as a systolic blood pressure > 180 mmHg or a diastolic blood pressure > 120 mmHg with evidence of new or progressive end-organ damage. The purpose of this paper is to review advances in the treatment of hypertensive emergencies within the last 5 years. RECENT FINDINGS: New literature and recommendations for managing hypertensive emergencies in the setting of pregnancy, stroke, and heart failure have been published. Oral nifedipine is now considered an alternative first-line therapy, along with intravenous hydralazine and labetalol for women presenting with pre-eclampsia. Clevidipine is now endorsed by guidelines as a first-line treatment option for blood pressure reduction in acute ischemic stroke and may be considered for use in intracranial hemorrhage. Treatment of hypertensive heart failure remains challenging; clevidipine and enalaprilat can be considered for use in this population although data supporting their use remains limited.

A Soluble Guanylate Cyclase Activator Inhibits the Progression of Diabetic Nephropathy in the ZSF1 Rat.

Therapies that restore renal cGMP levels are hypothesized to slow the progression of diabetic nephropathy. We investigated the effect of BI 703704, a soluble guanylate cyclase (sGC) activator, on disease progression in obese ZSF1 rats. BI 703704 was administered at doses of 0.3, 1, 3, and 10 mg/kg/d to male ZSF1 rats for 15 weeks, during which mean arterial pressure (MAP), heart rate (HR), and urinary protein excretion (UPE) were determined. Histologic assessment of glomerular and interstitial lesions was also performed. Renal cGMP levels were quantified as an indicator of target modulation. BI 703704 resulted in sGC activation, as evidenced by dose-dependent increases in renal cGMP levels. After 15 weeks of treatment, sGC activation resulted in dose-dependent decreases in UPE (from 463 ± 58 mg/d in vehicle controls to 328 ± 55, 348 ± 23, 283 ± 45, and 108 ± 23 mg/d in BI 703704-treated rats at 0.3, 1, 3, and 10 mg/kg, respectively). These effects were accompanied by a significant reduction in the incidence of glomerulosclerosis and interstitial lesions. Decreases in MAP and increases in HR were only observed at the high dose of BI 703704. These results are the first demonstration of renal protection with sGC activation in a nephropathy model induced by type 2 diabetes. Importantly, beneficial effects were observed at doses that did not significantly alter MAP and HR.

Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines.

The renin-angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5µg/h) or vehicle for 4weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1ß and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy.

A Transcriptomics-Based Bioinformatics Approach for Identification and In Vitro Screening of FDA-Approved Drugs for Repurposing against Dengue Virus-2.

The rising incidence of dengue virus (DENV) infections in the tropical and sub-tropical regions of the world emphasizes the need to identify effective therapeutic drugs against the disease. Repurposing of drugs has emerged as a novel concept to combat pathogens. In this study, we employed a transcriptomics-based bioinformatics approach for drug identification against DENV. Gene expression omnibus datasets from patients with different grades of dengue disease severity and healthy controls were used to identify differentially expressed genes in dengue cases, which were then applied to the query tool of Connectivity Map to identify the inverse gene-disease-drug relationship. A total of sixteen identified drugs were investigated for their prophylactic, virucidal, and therapeutic effects against DENV. Focus-forming unit assay and quantitative RT-PCR were used to evaluate the antiviral activity. Results revealed that five compounds, viz., resveratrol, doxorubicin, lomibuvir, elvitegravir, and enalaprilat, have significant anti-DENV activity. Further, molecular docking studies showed that these drugs can interact with a variety of protein targets of DENV, including the glycoprotein, the NS5 RdRp, NS2B-NS3 protease, and NS5 methyltransferase The in vitro and in silico results, therefore, reveal that these drugs have the ability to decrease DENV-2 production, suggesting that these drugs or their derivatives could be attempted as therapeutic agents against DENV infections.

Combining angiotensin II blockade and renin receptor inhibition results in enhanced antifibrotic effect in experimental nephritis.

The limited antifibrotic effect of therapeutic angiotensin blockade, the fact that angiotensin blockade dramatically elevates renin levels, and recent evidence that renin has an angiotensin-independent, receptor-mediated profibrotic action led us to hypothesize that combining renin receptor inhibition and ANG II blockade would increase the antifibrotic effect of angiotensin blockade alone. Using cultured nephritic glomeruli from rats with anti-Thy-1-induced glomerulonephritis, the maximally effective dose of enalaprilate was determined to be 10(-4) M, which reduced mRNAs for transforming growth factor (TGF)-ß1, fibronectin (FN), and plasminogen activator inhibitor-1 (PAI-1) by 49, 65, and 56% and production of TGF-ß1 and FN proteins by 60 and 49%, respectively. Disease alone caused 6.8-fold increases in ANG II levels that were reduced 64% with enalaprilate. In contrast, two- and threefold disease-induced increases in renin mRNA and activity were further increased 2- and 3.7-fold with 10(-4) M enalaprilate treatment. Depressing the renin receptor by 80% with small interfering (si) RNA alone reduced fibrotic markers in a manner remarkably similar to enalaprilate alone but had no effect on glomerular renin expression. Enalaprilate and siRNA combination therapy further reduced disease markers. Notably, elevated TGF-ß1 and FN production was reduced by 73 and 81%, respectively. These results support the notion of a receptor-mediated profibrotic action of renin, suggest that the limited effectiveness of ANG II blockade may be due, at least in part, to the elevated renin they induce, and support our hypothesis that adding renin receptor inhibitor to ANG II blockade in patients may have therapeutic potential.

Diallyl sulfide protects against dilated cardiomyopathy via inhibition of oxidative stress and apoptosis in mice.

Cytochrome P450 family 2 subfamily E member 1 (CYP2E1) is a member of the cytochrome P450 enzyme family and catalyzes the metabolism of various substrates. CYP2E1 is upregulated in multiple heart diseases and causes damage mainly via the production of reactive oxygen species (ROS). In mice, increased CYP2E1 expression induces cardiac myocyte apoptosis, and knockdown of endogenous CYP2E1 can attenuate the pathological development of dilated cardiomyopathy (DCM). Nevertheless, targeted inhibition of CYP2E1 via the administration of drugs for the treatment of DCM remains elusive. Therefore, the present study aimed to investigate whether diallyl sulfide (DAS), a competitive inhibitor of CYP2E1, can be used to inhibit the development of the pathological process of DCM and identify its possible mechanism. Here, cTnTR141W transgenic mice, which developed typical DCM phenotypes, were used. Following treatment with DAS for 6 weeks, echocardiography, histological analysis and molecular marker detection were conducted to investigate the DAS­induced improvement on myocardial function and morphology. Biochemical analysis, western blotting and TUNEL assays were used to detected ROS production and myocyte apoptosis. It was found that DAS improved the typical DCM phenotypes, including chamber dilation, wall thinning, fibrosis, poor myofibril organization and decreased ventricular blood ejection, as determined using echocardiographic and histopathological analyses. Furthermore, the regulatory mechanisms, including inhibition both of the oxidative stress levels and the mitochondria­dependent apoptosis pathways, were involved in the effects of DAS. In particular, DAS showed advantages in terms of improved chamber dilation and dysfunction in model mice, and the improvement occurred in the early stage of the treatment compared with enalaprilat, an angiotensin­converting enzyme inhibitor that has been widely used in the clinical treatment of DCM and HF. The current results demonstrated that DAS could protect against DCM via inhibition of oxidative stress and apoptosis. These findings also suggest that inhibition of CYP2E1 may be a valuable therapeutic strategy to control the development of heart diseases, especially those associated with CYP2E1 upregulation. Moreover, the development of DAS analogues with lower cytotoxicity and metabolic rate for CYP2E1 may be beneficial.

Perioperative hypertension management.

Perioperative hypertension is commonly encountered in patients that undergo surgery. While attempts have been made to standardize the method to characterize the intraoperative hemodynamics, these methods still vary widely. In addition, there is a lack of consensus concerning treatment thresholds and appropriate therapeutic targets, making absolute recommendations about treatment difficult. Nevertheless, perioperative hypertension requires careful management. When treatment is necessary, therapy should be individualized for the patient. This paper reviews the pharmacologic agents and strategies commonly used in the management of perioperative hypertension.

[Protective effect of enalaprilat injection against early postburn organ damage in rats].

OBJECTIVE: To investigate the dose-effect relationship of enalaprilat (ENA) injection on the organ damage following early burn injury in rats. METHODS: A total of 54 SD rats were subjected to 30% total body surface area III scald injury, and were randomly divided into simple scald group (B group, with conventional fluid transfusion after scald), ENA treated group (E1, E2, E3 group, with intraperitoneal enalaprilat injection of 1, 2, 4 mg/kg after scald respectively). Other 6 rats were taken as normal control. Aortic systolic pressure (AOSP), aortic diastolic blood pressure (AODP), mean arterial pressure (MAP), angiotensin 1, blood urea nitrogen (Bun), creatinine (Cr), creatinine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST) of the simple scald group, E1 group, E2 group and E3 group were investigated at 6 h and 12 h post burn. RESULTS: Ang II, Bun, Cr, CK, ALT, AST levels in ENA treated group after 6 h and 12 hours were significantly lower than those of simple scald group (all P < 0.05). AOSP, AODP, MAP in ENA treated group after 6 and 12 hours were significantly higher than those of simple scald group (all P < 0.05). CONCLUSION: Low-dose enalaprilat, injection (1 mg/kg) could alleviate organ damage in post-burned rats, but has little effect on AOSP and AODP.

Effects of enalaprilat on acute necrotizing pancreatitis in rats.

The aim of this study was to investigate the influence of enalaprilat on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. The induction of ANP resulted in a significant increase in the mortality rate, pancreatic necrosis, serum activity of amylase, alanine aminotransferase (ALT), and interleukin-6 (IL-6), lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, serum concentration of urea, and tissue activity of myeloperoxidase (MPO) and maondialdehyde (MDA) in the pancreas and lung, and a significant decrease in concentrations of calcium, blood pressure, urine output and p0(2). The use of enalaprilat inhibited the changes in urine output, blood pressure, serum concentration of urea, p0(2), and tissue activity of MPO and MDA in the pancreas and lungs. It reduced the mortality and pancreatic damage. Enalaprilat demonstrated a beneficial effect on the course of ANP in rats; therefore, it may be used in the treatment of acute pancreatitis.

Effect of low dose aspirin on cardiorenal function and acute hemodynamic response to enalaprilat in a canine model of severe heart failure.

OBJECTIVES: This study examined the effect of low dose aspirin on cardiorenal and neurohumoral function and on the acute hemodynamic response to enalaprilat in a canine model of heart failure. BACKGROUND: Low dose aspirin is frequently prescribed for patients with systolic dysfunction who also benefit from angiotensin-converting enzyme inhibition. Although high doses of potent cyclo-oxygenase inhibitors cause fluid retention and vaso-constriction and antagonize the effects of angiotensin-converting enzyme inhibitors, the effects of low dose aspirin in heart failure are unknown. METHODS: A model of heart failure was produced in 11 mongrel dogs by rapid ventricular pacing (250 beats/min for 12 to 14 days). Five dogs received 325 mg aspirin/day for the final 4 days of pacing before the acute experiment; six control dogs received no aspirin. Cardiorenal and neurohumoral function was measured during chloralose anesthesia. Hemodynamic and renal responses to enalaprilat were assessed. RESULTS: Both groups demonstrated severe heart failure with decreased cardiac output; increased atrial pressures and systemic resistance; activation of plasma renin activity, aldosterone and atrial natriuretic factor; and sodium retention. Low dose aspirin had no detrimental effect on cardiorenal or neurohumoral function. Mean arterial pressure, pulmonary capillary wedge pressure and systemic vascular resistance decreased to a similar degree with enalaprilat in both groups. There was no difference between the groups with respect to renal response to enalaprilat. CONCLUSIONS: The present study demonstrates that low dose aspirin has no adverse effect on hemodynamic, neurohumoral or renal function in heart failure. Furthermore, aspirin has no adverse effect on the acute response to enalaprilat. These findings suggest that there is no contraindication to concomitant treatment with low dose aspirin and angiotensin-converting enzyme inhibitors in humans with heart failure.

The utility of renal venous renin studies in selection of patients with renal artery stenosis for angioplasty: a retrospective study.

OBJECTIVES: Recent studies of renal artery stenosis (RAS) failed to demonstrate greater benefit from angioplasty in terms of blood pressure (BP) lowering than medical treatment. Not all RAS are haemodynamically significant and identification of patients likely to benefit from angioplasty remains essential. METHODS: We examined whether performing renal venous renin studies under stringent conditions might predict BP improvement. Patients with at least 60% RAS who underwent renal venous renin measurements in 2008-2013 were identified. Renal venous renin lateralization ratios (RVRRs) were calculated by dividing venous renin from the stenotic kidney with contralateral levels before and after stimulation with enalaprilat or captopril. Benefit was defined as BP less than 140/90  mmHg without medication, 10% decreased mean BP without increased daily defined doses (DDDs) or decreased DDD without a significant increase of mean BP. RESULTS: Twenty-eight patients were treated medically and 42 with angioplasty (median age 60.1 years, 41% male, 29% chronic kidney disease, 50% resistant hypertension). At 11.4 ±â€Š3.3 months, 69% of patients treated with angioplasty had BP benefit compared with 25% with medical treatment (P < 0.001). Logistic regression identified resistant hypertension [odds ratio (OR) 0.18, 95% confidence interval (95% CI) 0.04-0.82, P = 0.03] and baseline DDD (OR 0.69, 95% CI 0.48-0.98, P = 0.04) as being negatively associated, and positive stimulated RVRR (OR 21.6, 95% CI 3.50-133.3, P = 0.001) positively associated with benefit from angioplasty. On multivariate logistic regression, only stimulated RVRR positivity predicted BP benefit (OR 20.5, 95% CI 2.9-145.0, P = 0.003). CONCLUSION: These findings suggest that a positive stimulated RVRR measured under optimal conditions may help to identify patients with RAS likely to improve from angioplasty.

A study of the interaction between the hypotensive actions of doxazosin and enalaprilat in anaesthetized rats.

OBJECTIVE AND DESIGN: This study was designed to test whether previous work, which showed that the angiotensin converting enzyme (ACE) inhibitor enalaprilat potentiated the alpha 1-adrenoceptor antagonist activity of doxazosin in isolated rat tail arteries, could be extended to demonstrate a synergistic hypotensive effect of these two drugs. METHODS: Groups of untreated or chronically deoxycorticosterone acetate (DOCA)-salt-treated female Sprague-Dawley rats were used. Rats were anaesthetized with Inactin (barbiturate); drugs were administered via a jugular venous catheter; blood pressure was monitored via a carotid arterial catheter. RESULTS: In previously untreated rats, pretreatment with enalaprilat shifted the dose-response curve for the hypotensive effect of doxazosin to the left, indicating synergism. In rats dosed with DOCA-salt (which suppresses renin and angiotensin II production): (1) there was no synergism between the hypotensive actions of enalaprilat and doxazosin; (2) doxazosin was more potent than in untreated rats; and (3) enalaprilat lowered blood pressure, suggesting a hypotensive mechanism separate from ACE inhibition. CONCLUSION: In the absence of angiotensin II (resulting from enalaprilat administration or from chronic DOCA-salt), doxazosin had a greater hypotensive action than in the presence of angiotensin II. This is consistent with the concept that angiotensin II modulates alpha 1-adrenoceptor activity.

Attenuation of thrombolysis-induced increase of plasminogen activator inhibitor-1 by intravenous enalaprilat.

We examined the effect of intravenous enalaprilat on the course of PAI-1 plasma levels in 23 patients with acute myocardial infarction undergoing thrombolytic therapy. All patients received 100 mg aspirin, 1000 IU/h heparin, thrombolysis with 100 mg rt-PA within 90 min, and betablockers. Eleven out of 23 patients received 5 mg enalaprilat intravenously prior to thrombolysis. Blood samples for determination of PAI-1 plasma levels were collected on admission, 2, 4, 6, 12, and 24 h after thrombolysis. PAI-1 plasma levels in patients receiving enalaprilat were similar to those of the control patients before thrombolysis (5 ng/ml, 95% confidence interval: 2-10 vs. 7 ng/ml, 95% confidence interval: 2-10; p = 0.5). The PAI-1AUC was 9 ng/ml/h (95% confidence interval: 5-10) in the enalaprilat group and 19 ng/ml/h (95% confidence interval: 13-26) in the control group (p = 0.0006). The maximum difference was observed 6 h after thrombolysis (enalaprilat: 13 ng/ml, 95% confidence interval: 5-25, control: 42 ng/ml, 95% confidence interval: 18-55; p = 0.003). Our study clearly demonstrates that application of intravenous enalaprilat prior to thrombolysis attenuates the thrombolysis-related increase of PAI-1. This finding may suggest a possible therapeutic approach to influence the fibrinolytic system in patients with acute myocardial infarction after thrombolysis.

Blood pressure response to the first dose of angiotensin-converting enzyme inhibitors in congestive heart failure.

Angiotensin-converting enzyme (ACE) inhibitors improve survival in heart failure and delay progression to clinical heart failure in patients with left ventricular dysfunction after myocardial infarction. Increasing numbers of older patients are being considered for such treatment. However, there are reports of excessive and prolonged decreases in blood pressure (BP) after the first dose of some ACE inhibitors. We have studied the hemodynamics, pharmacokinetics, and neurohumoral responses to the first dose of oral captopril 6.25 mg, enalapril 2.5 mg, perindopril 2.0 mg, intravenous enalaprilat 1.5 mg, and perindoprilat 1.0 mg, compared with oral or intravenous placebo in 6 parallel groups of 12 elderly patients each with moderate-to-severe (New York Heart Association classes II-IV) heart failure. Oral dosing with active drugs led to different temporal responses. After captopril, there was an early short-lived decrease in BP. Enalapril led to a later long-lasting decrease, but perindopril was not different from placebo. Intravenous enalaprilat and intravenous perindoprilat each lowered BP to a similar extent. The doses of drugs used appeared to be comparable because plasma ACE inhibition was similar following perindopril or enalapril and also comparing perindoprilat and enalaprilat. These studies indicate that oral ACE inhibitors have different profiles of acute BP changes after the first dose. The explanation is not clear, but could include physicochemical differences in the interaction between prodrug ester and diacid metabolites leading to differences in tissue distribution and local enzyme inhibition.

Effect of enalaprilat on nitric oxide activity in coronary artery disease.

Atherosclerosis is associated with vascular endothelial dysfunction and reduced nitric oxide (NO) activity. Enhancement of NO activity may have an antiatherogenic action. This study was performed to determine whether angiotensin-converting enzyme (ACE) inhibition improves peripheral vascular NO activity in patients with atherosclerosis. In the femoral circulation of 43 patients with atherosclerosis and 10 controls, we studied endothelium-dependent vasodilation with bradykinin and acetylcholine, and endothelium-independent vasodilation with sodium nitroprusside before and after enalaprilat. In 22 patients, we repeated these infusions in the presence of L-N(G) monomethyl arginine (L-NMMA). Doppler-femoral artery flow velocity was measured. Before ACE inhibition, acetylcholine responses were depressed in patients with atherosclerosis compared with controls (p = 0.03). Enalaprilat did not alter femoral vascular tone at rest or vasodilation with sodium nitroprusside, but potentiated bradykinin-mediated vasodilation in patients (p<0.001) and controls (p = 0.02). Acetylcholine-mediated vasodilation was augmented only in patients (p<0.001), but not in control subjects. L-NMMA inhibited the potentiation by enalaprilat of acetylcholine and bradykinin responses. This study demonstrates that ACE inhibition selectively improves endothelial dysfunction in human atherosclerosis by enhancing NO activity. The antithrombotic and antiproliferative effects of NO may reduce adverse manifestations related to atherosclerosis during long-term therapy.

Effect of enalaprilat on bradykinin and des-Arg9-bradykinin release following reperfusion of the ischaemic rat heart.

1. The release of bradykinin (BK) and its metabolite, des-Arg9-bradykinin (des-Arg9-BK), was studied following reperfusion of a globally ischaemic rat heart. 2. BK-like immunoreactivity increased from 13 +/- 3 (preischaemic value) to 48 +/- 12 fmol min-1 g-1 (P < 0.05, n = 14) 30 s after reperfusion. No difference in BK release was found between control hearts and hearts pretreated with the angiotensin converting enzyme (ACE or kininase II) inhibitor, enalaprilat (50 ng ml-1). 3. No significant change in des-Arg9-BK-like immunoreactivity during reperfusion was observed in control hearts. In contrast, des-Arg9-BK-like immunoreactivity rose from 44 +/- 15 to 177 +/- 61 fmol min-1 g-1 (P < 0.05, n = 7) 30 s after reperfusion in enalaprilat-treated hearts. 4. In conclusion, BK is released upon reperfusion of the globally ischaemic rat heart. ACE inhibitors, through the inhibition of kininase II, increase the formation of the active metabolite, des-Arg9-BK.

Comparison of the effects of EXP3174, an angiotensin II antagonist and enalaprilat on myocardial infarct size in anaesthetized dogs.

1. In order to determine whether the renin-angiotensin system is involved in myocardial ischaemia-reperfusion injury, we investigated and compared the effects on infarct size of two different drugs which interfere with this system, i.e., an angiotensin II (AT1) antagonist, EXP3174, and an angiotensin I-converting enzyme inhibitor (ACEI), enalaprilat in a canine model of ischaemia-reperfusion. 2. EXP3174 (0.1 mg kg-1, i.v. followed by 0.02 mg kg-1 h-1 for 5.5 h) and enalaprilate (0.3 mg kg-1, i.v. followed by 0.06 mg kg-1 h-1 for 5.5 h) were used in doses inducing a similar level of inhibition (87 +/- 4 and 91 +/- 3%, respectively) of the pressor responses to angiotensin I. Control animals received saline. 3. Infarct size and area at risk were quantified by ex vivo dual coronary perfusion with triphenyltetrazolium chloride and monastral blue dye. Regional myocardial blood flows (ischaemic and nonischaemic, endocardial, epicardial) were assessed by the radioactive microsphere technique. 4. Both EXP3174 and enalaprilat induced a decrease in mean arterial blood pressure. However, non significant changes in regional myocardial blood flows, whether ischaemic or nonischaemic, were observed after administration of either the ACEI or the AT1 antagonist. 5. The size of the area at risk was similar in the three groups. By direct comparison, there were no significant differences between infarct sizes in the three groups. Furthermore, there was a close inverse relationship between infarct size and transmural mean collateral blood flow in controls, and none of the treatments altered this correlation. Thus, neither EXP3174 nor enalaprilat limited infarct size. 6. These results indicate that activation of the renin-angiotensin system does not contribute to myocyte death in this canine ischaemia/reperfusion model.

Systemic and coronary haemodynamics and pharmacodynamics of enalapril and enalaprilat in congestive heart failure.

Enalapril is an effective angiotensin-converting enzyme (ACE) inhibitor which produces salutary, beneficial haemodynamic effects in patients with congestive heart failure. Enalapril also produces beneficial neurohumoral changes, as well as improving abnormal coronary haemodynamics and myocardial energetics that are frequently encountered in these patients. Administration of enalapril once or twice daily appears to be quite effective during maintenance therapy in patients with chronic congestive heart failure.

Enalaprilat improves gut perfusion in critically injured patients.

Inadequate splanchnic perfusion, detected as a low gastric intramucosal pH (pHi), in the face of normal systemic perfusion predicts an increased risk for multiple organ failure after trauma. Although the exact etiology of this low pHi is unknown, angiotensin II is thought to be an important regulator of gut perfusion during and after resuscitation from shock. The purpose of this study is to determine whether enalaprilat, an angiotensin-converting enzyme inhibitor, improves gut perfusion in critically injured patients. To test this hypothesis, 18 trauma patients monitored with a nasogastric tonometer and a pulmonary artery catheter were enrolled in a prospective study. A single dose of enalaprilat, .625 mg, was given as an i.v. bolus or a 4 h infusion following systemic resuscitation. Pre- and postdrug tonometric and hemodynamic data, including cardiac index, mean arterial pressure, right ventricular end-diastolic volume index, systemic vascular resistance index, and oxygen transport variables were compared using the paired t test. Results demonstrate that pHi was significantly improved after 4 h (7.13 +/- .04 to 7.19 +/- .03, p = .03) and after 24 h compared with baseline (7.14 +/- .04 to 7.25 +/- .04, p = .04). Overall, pHi increased in 12 of 18 patients. No significant differences were observed in any of the studied hemodynamic or systemic perfusion variables including mean arterial pressure (92 +/- 4 to 87 +/- 4, p = .24) and oxygen delivery (669 +/- 33 to 675 +/- 32, p = .82). In examining the determinants of pHi, the intramucosal-arterial PCO2 difference was improved after enalaprilat administration (27 +/- 6 to 17 +/- 3 mmHg, p = .04) while no difference was observed in arterial bicarbonate (19.5 +/- .7 to 19.7 +/- .8, p = .90). Additionally, the change in pHi observed with enalaprilat correlated with predrug intramucosal-arterial PCO2 difference (r = .74, r2 = .55, p = .0005). These results demonstrate that enalaprilat improves gut perfusion as measured by gastric tonometry in critically injured patients, and that this effect appears to be independent of changes in systemic perfusion.