enalaprilat-anhydrous and Disease-Models--Animal

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, cTnT

Topics: Allyl Compounds; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Cardiomyopathy, Dilated; Cardiotonic Agents; Cell Line; Cytochrome P-450 CYP2E1; Disease Models, Animal; Enalaprilat; Female; Male; Mice, Transgenic; Mitochondria; Oxidative Stress; Rats; Sulfides; Troponin T

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Blockade of the renin-angiotensin system (RAS) has been shown to alleviate inflammatory processes in the gastrointestinal tract. The aim of this study was to determine if blockade of the RAS would be effective in an immunologically relevant colitis model, and to compare outcome with an acute colitis model.. In the DSS model, weight loss and histologic score for CCG-203025 were better than with placebo. In the IL10-/-model, ACE-I suppressed histologic damage better than CCG-203025. Both ACE-I and CCG-203025 reduced pro-inflammatory cytokines and chemokines.. This study demonstrated the therapeutic efficacy of both ACE-I and AT1aR-A for preventing the development of both acute and immunologically relevant colitis.

Topics: Acute Disease; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Colitis; Cyclooxygenase Inhibitors; Disease Models, Animal; Enalaprilat; Losartan; Mice; Mice, Inbred C57BL; Piroxicam; Renin-Angiotensin System

BPH/2J mice are recognized as a neurogenic model of hypertension primarily based on overactivity of the sympathetic nervous system and greater neuronal activity in key autonomic cardiovascular regulatory brain regions. The medial amygdala (MeAm) is a forebrain region that integrates the autonomic response to stress and is the only region found to have greater Fos during the night and daytime in BPH/2J compared with BPN/3J mice. To determine the contribution of the MeAm to hypertension, the effect of neuronal ablation on blood pressure (BP) was assessed in BPH/2J (n=7) and normotensive BPN/3J mice (n=7). Mice were preimplanted with radiotelemetry devices to measure 24-hour BP and cardiovascular responses to stress, before and 1 to 3 weeks after bilateral lesions of the MeAm. Baseline BP was 121±4 mm Hg in BPH/2J and 101±2 mm Hg in BPN/3J mice (Pstrain<0.001). MeAm lesions reduced BP by 11±2 mm Hg in BPH/2J mice (Plesion<0.001) but had no effect in BPN/3J mice. The hypotensive effect of lesions in BPH/2J mice was similar during both day and night, suggesting that the MeAm has tonic effects on BP, but the pressor response to stress was maintained in both strains. Midfrequency BP power was attenuated in both strains (Plesion<0.05) and the depressor responses to pentolinium after enalaprilat pretreatment was attenuated after lesions in BPH/2J mice (Plesion<0.001; n=3). These findings indicate that the MeAm provides a tonic contribution to hypertension in BPH/2J mice, which is independent of its role in stress reactivity or circadian BP influences.

Topics: Amygdala; Animals; Blood Pressure; Circadian Rhythm; Disease Models, Animal; Enalaprilat; Hypertension; Male; Mice; Mice, Mutant Strains; Pentolinium Tartrate; Sympathetic Nervous System; Telemetry

Neurogenic pulmonary edema (NPE ) was indicative of poor prognosis in the epidemic of enterovirus 71 infections. The pathogenesis of NPE remains poorly understood. The objectives of this experimental study were to explore whether RAS is activated during NPE in rabbit models induced by fibrin and the effects of an angiotensin converting enzyme inhibitor (enalaprilat) on NPE.. NPE models were induced by intracisternal injection of fibrinogen and thrombin. According to random number table method, 18 healthy adult New Zealand rabbits were assigned to three groups (with 6 in each) : normal control group (Con group), NPE group and enalaprilat treated (Ena) group. After establishment of NPE models, rabbits in Ena group were given intravenous enalaprilat 0.5 mg/kg. Expression of ACE,ACE2,AT1R mRNA of the lung tissue were evaluated by real-time polymerise chain reaction; and Ang II of the lung tissue was determined by enzyme linked immunosorbent assay ( ELISA ). Meanwhile, histopathological lung injury scores were evaluated.. ACE mRNA expression level in NPE group ( 17.2 ± 3.3) appeared an increasing trend in contrast to Con group ( 12.6 ± 5.2 ) and Ena group ( 11.5 ± 2.4, both P > 0.05 ). Compared with Con group (81 ± 22 ), ACE2 mRNA expression levels of NPE group ( 52 ± 6 ) and Ena group ( 45 ± 13 ) both decreased ( both P < 0.05 ) . ACE mRNA/ACE2 mRNA expression levels of NPE group ( 0.33 ± 0.06 ) and Ena group ( 0.26 ± 0.04 ) were higher than those of Con group ( 0.16 ± 0.05, both P < 0.05 ), as well as the ratio of Ena group decreased compared with untreated NPE group ( 0.26 ± 0.04 vs. 0.33 ± 0.06, P < 0.05 ) . There were no statistically significant differences in expression of AT1 mRNA of the lung tissue among three groups, but Ena group ( 4.8 ± 1.1) in contrast to NPE group ( 6.7 ± 1.3) has no significant difference (P > 0.05). Lung AngII level of NPE group [(540 ± 147) pg/ml] was significantly higher than that of Con group [(253 ± 37 ) pg/ml] and Ena group [(309 ± 35 ) pg/ml, both P < 0.05 ]. Gross pathologic examination showed that pink foamy edema fluid appeared in the tracheal tubes in NPE group, but spontaneously appeared in neither Con group nor Ena group; and the level of pulmonary subpleural bleeding in Con group, 12 graded 0; in NPE group, 2 graded II, 10 graded III; in Ena group, 2 graded, 8 grade II, 2 grade III. The histopathologic lung injury scores in Ena group was decreased in contrast to NPE group (1.36 ± 0.26 vs.2.32 ± 0.49, P < 0.05) and mainly for the improvement of alveolar overdistension and interstitial edema.. The present study showed that when NPE occurs, a high lung AngII concentration was associated with an imbalance between ACE mRNA to ACE2 mRNA expression level. Activated local RAS in lung tissue resulted in lung injury. Enalaprilat treatment may attenuate lung injury by interventing local RAS in lung tissue with decreased ratio of ACE mRNA to ACE2 mRNA and lung AngII concentration. The result will be significant for the angiotensin converting enzyme inhibitor used in the theatment of NPE.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalaprilat; Female; Fibrinogen; Gene Expression Regulation, Enzymologic; Lung; Male; Peptidyl-Dipeptidase A; Pulmonary Edema; Rabbits; Random Allocation; Real-Time Polymerase Chain Reaction; RNA, Messenger

Anthracycline therapy is limited by a cardiotoxicity that may eventually lead to chronic heart failure which is thought to be prevented by ACE inhibitors (ACEi). However, the protective effect of ACEi in early stages of this specific injury remains elusive. Activated nuclear transcription factors peroxisome proliferator-activated receptors (PPAR) regulate cellular metabolism, but their involvement in anthracycline cardiomyopathy has not been investigated yet. For this purpose, Wistar rats were administered with daunorubicin (i.p., 3 mg/kg, in 48 h intervals) or co-administered with daunorubicine and enalaprilat (i.p., 5 mg/kg in 12 h intervals). Control animals received vehicle. Left ventricular function was measured invasively under anesthesia. Cell-shortening was measured by videomicroscopy in isolated cardiomyocytes. Expression of PPARs mRNA in cardiac tissue was measured by Real-Time PCR. Although the hemodynamic parameters of daunorubicin-treated rats remained altered upon ACEi co-administration, ACEi normalized daunorubicin-induced QT prolongation. On cellular level, ACEi normalized altered basal and isoproterenol-stimulated cardiac cell shortening in daunorubicine-treated group. Moreover, anthracycline administration significantly up-regulated heart PPARα mRNA and its expression remained increased after ACEi co-administration. On the other hand, the expression of cardiac PPARβ/δ was not altered in anthracycline-treated animals, whereas co-administration of ACEi increased its expression. Conclusively, effect of ACEi can be already detected in sub-acute phase of anthracycline-induced cardiotoxicity. Altered expression of heart PPARs may suggest these nuclear receptors as a novel target in anthracycline cardiomyopathy.

Topics: Animals; Cardiomyopathies; Daunorubicin; Disease Models, Animal; Enalaprilat; Gene Expression Regulation; Heart; Hemodynamics; PPAR delta; PPAR-beta; Rats; Rats, Wistar

Intestinal adaptation in short bowel syndrome (SBS) consists of increased epithelial cells (ECs) proliferation as well as apoptosis. Angiotensin-converting enzyme (ACE) has been shown to regulate ECs apoptosis. In this study, we investigated the effect of ACE inhibition on intestinal adaptation after small bowel resection (SBR) in a rat model.. Sprague-Dawley rats were used and were divided into four groups: (1) Sham group received an ileum transection (n = 6); (2) Sham + ACE-I group received an ileum transaction and lavage with ACE inhibitor (ACE-I, enalaprilat, 2 mg/kg/day) (n = 6); (3) SBS group received a 70 % mid-intestinal resection (n = 6); (4) SBS + ACE-I group received a 70 % mid-intestinal resection and lavage with enalaprilat (2 mg/kg/day) (n = 6). Sampling was done 10 days after surgery. ECs apoptosis was studied by TUNEL staining. ACE, angiotensin II (ANGII) receptor type 1 (AT1R) and receptor type 2 (AT2R) expressions were detected with RT-PCR and immunofluorescent confocal microscopy.. SBR leads to significant intestinal hypertrophy. The addition of ACE-I to SBS rat resulted in a significant decline in ECs apoptosis. ACE mRNA expression was significantly elevated after SBS creation (0.24 ± 0.07 vs. 0.42 ± 0.11), and ACE-I administration further increased mucosal ACE mRNA expression (0.54 ± 0.12). Interestingly, AT1R mRNA expression showed a significant decline in the SBS group compared to Sham levels, and ACE-I administration increased AT1R mRNA expression to Sham levels. No significant difference in AT2R mRNA expression was found between Sham and SBS group.. These results offer further insight into the role of ACE on intestinal mucosal remolding after massive bowel resection. ACE-I may be beneficial to SBS patients via a reduction of the apoptotic rate, thus facilitating the degree of adaptation.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Disease Models, Animal; Enalaprilat; In Situ Nick-End Labeling; Male; Microscopy, Confocal; Microscopy, Fluorescence; Polymerase Chain Reaction; Random Allocation; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome

Topics: Animals; Burns; Disease Models, Animal; Enalaprilat; Humans; Hypoxia; Mitogen-Activated Protein Kinases; Nitric Oxide Synthase; Protoporphyrins; Sepsis; Shock

The study aimed to predict effective human jejunal permeability (P(eff)) using a biophysical model based on parametrized paracellular, aqueous boundary layer, and transcellular permeabilities, and the villus-fold surface area expansion factor (k(VF)). Published human jejunal data (119 P(eff), 53 compounds) were analyzed by a regression procedure incorporating a dual-pore size paracellular model. Transcellular permeability, scaled by k(VF), was equated to that of Caco-2 at pH 6.5. The biophysical model predicted human jejunal permeability data within the experimental uncertainty. This investigation revealed several surprising predictions: (i) many molecules permeate predominantly (but not exclusively) by the paracellular route, (ii) the aqueous boundary layer thickness in the intestinal perfusion experiments is larger than expected, (iii) the mucosal surface area in awake humans is apparently nearly entirely accessible to drug absorption, and (iv) the relative "leakiness" of the human jejunum is not so different from that observed in a number of published Caco-2 studies.

Topics: Animals; Disease Models, Animal; Dogs; Humans; Jejunal Diseases; Kidney Diseases; Models, Biological; Permeability; Porosity; Regression Analysis

Angiotensin II maintains renal cortical blood flow and renal oxygenation in the clipped kidney of early 2-kidney, 1-clip Goldblatt hypertensive (2K,1C) rats. The involvement of Ang II is believed to decline, whereas oxidative stress increases during the progression of 2K,1C hypertension. We investigated the hypothesis that the acute administration of drugs to inhibit reactive oxygen species (Tempol), angiotensin II type 1 receptors (candesartan), or angiotensin-converting enzyme (enalaprilat) lowers mean arterial pressure and increases kidney blood flow and oxygenation in the clipped kidney of chronic 2K,1C rats in contrast to sham controls. Twelve months after left renal artery clipping or sham, mean arterial pressure, renal cortical blood flow, and renal cortical and medullary oxygen tension were measured after acute administration of Tempol followed by enalaprilat or candesartan followed by enalaprilat. The mean arterial pressure of the 2K,1C rat was reduced by candesartan (-9%) and, more effectively, by Tempol (-35%). All of the applied treatments had similar blood pressure-lowering effects in sham rats (average: -21%). Only Tempol increased cortical blood flow (+35%) and cortical and medullary oxygen tensions (+17% and +94%, respectively) in clipped kidneys of 2K,1C rats. Administration of enalaprilat had no additional effect, except for a modest reduction in cortical blood flow in the clipped kidney of 2K,1C rats when coadministered with candesartan (-10%). In conclusion, acute administration of Tempol is more effective than candesartan in reducing the mean arterial blood pressure and improving renal blood perfusion and oxygenation in the clipped kidney of chronic 2K,1C rats.

Topics: Analysis of Variance; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cyclic N-Oxides; Disease Models, Animal; Enalaprilat; Glomerular Filtration Rate; Hypertension, Renovascular; Male; Organ Size; Oxygen Consumption; Probability; Random Allocation; Rats; Rats, Sprague-Dawley; Renal Circulation; Spin Labels; Tetrazoles; Vascular Resistance

To investigate the dose-effect relationship of enalaprilat (ENA) injection on the organ damage following early burn injury in rats.. 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.. 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).. Low-dose enalaprilat, injection (1 mg/kg) could alleviate organ damage in post-burned rats, but has little effect on AOSP and AODP.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Burns; Disease Models, Animal; Dose-Response Relationship, Drug; Enalaprilat; Female; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Viscera

To investigate the effects of single or combined administration of cedilanid and small-dose of enalaprilat on heart, liver, kidney and intestine damages at early stage of severe scald in rats.. Forty healthy male Wistar rats were enrolled in the study and randomly divided into: sham, burn control, cedilanid, enalaprilat, cedilanid + enalaprilat groups, with 8 rats in each group. Rats, except that of sham group (simulated scald with 37 degrees C water) were inflicted with 30% TBSA full-thickness scald, and were injected with Ringer's lactate solution (4 mLxkg(-1)x1% TBSA(-1)) intraperitoneally 30 minutes after burn. Then rats in cedilanid group were given cedilanid injection (0.2 mg/kg) intravenously, and those in enalaprilat group were given enalaprilat (1 mg/kg), and cedilanid + enalaprilat group with cedilanid and enalapril in the same dosage. At 6 post burn hour (PBH) or sham injury, parameters of myocardiac mechanics were recorded with the Multiple Channel Physiological Signal Collecting and Processing System. The blood flow of the liver, kidney and intestine was respectively detected with the Laser Doppler Flowmetry at 6 PBH. Serum contents of cTnI, TBA, beta2-MG and DAO were determined at 6 PBH to reflect visceral damages.. Compared with those in sham group, the parameters of myocardiac mechanics and blood flow of liver, kidney, intestine (158 +/- 32, 156 +/- 46, 119 +/- 30 PU, respectively) in burn control group were obviously decreased (P < 0.05), and the serum contents of cTnI, TBA, beta2-MG, DAO (5.0 +/- 0.3 microg/L, 82 +/- 23 micromol/L, 2.55 +/- 0.15 mg/L, 1.52 +/- 0.08 kU/L, respectively) in burn control group were obviously increased (P < 0.05). Compared with those in burn control group, the parameters of myocardiac mechanics and blood flow of liver, kidney, intestine in the cedilanid or enalaprilat groups increased markedly, and their serum contents of cTnI, TBA, beta2-MG, DAO decreased significantly (P < 0.05). Compared with those in burn control group, the parameters of myocardiac mechanics and blood flow of liver, kidney, intestine (240 +/- 49, 239 +/- 75, 194 +/- 55 PU, respectively) in cedilanid + enalaprilat group increased significantly (P < 0.05), and the serum contents of cTnI, TBA, beta2-MG, DAO (3.43 +/- 0.21 microg/L, 47 +/- 8 micromol/L, 2.01 +/- 0.16 mg/L, 1.17 +/- 0.15 kU/L, respectively) were decreased (P < 0.05).. Single administration of cedilanid or small-dose enalaprilat can ameliorate impairment of cardiac functions, prevent damages to liver, kidney and intestine in early stage of severe scald in rats. Combined administration of cedilanid and small-dose enalaprilat seems to be more effective.

Topics: Animals; Burns; Deslanoside; Disease Models, Animal; Drug Therapy, Combination; Enalaprilat; Male; Random Allocation; Rats; Rats, Wistar; Viscera

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.

Topics: Alanine Transaminase; Amylases; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bronchoalveolar Lavage Fluid; Calcium; Ceruletide; Disease Models, Animal; Enalaprilat; Glycodeoxycholic Acid; Interleukin-6; L-Lactate Dehydrogenase; Lung; Male; Malondialdehyde; Oxygen; Pancreas; Pancreatitis, Acute Necrotizing; Partial Pressure; Peroxidase; Rats; Rats, Sprague-Dawley; Urea; Urination

Angiotensin-converting enzyme inhibitors have been shown to improve splanchnic perfusion in distinct shock states. We hypothesized that enalaprilat potentiates the benefits of early fluid resuscitation in severe experimental sepsis, particularly in the splanchnic region. Anesthetized and mechanically ventilated mongrel dogs received an intravenous infusion of live Escherichia coli over a period of 30 min. Thereafter, two interventions were performed: fluid infusion (normal saline, 32 mL/kg over 30 min) and enalaprilat infusion (0.02 mg kg(-1) min(-1) for 60 min) in randomized groups. The following groups were studied: controls (fluid infusion, N = 4), E1 (enalaprilat infusion followed by fluid infusion, N = 5) and E2 (fluid infusion followed by enalaprilat infusion, N = 5). All animals were observed for a 120 min after bacterial infusion. Mean arterial pressure, cardiac output (CO), portal vein blood flow (PVBF), systemic and regional oxygen-derived variables, and lactate levels were measured. Rapid and progressive reductions in CO and PVBF were induced by the infusion of live bacteria, while minor changes were observed in mean arterial pressure. Systemic and regional territories showed a significant increase in oxygen extraction and lactate levels. Widening venous-arterial and portal-arterial pCO2 gradients were also detected. Fluid replacement promoted transient benefits in CO and PVBF. Enalaprilat after fluid resuscitation did not affect systemic or regional hemodynamic variables. We conclude that in this model of normotensive sepsis inhibition of angiotensin-converting enzyme did not interfere with the course of systemic or regional hemodynamic and oxygen-derived variables.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiac Output; Disease Models, Animal; Dogs; Enalaprilat; Escherichia coli Infections; Fluid Therapy; Infusions, Intravenous; Lactic Acid; Male; Portal Vein; Regional Blood Flow; Resuscitation; Severity of Illness Index; Shock, Septic

Acute cyclosporine (CsA) nephrotoxicity cannot be easily differentiated from other renal parenchymal complications, such as acute tubular necrosis (ATN), that cause renal function impairment at the early posttransplantation period. The purpose of this study was to differentiate acute CsA nephrotoxicity from ATN using enalaprilat renal scintigraphy in rats.. Twenty-six rats were divided into 4 experimental groups: CsA group, who were treated with CsA (50 mg/kg/d) for 2 days; ATN group, who received clamping of both renal arteries for 45 minutes; vehicle group, who were treated with olive oil (1 mL/kg/d) for 2 days; and sham-operated group, who received the same surgical procedure as ATN group without clamping of renal arteries. The baseline study was performed with 300 microCi of technetium-99m diethylenetriaminepentaacetic acid and enalaprilat scintigraphy with 2 mCi of technetium-99m diethylenetriaminepentaacetic acid 5 minutes after intravenous enalaprilat injection (30 microg/kg). The changes of renogram grade and the renal function indices such as T(max), T(1/2), residual cortical activity, and mean transit time between 2 studies were analyzed. Immediately after renal scintigraphy, blood urea nitrogen and serum creatinine levels were measured and renal tissues stained by periodic acid Schiff reaction were examined in each group.. Blood urea nitrogen and serum creatinine levels in the CsA and ATN groups were higher than their control groups (P < 0.05). Histologic study revealed severe ischemic necrosis of tubular epithelium in ATN group, but the other groups remained with essentially normal morphology. After enalaprilat injection, renal function indices became improved in CsA group, whereas they deteriorated in ATN group. The renogram grade was decreased in CsA group and increased or unchanged in ATN group after enalaprilat injection. The T(max), residual cortical activity, and mean transit time ratio were statistically different between the 2 groups on enalaprilat study (P < 0.05).. These results suggest that enalaprilat renal scintigraphy could be used clinically in differentiating acute CsA nephrotoxicity from ATN after renal transplantation.

Topics: Animals; Blood Urea Nitrogen; Creatinine; Cyclosporine; Diagnosis, Differential; Disease Models, Animal; Enalaprilat; Kidney Function Tests; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Male; Nephrons; Radionuclide Imaging; Rats; Rats, Sprague-Dawley

The stress-responsive mitogen-activated protein kinases (MAPKs) (p38-MAPK, c-Jun NH2-terminal kinase [JNK-1 and JNK-2], and extracellular signal regulated kinases [ERK-1 and ERK-2]) might be involved in angiotensin II (AII)-induced ischemia-reperfusion injury. Cardioprotection induced by AII type 1 (AT1) and type 2 (AT2) receptor blockade during ischemia-reperfusion is associated with protein kinase Cepsilon (PKCepsilon), nitric oxide, and cyclic guanosine monophosphate (cGMP) signaling. Our aim was to assess the effect of selective AT1 and AT2 receptor blockade with losartan and PD123,319, respectively, on MAPK expression after ischemia-reperfusion in isolated working rat hearts.. Groups of six hearts were subjected to global ischemia (30 minutes) followed by reperfusion (30 minutes) and exposed to no drug/no ischemia-reperfusion (control), ischemia-reperfusion/no drug, and ischemia-reperfusion with losartan (1 microM), or PD123,319 (0.3 microM) and additional groups. AT1/AT2 receptor expression, MAPKs, PKCepsilon, and cGMP, and changes in mechanical function were measured. Western blotting was done on left ventricular tissue for AT1/AT2, p38/phosphorylated-p38 (p-p38), phosphorylated (p)-JNK-1/-2, phosphorylated (p)-ERK-1/-2, and PKCepsilon proteins; Northern blots for AT1/AT2 mRNA; and enzyme immunoassay for cGMP.. Compared with controls, ischemia-reperfusion induced significant left ventricular dysfunction, decreased AT2 protein and mRNA, increased p-p38 and p-JNK-1/-2, did not change p-ERK-1/-2 or PKCepsilon, and decreased cGMP. PD123,319 improved left ventricular recovery after ischemia-reperfusion, increased AT2 protein and mRNA, mildly increased p-p38, normalized p-JNK-1, did not change p-ERK-1/-2, and increased PKCepsilon and cGMP. Losartan did not change p-p38, increased p-JNK-1, and did not change pERK-1/-2, PKCepsilon, or cGMP.. The overall results suggest that the activation of p38-MAPK and JNK might be linked to AII signaling and play a significant role in acute ischemia-reperfusion injury as well as in the cardioprotective effect of AT2 receptor blockade.

Topics: Angiotensin II Type 2 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Cardiac Output; Coronary Circulation; Cyclic GMP; Disease Models, Animal; Enalaprilat; Enzyme Activation; Heart; Losartan; Male; Mitogen-Activated Protein Kinases; Models, Cardiovascular; Phosphorylation; Protein Kinase C; Protein Kinase C-epsilon; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger

In humans with hypertension and LV hypertrophy, beneficial effects of angiotensin inhibition may be associated with preserved autoregulatory capacity. We studied the effect of acute angiotensin converting enzyme (ACE) inhibition on coronary autoregulatory pressure-flow relations and transmural distribution of blood flow in sham and LV hypertrophy dogs. Heart/body weight ratio increased (p = 0.001) from 5.5 +/- 0.7 in sham to 6.9 +/- 0.5 in LV hypertrophy dogs. The lower coronary pressure limit (LPL) on the pressure-flow relation was 47 +/- 2 mmHg in sham and 57 +/- 6 mmHg (p = 0.001) in LV hypertrophy dogs; after acute ACE-inhibition the LPL was reduced to 40 +/- 5 mmHg and 49 +/- 6 mmHg (p = 0.001), respectively. Transmural distribution of blood flow was preserved at the LPL in both groups before and after acute ACE-inhibition. Concomitant blockade of prostaglandin and nitric oxide release and bradykinin catabolism had no additional effects on the LPL and distribution of blood flow. After acute ACE-inhibition in LV hypertrophy dogs, distribution of blood flow across the LV wall was preserved and subendocardial vascular reserve was maintained even though the LPL was significantly lower. Preservation of autoregulatory capacity by ACE inhibitors contributes to beneficial outcome in patients with hypertension and LV hypertrophy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Flow Velocity; Coronary Circulation; Disease Models, Animal; Dogs; Enalaprilat; Hemodynamics; Homeostasis; Hyperemia; Hypertrophy, Left Ventricular

The study was done to determine the effects of propranolol, enalaprilat, verapamil, and caffeine on the vasodilatory properties of the adenosine A(2A)-receptor agonist ATL-146e (ATL).. ATL is a new adenosine A(2A)-receptor agonist proposed as a vasodilator for myocardial stress perfusion imaging. Beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium blockers are commonly used for the treatment of coronary artery disease (CAD), and their effect on ATL-mediated vasodilation is unknown. Dietary intake of caffeine is also common.. In 19 anesthetized, open-chest dogs, hemodynamic responses to bolus injections of ATL (1.0 microg/kg) and adenosine (60 microg/kg) were recorded before and after administration of propranolol (1.0 mg/kg, ATL only), enalaprilat (0.3 mg/kg, ATL only), caffeine (5.0 mg/kg, ATL only), and verapamil (0.2 mg/kg bolus, ATL and adenosine).. Neither propranolol nor enalaprilat attenuated the ATL-mediated vasodilation (225 +/- 86% and 237 +/- 67% increase, respectively, p = NS vs. control). Caffeine had an inhibitory effect (97 +/- 28% increase, p < 0.05 vs. control). Verapamil blunted both ATL- and adenosine-induced vasodilation (63 +/- 20% and 35 +/- 7%, respectively, p < 0.05 vs. baseline), and also inhibited the vasodilation induced by the adenosine triphosphate-sensitive potassium (K(ATP)) channel activator pinacidil.. Beta-blockers and ACE inhibitors do not reduce the maximal coronary flow response to adenosine A(2A)-agonists, whereas verapamil attenuated this vasodilation through inhibition of K(ATP) channels. The inhibitory effect of verapamil and K(ATP) channel inhibitors like glybenclamide on pharmacologic stress using adenosine or adenosine A(2A)-receptor agonists should be evaluated in the clinical setting to determine their potential for reducing the sensitivity of CAD detection with perfusion imaging.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Caffeine; Calcium Channel Blockers; Coronary Circulation; Cyclohexanecarboxylic Acids; Disease Models, Animal; Dogs; Enalaprilat; Hemodynamics; Phosphodiesterase Inhibitors; Propranolol; Purines; Receptor, Adenosine A2A; Receptors, Purinergic P1; Vasodilation; Verapamil

To determine the short-term effects of angiotensin-converting enzyme (ACE) inhibition on hemodynamics and circulating levels of norepinephrine, angiotensin, and bradykinin, responses to enalaprilat and perindoprilat were examined at doses of 0.03, 0.3, and 1 mg/kg in permanently instrumented conscious dogs with pacing-induced heart failure (right ventricular pacing, 240-250 beats/min, 3 weeks). All doses of the two inhibitors produced similar decrease in mean aortic pressure and increase in cardiac output. Neither inhibitor affected plasma norepinephrine level. Both compounds induced a similar 60-80% decrease in blood angiotensin II level, a similar two- to eightfold increase in blood angiotensin I level, and a 80-95% decrease in the angiotensin II/angiotensin I ratio. There were also a fourfold to 10-fold increase in blood bradykinin-(1-9) level, a twofold increase in blood bradykinin-(1-7) level, and a 70-85% decrease in bradykinin-(1-7)/bradykinin-(1-9) ratio. In addition, the changes in total peripheral resistance induced by the two ACE inhibitors were weakly but significantly correlated with the changes in blood angiotensin II or blood bradykinin-(1-9). Thus whatever the specificity of enalaprilat and perindoprilat, both inhibitors produced similar acute hemodynamic effects in dogs with heart failure, which was associated with marked decrease in circulating angiotensin II level and increase in bradykinin-(1-9) level. This study, which measures for the first time in heart failure the blood bradykinin level after ACE inhibitors, indicates, in concert with angiotensin II reduction, a role for increased bradykinin-(1-9) level in mediating short-term hemodynamic effects of ACE inhibition in this model of heart failure.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Cardiac Output; Cardiac Pacing, Artificial; Disease Models, Animal; Dogs; Enalaprilat; Heart Failure; Indoles; Norepinephrine; Peptide Fragments; Ventricular Function, Left

Toborinone (OPC-18790), a phosphodiesterase III inhibitor, enhances cardiac contractility and is an arterial dilator. However, its effects on the venous system have not yet been clearly defined. Because toborinone administration reduces left ventricular (LV) end-diastolic pressure, it is probably also a venodilator. Because of the known arterial effects and the hypothesized venous effects, we compared changes in systemic vascular conductance (the inverse of resistance) with changes in venous capacitance.. In 15 anesthetized, splenectomized dogs (10 treatment, 5 control), pressures were measured in the right atrium, aorta, portal vein, and LV. A cuff constrictor was placed around the portal vein. Cardiac output was measured by thermodilution, and splanchnic vascular capacitance was measured by blood-pool scintigraphic methods. Data were collected at baseline, after induction of heart failure (microsphere embolization into the left coronary artery), and then after toborinone boluses of 0.1, 0.2, 0.4, and 0.8 mg/kg. Heart failure was associated with decreased capacitance and conductance (to 87+/-3% and 64+/-4% of baseline values, respectively, P<0.05). After administration of the lower doses of toborinone, capacitance increased more than conductance; however, the effects were more balanced at the higher doses. Compared with nitroglycerin, hydralazine, and enalaprilat (results of an earlier study) in the same model, toborinone increased capacitance to a degree similar to that with nitroglycerin, at higher doses increased conductance similarly to hydralazine, and increased both capacitance and conductance considerably more than did enalaprilat.. Toborinone is a potent balanced venous and arterial dilator in experimental acute heart failure. These marked effects suggest that it may prove to be a clinically important alternative to other vasodilators.

Topics: Animals; Cardiotonic Agents; Disease Models, Animal; Dogs; Enalaprilat; Female; Heart Failure; Hemodynamics; Hydralazine; Male; Nitroglycerin; Phosphodiesterase Inhibitors; Quinolones; Vascular Capacitance; Vasodilator Agents

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

Topics: Analysis of Variance; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enalaprilat; Female; Heart Failure; Hemodynamics; Imidazoles; Male; Swine; Tetrazoles

Angiotensin II has been suggested to be involved in the pathogenesis of diastolic dysfunction in left ventricular hypertrophy (LVH). The purpose of this study was to asses the effects of enalaprilat and L-158,809, an angiotensin II type-1 receptor antagonist, on LV diastolic function in 16 normal control dogs and 20 LVH dogs with perinephritic hypertension.. LV hemodynamics was studied before and after intravenous injection of enalaprilat (0.25 mg/kg) or L-158,809 (0.3 mg/kg). The hemodynamic data were analyzed in relation to the changes in myocardial blood flow (measured by radioactive microspheres) and in the circulating angiotensin II and norepinephrine levels.. At baseline, significant increases were observed for LV/body weight ratio as well as LV systolic and end-diastolic pressure in the LVH dogs (all P < 0.01 vs. the control group). In addition, LV relaxation time constant was prolonged and the chamber and myocardial stiffness constants were increased (P < 0.01) in the LVH dogs, suggesting an impairment of LV diastolic function. Administration of enalaprilat or L-158,809 improved LV stiffness constants in the LVH dogs (P < 0.05). The diastolic LV pressure-diameter relation shifted downwards in the LVH dogs whereas diastolic distensibility was not altered in the control dogs. Although the circulating angiotensin II levels were significantly decreased by enalaprilat in the LVH dogs, they did not correlate with the changes in the stiffness constants. Furthermore, the alterations of LV diastolic properties in the LVH group could not be attributed to myocardial perfusion, which was rather decreased by administration of enalaprilat and L-158,809. These results suggest that angiotensin II, particularly at the local level, is involved in the pathogenesis of diastolic dysfunction in pressure-overload LVH. The data also support the concept that ACE inhibitors and angiotensin II receptor blockers are potentially beneficial in the treatment of the hypertrophied heart.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Diastole; Disease Models, Animal; Dogs; Enalaprilat; Hypertension, Renal; Hypertrophy, Left Ventricular; Imidazoles; Receptors, Angiotensin; Tetrazoles; Ventricular Function, Left

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.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Disease Models, Animal; Enalaprilat; Heart; Heart Rate; Male; Myocardial Reperfusion Injury; Rats; Rats, Sprague-Dawley; Ventricular Fibrillation

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.. 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.. 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.. 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.. 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.

Topics: Aldosterone; Animals; Aspirin; Atrial Natriuretic Factor; Disease Models, Animal; Dogs; Drug Administration Schedule; Drug Interactions; Enalaprilat; Heart Failure; Hemodynamics; Kidney; Renin; Ventricular Dysfunction

Intimal hyperplasia appears to result from the deposition of collagen and matrix by medial myofibroblasts, which are stimulated in response to vascular injury. We hypothesized that pharmacologic inhibitors of fibroblast proliferation would suppress the development of intimal hyperplasia. We evaluated the effect of two agents known to inhibit fibroblast proliferation in vitro: enalaprilat, an angiotensin-converting enzyme (ACE) inhibitor, and dimethyl sulfoxide (DMSO), an organic solvent. Thirty-five New Zealand white rabbits underwent standardized balloon catheter injury of the left common carotid artery. Experimental groups received daily intramuscular injections of the following: group I (n = 15), saline solution; group II (n = 10), 0.07 mg/kg enalaprilat; and group III (n = 10), 2 ml/kg of a 25% by weight DMSO solution. Injections were started 1 day prior to injury and continued 5 days a week for 8 weeks. Carotid arteries were perfusion-fixed at 12 weeks and cross-sectioned for measurement by planimetry. Intimal hyperplasia was measured as the ratio of the absolute area of intimal hyperplasia to the normalized area enclosed by the internal elastic lamina (IH/IEL) and was expressed as a percent. Mean values for IH/IEL were as follows: group I (control), 20.6 +/- 2.3%; group II (enalaprilat), 9.5 +/- 0.7%; and group III (DMSO), 17.6 +/- 2.6%. Enalaprilat-treated animals demonstrated a statistically significant suppression of intimal hyperplasia compared with controls (p < 0.01, ANOVA, Student's t test), whereas the DMSO-treated group did not. We conclude that enalaprilat is effective in suppressing the development of intimal hyperplasia in this model of arterial injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angioplasty, Balloon; Animals; Carotid Artery Injuries; Carotid Artery, Common; Dimethyl Sulfoxide; Disease Models, Animal; Enalaprilat; Hyperplasia; Male; Rabbits; Random Allocation; Tunica Intima

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.

Topics: Anesthesia; Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Coronary Circulation; Disease Models, Animal; Dogs; Enalaprilat; Female; Furosemide; Heart Rate; Imidazoles; Injections, Intravenous; Losartan; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Renin-Angiotensin System; Tetrazoles

The hemodynamic effects of acute intravenous administration of nitroprusside, dobutamine, enalaprilat, and digoxin was investigated in a canine model of chronic heart failure (CHF) produced by multiple sequential intracoronary microembolizations. Dobutamine (4 micrograms/kg/min) increased cardiac output (2.4 +/- 0.1 vs. 4.0 +/- 0.4 l/min; p < .001) and LV ejection fraction (LVEF; 26 +/- 1 vs. 30 +/- 4%; p < .01), and decreased systemic vascular resistance (SVR; 3620 +/- 170 vs. 2470 +/- 190 dynes sec cm-5; p < .001). Nitroprusside (3 micrograms/kg/min) acted as a venodilator; it decreased pulmonary artery wedge pressure (16 +/- 1 vs. 13 +/- 1 mmHg; p < .01) and SVR (3730 +/- 440 vs. 3210 +/- 280 dynes sec cm-5; NS) but had no effect on cardiac output. Enalaprilat (1.875 mg) produced a significant increase of cardiac output (3.0 +/- 0.5 vs. 3.8 +/- 0.5 l/min; p < .001) and LVEF (22 +/- 1 vs. 30 +/- 1%; p < .01), and decreased SVR (3280 +/- 400 vs. 2450 +/- 250 dynes sec cm-5; p < .01). Intravenous digoxin at a cumulative dose of 0.75 mg increased LVEF (23 +/- 2 vs. 31 +/- 2%; p < .01) but had no effect on SVR. These data indicate that this canine model of CHF responds to acute pharmacologic intervention in a manner comparable to that seen in patients with CHF. Accordingly, this model may be a useful tool for the preclinical evaluation of new drugs targeted toward the treatment of CHF and for investigating the mechanisms of action of drugs currently used for the treatment of this disease state.

Topics: Animals; Blood Pressure; Cardiac Output; Digoxin; Disease Models, Animal; Dobutamine; Dogs; Enalaprilat; Heart Failure; Heart Rate; Hemodynamics; Nitroprusside; Stroke Volume; Vascular Resistance; Ventricular Function, Left

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.. 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.. 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.. 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.

Topics: Anesthesia; Animals; Antihypertensive Agents; Desoxycorticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Doxazosin; Drug Evaluation, Preclinical; Drug Interactions; Enalaprilat; Female; Hypertension; Prazosin; Rats; Rats, Inbred Strains; Thiopental

Earlier studies on the cardiovascular effects of intracerebroventricular (i.c.v.) administration of angiotensin converting enzyme (ACE) inhibitors implicate angiotensin II (AII) present in the central nervous system in the pathogenesis of hypertension. We have now examined whether central AII contributes to the maintenance of established hypertension in adult stroke-prone spontaneously hypertensive rats (SHRSP). The ACE inhibitor, enalaprilat, was infused i.c.v. for two weeks at a rate of 5 micrograms/h via osmotic minipumps. Control rats were either untreated or infused with saline. Mean arterial pressure (MAP), measured via an indwelling catheter, fell within 24 h in the enalaprilat-treated rats and remained at least 30 mmHg lower than in controls. This difference persisted after intravenous (i.v.) administration of a vasopressin (AVP) antagonist but was eliminated by subsequent ganglion blockade with i.v. pentolinium. Without prior administration of the AVP antagonist, however, the reductions of MAP after pentolinium were smaller. The reduction was still attenuated in treated rats compared with controls but there was a significant difference in the residual MAP. Circulating catecholamine levels were reduced by central ACE inhibition. However, pressor responsiveness to i.v. phenylephrine was unaffected. The results suggest that, in SHRSP, central ACE inhibition lowers blood pressure by reducing sympathetic outflow, implying that central AII has a tonic sympathoexcitatory effect in this strain.

Topics: Animals; Blood Pressure; Cerebrovascular Disorders; Disease Models, Animal; Enalaprilat; Epinephrine; Hypertension; Injections, Intraventricular; Male; Norepinephrine; Pentolinium Tartrate; Rats; Rats, Mutant Strains