Effects of soluble guanylate cyclase stimulator on renal function in ZSF-1 model of diabetic nephropathy.

BACKGROUND: Diabetic nephropathy is associated with endothelial dysfunction and oxidative stress, in which the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway is impaired. We hypothesize that sGC stimulator Compound 1 can enhance NO signaling, reduce proteinuria in a diabetic nephropathy preclinical model with diminished NO bioavailability and increased oxidized sGC. Therefore, we evaluated the effect of sGC stimulator Compound 1 on the renal effect in obese ZSF1 (ZSF1 OB) rats. MATERIALS AND METHODS: The sGC stimulator Compound 1, the standard of care agent Enalapril, and a combination of Compound 1 and Enalapril were administered chronically to obese ZSF1 rats for 6 months. Mean arterial pressure, heart rate, creatinine clearance for glomerular filtration rate (eGFR), urinary protein excretion to creatinine ratio (UPCR), and urinary albumin excretion ratio (UACR) were determined during the study. The histopathology of glomerular and interstitial lesions was assessed at the completion of the study. RESULTS: While both Compound 1 and Enalapril significantly reduced blood pressure, the combination of Compound 1 and Enalapril normalized blood pressure levels. Compound 1 improved eGFR and reduced UPCR and UACR. A combination of Enalapril and Compound 1 resulted in a marked reduction in UPCR and UACR and improved GFR. CONCLUSION: The sGC stimulator Compound 1 as a monotherapy slowed renal disease progression, and a combination of the sGC stimulator with Enalapril provided greater renal protection in a rodent model of diabetic nephropathy.

Upregulation of SERCA2a following short-term ACE inhibition (by enalaprilat) alters contractile performance and arrhythmogenicity of healthy myocardium in rat.

Chronic angiotensin-converting enzyme inhibitor (ACEIs) treatment can suppress arrhythmogenesis. To examine whether the effect is more immediate and independent of suppression of pathological remodelling, we tested the antiarrhythmic effect of short-term ACE inhibition in healthy normotensive rats. Wistar rats were administered with enalaprilat (ENA, i.p., 5 mg/kg every 12 h) or vehicle (CON) for 2 weeks. Intraarterial blood pressure in situ was measured in A. carotis. Cellular shortening was measured in isolated, electrically paced cardiomyocytes. Standard 12-lead electrocardiography was performed, and hearts of anaesthetized open-chest rats were subjected to 6-min ischemia followed by 10-min reperfusion to examine susceptibility to ventricular arrhythmias. Expressions of calcium-regulating proteins (SERCA2a, cardiac sarco/endoplasmic reticulum Ca(2+)-ATPase; CSQ, calsequestrin; TRD, triadin; PLB, phospholamban; Thr(17)-PLB-phosphorylated PLB at threonine-17, FKBP12.6, FK506-binding protein, Cav1.2-voltage-dependent L-type calcium channel alpha 1C subunit) were measured by Western blot; mRNA levels of L-type calcium channel (Cacna1c), ryanodine receptor (Ryr2) and potassium channels Kcnh2 and Kcnq1 were measured by qRT-PCR. ENA decreased intraarterial systolic as well as diastolic blood pressure (by 20%, and by 31%, respectively, for both P < 0.05) but enhanced shortening of cardiomyocytes at basal conditions (by 34%, P < 0.05) and under beta-adrenergic stimulation (by 73%, P < 0.05). Enalaprilat shortened QTc interval duration (CON 78 ± 1 ms vs. ENA 72 ± 2 ms; P < 0.05) and significantly decreased the total duration of ventricular fibrillations (VF) and the number of VF episodes (P < 0.05). Reduction in arrhythmogenesis was associated with a pronounced upregulation of SERCA2a (CON 100 ± 20 vs. ENA 304 ± 13; P < 0.05) and complete absence of basal Ca(2+)/calmodulin-dependent phosphorylation of PLB at Thr(17). Short-term ACEI treatment can provide protection against I/R injury-induced ventricular arrhythmias in healthy myocardium, and this effect is associated with increased SERCA2a expression.

Pharmacokinetics and pharmacodynamics of enalapril and its active metabolite, enalaprilat, at four different doses in healthy horses.

Pharmacokinetic and pharmacodynamic of IV enalapril at 0.50 mg/kg, PO placebo and PO enalapril at three different doses (0.50, 1.00 and 2.00 mg/kg) were analyzed in 7 healthy horses. Serum concentrations of enalapril and enalaprilat were determined for pharmacokinetic analysis. Angiotensin-converting enzyme (ACE) activity, serum ureic nitrogen (SUN), creatinine and electrolytes were measured, and blood pressure was monitored for pharmacodynamic analysis. The elimination half-lives of enalapril and enalaprilat were 0.67 and 2.76 h respectively after IV enalapril. Enalapril concentrations after PO administrations were below the limit of quantification (10 ng/ml) in all horses and enalaprilat concentrations were below the limit of quantification in 4 of the 7 horses. Maximum mean ACE inhibitions from baseline were 88.38, 3.24, 21.69, 26.11 and 30.19% for IV enalapril at 0.50 mg/kg, placebo and PO enalapril at 0.50, 1.00 and 2.00 mg/kg, respectively. Blood pressures, SUN, creatinine and electrolytes remained unchanged during the experiments.

Reninoma: the importance of renal vein renin ratios for lateralisation and diagnosis.

BACKGROUND/AIM: Reninomas are rare juxtaglomerular tumours which can cause severe hypertension and hypokalaemia. Diagnosis can be problematic and these tumours can be difficult to locate on imaging. In this report we aim to demonstrate the value of carefully performed renal vein renin ratios (RVRRs) to assist in locating these tumours. METHOD/RESULTS: We report on 3 patients diagnosed with reninoma in our unit. The patients were all female, young (17, 16 and 30 years), severely hypertensive and hypokalaemic (2.5, 2.5 and 3.1 mmol/l). Plasma renin activity (PRA) was elevated (31.9, 274 and 175 ng/ml/h), and aldosterone was high-normal (19.9 ng/dl) or elevated (207 and 109.3 ng/dl). Renal artery stenosis was excluded by renal artery Doppler, DTPA scan and angiography. Renal CT detected the lesion in 2 patients, with one lesion visible on pre- and post-contrast CT and the other on post-contrast CT only. RVRRs were performed several weeks after withdrawing interfering medications, maintaining a <40 mmol/day low-sodium diet and maintaining recumbency overnight the night before and during the procedure. Ratios before and after captopril or enalaprilat administration were obtained and lateralised the tumours in all 3 cases (dominant/non-dominant ratios of 2.3, 4.3 and 3.8). All of the patients underwent nephrectomy yielding a typical juxtaglomerular tumour and resulting in cure of hypertension and hypokalaemia. CONCLUSIONS: Reninoma should be suspected in young hypertensives (especially females) with significant hypokalaemia and high PRA or direct renin concentration after renovascular hypertension has been excluded. CT imaging and carefully performed RVRRs provide the highest likelihood of locating these tumours.

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.

Intracoronary EnalaPrilat to Reduce MICROvascular Damage During Percutaneous Coronary Intervention (ProMicro) study.

OBJECTIVES: This study investigated the influence of intracoronary enalaprilat on coronary microvascular function and peri-procedural outcome measures in patients with stable angina undergoing percutaneous coronary intervention (PCI). BACKGROUND: Intracoronary angiotensin-converting enzyme inhibitors have been shown to relieve myocardial ischemia in stable patients and to improve epicardial flow in patients with ST-segment elevation myocardial infarction. Yet, it is still unclear whether these effects are mediated by a modulation of the coronary microcirculation. METHODS: We randomly assigned 40 patients to receive either an intracoronary bolus of enalaprilat (50 µg) or placebo before elective PCI. The index of microvascular resistance was measured at baseline, 10 minutes after study drug administration, and after PCI. High-sensitivity cardiac troponin T was measured as a marker of myocardial injury. RESULTS: Infusion of enalaprilat resulted in a significant reduction in index of microvascular resistance (27 ± 11 at baseline vs. 19 ± 9 after drug vs. 15 ± 8 after PCI), whereas a significant post-procedural increase in index of microvascular resistance levels was observed in the placebo group (24 ± 15 at baseline vs. 24 ± 15 after drug vs. 33 ± 19 after PCI). Index of microvascular resistance levels after PCI were significantly lower in the enalaprilat group (p < 0.001). Patients pre-treated with enalaprilat also showed lower peak values (mean: 21.7 ng/ml, range: 8.2 to 34.8 ng/ml vs. mean: 32.3 ng/ml, range: 12.6 to 65.2 ng/ml, p = 0.048) and peri-procedural increases of high-sensitivity cardiac troponin T (mean: 9.9 ng/ml, range: 2.7 to 19.0 ng/ml vs. mean: 26.6 ng/ml, range: 6.3 to 60.5 ng/ml, p = 0.025). CONCLUSIONS: Intracoronary enalaprilat improves coronary microvascular function and protects myocardium from procedure-related injury in patients with coronary artery disease undergoing PCI. Larger studies are warranted to investigate whether these effects of enalaprilat could result into a significant clinical benefit.

An integrated physiology-based model for the interaction of RAA system biomarkers with drugs.

The renin angiotensin aldosterone system (RAAS) is a paramount target for the pharmacological treatment of cardiovascular diseases. As modeling and simulation techniques are becoming increasingly utilized in cardiovascular research, our aim was to develop a physiology-based model that describes the effect of different drugs at different doses on the RAAS and integrates physiology-based description drug pharmacokinetics (PK). First, a basic RAAS model was developed in which equations for drug effects were included and missing parameters estimated. Next, a physiology-based PK model for enalapril and enalaprilat was developed and coupled to the RAAS model. Simulation of the effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aliskiren administration on angiotensins I and II did not reveal significant overestimation or underestimation. For all drugs, the error numerics were acceptable. The model also encompassed the PK of intravenous and oral enalapril and its conversion to enalaprilat. In summary, we report a physiology-based model for the interaction of the RAAS biomarkers angiotensin I and II with enalapril, benazepril, aliskiren, and losartan that allows for an adequate description of the RAAS response after single administration of the drugs. Such a comprehensive description may lead to a better understanding of the effects of pharmacological interventions in the RAAS.

Acute effects of the ACE inhibitor enalaprilat on the pulmonary, cerebral and systemic blood flow and resistance after the bidirectional cavopulmonary connection.

BACKGROUND: The bidirectional cavopulmonary connection (BCPC) is used in the staged palliation of univentricular hearts and places the cerebral and pulmonary vascular beds in series. Angiotensin-converting enzyme inhibitors (ACEI) are often used in this complex circulation, but the effects of their vasodilation are unclear. OBJECTIVE: Assessment of the acute response of perfusion pressure, flow and resistance across the systemic, cerebral and pulmonary vascular beds to ACEI in patients with a BCPC. DESIGN: Prospective interventional study. SETTING: Single tertiary care centre. PATIENTS: 12 patients with a BCPC (median age 28 months, weight 11.8 kg) undergoing a pre-Fontan catheterisation with MRI measurement of flows. INTERVENTION: Intravenous enalaprilat 0.005 or 0.01 mg/kg. RESULTS: Enalaprilat increased descending aorta flow (median 21.6%, p=0.0005), decreased total pulmonary vein flow (median 10.6%, p=0.025), and both superior caval vein flow (median 8.6%, p=0.065) and aortopulmonary collateral flow (median 15.5%, p=0.077) tended to decrease. Total cardiac output was unchanged (p=0.57). Systemic vascular resistance (median 41.9%, p=0.0005) and cerebral vascular resistance (median 23.4%, p=0.0005) decreased, but pulmonary vascular resistance (p=0.73) showed little change. There was evidence of autoregulation of cerebral blood flow. The proportion of descending aortic flow to total cardiac output increased (median 27 to 35%, p=0.001). Systemic oxygen saturation decreased from 87% to 83% (p=0.02). CONCLUSION: Enalaprilat did not increase total cardiac output but redistributed flow to the lower body, with a concomitant decrease in arterial oxygen saturation. It is difficult to increase cardiac output in patients with a BCPC and ACEI should be used with caution in those with borderline aortic saturations.

Reduced systolic pressure load decreases cell-cycle activity in the fetal sheep heart.

The fetal heart is highly sensitive to changes in mechanical load. We have previously demonstrated that increased cardiac load can stimulate cell cycle activity and maturation of immature cardiomyocytes, but the effects of reduced load are not known. Sixteen fetal sheep were given either continuous intravenous infusion of lactated Ringer solution (LR) or enalaprilat, an angiotensin-converting enzyme inhibitor beginning at 127 days gestational age. After 8 days, fetal arterial pressure in the enalaprilat-infused fetuses (23.8 +/- 2.8 mmHg) was lower than that of control fetuses (47.5 +/- 4.7 mmHg) (P < 0.0001). Although the body weights of the two groups of fetuses were similar, the heart weight-to-body weight ratios of the enalaprilat-infused fetuses were less than those of the LR-infused fetuses (5.6 +/- 0.5 g/kg vs. 7.0 +/- 0.6 g/kg, P < 0.0001). Dimensions of ventricular myocytes were not different between control and enalaprilat-infused fetuses. However, there was a significant decrease in cell cycle activity in both the right ventricle (P < 0.005) and the left ventricle (P < 0.002) of the enalaprilat-infused fetuses. Thus, we conclude a sustained reduction in systolic pressure load decreases hyperplastic growth in the fetal heart.

Attenuation of renal excretory responses to ANG II during inhibition of superoxide dismutase in anesthetized rats.

To examine the functional interaction between superoxide dismutase (SOD) and NADPH oxidase activity, we assessed renal responses to acute intra-arterial infusion of ANG II (0.5 ng x kg(-1) x min(-1)) before and during administration of a SOD inhibitor, diethyldithiocarbamate (DETC, 0.5 mg x kg(-1) x min(-1)), in enalaprilat-pretreated (33 microg x kg(-1) x min(-1)) rats (n = 11). Total (RBF) and regional (cortical, CBF; medullary; MBF) renal blood flows were determined by Transonic and laser-Doppler flowmetry, respectively. Renal cortical and medullary tissue NADPH oxidase activity in vitro was determined using the lucigenin-chemiluminescence method. DETC treatment alone resulted in decreases in RBF, CBF, MBF, glomerular filtration rate (GFR), urine flow (V), and sodium excretion (U(Na)V) as reported previously. Before DETC, ANG II infusion decreased RBF (-18 +/- 3%), CBF (-16 +/- 3%), MBF [-5 +/- 6%; P = not significant (NS)], GFR (-31 +/- 4%), V (-34 +/- 2%), and U(Na)V (-53 +/- 3%). During DETC infusion, ANG II also caused similar reductions in RBF (-20 +/- 4%), CBF (-19 +/- 3%), MBF (-2 +/- 2; P = NS), and in GFR (-22 +/- 7%), whereas renal excretory responses (V; -12 +/- 2%; U(Na)V; -24 +/- 4%) were significantly attenuated compared with those before DETC. In in vitro experiments, ANG II (100 muM) enhanced NADPH oxidase activity both in cortical [13,194 +/- 1,651 vs. 20,914 +/- 2,769 relative light units (RLU)/mg protein] and in medullary (21,296 +/- 2,244 vs. 30,597 +/- 4,250 RLU/mg protein) tissue. Application of DETC (1 mM) reduced the basal levels and prevented ANG II-induced increases in NADPH oxidase activity in both tissues. These results demonstrate that renal excretory responses to acute ANG II administration are attenuated during SOD inhibition, which seems related to a downregulation of NADPH oxidase in the deficient condition of SOD activity.

Enalaprilat and enalapril maleate eyedrops lower intraocular pressure in rabbits.

PURPOSE: This study aimed to develop low-viscosity aqueous eyedrops containing enalaprilat and its prodrug enalapril maleate in solution, and to evaluate the eyedrops in rabbits. METHODS: Aqueous eyedrops with hydroxypropyl-beta-cyclodextrin containing 0.01-2.9% (w/v) enalaprilat, 1.0% (w/v) enalapril maleate with cyclodextrin or 0.5% (w/v) timolol were prepared. The eyedrops were administered to rabbits and intraocular pressure (IOP) was measured at various time intervals after the administration and the results (mean of 10 experiments +/- standard error of the mean) are expressed as the change from baseline (24.7 +/- 3.3 mmHg). RESULTS: Enalaprilat possessed sufficient stability to be formulated as an aqueous eyedrop solution with a shelf-life of several years at room temperature. The maximum decline in IOP after topical administration of one drop of 2.9% enalaprilat solution was 6.2 +/- 0.7 mmHg at 4 hours after administration. Duration of activity exceeded 10 hours. A 1% enalaprilat solution lowered IOP by 4.4 +/- 0.8 mmHg at 4 hours after administration and had similar duration, and was more potent than 0.5% timolol. The enalapril maleate eyedrops resulted in delayed action, showing maximum potency at 10-22 hours after administration and duration of up to 32 hours. CONCLUSIONS: Enalaprilat eyedrops lower IOP in rabbits. The decline in IOP is proportional to the concentration of dissolved enalaprilat in low-viscosity aqueous eyedrop formulations.

Nanocomposites coated with xyloglucan for drug delivery: In vitro studies.

Enalaprilate (Enal), an active pharmaceutical component, was intercalated into a layered double hydroxide (Mg/Al-LDH) by an ion exchange reaction. The use of a layered double hydroxide (LDH) to release active drugs is limited by the low pH of the stomach (pH approximately 1.2), in whose condition it is readily dissolved. To overcome this limitation, xyloglucan (XG) extracted from Hymenaea courbaril (jatobá) seeds, Brazilian species, was used to protect the LDH and allow the drug to pass through the gastrointestinal tract. All the materials were characterized by X-ray diffraction, Fourier transform infrared spectroscopy, elemental analyses, transmission electronic microscopy, thermal analyses, and a kinetic study of the in vitro release was monitored by ultraviolet spectroscopy. The resulting hybrid system containing HDL-Enal-XG(3) slowly released the Enal. In an 8-h of test, the system protected 40% (w/v) of the drug. The kinetic profile showed that the drug release was a co-effect behavior, involving dissolution of inorganic material and ion exchange between the intercalated anions in the lamella and those of phosphate in the buffer solution. The nanocomposite coated protection with XG was therefore efficient in obtaining a slow release of Enal.

Myocardial protection with enalaprilat in patients unresponsive to ischemic preconditioning during percutaneous coronary intervention.

Cardioprotection due to angiotensin enzyme inhibitors is attributed, at least in part, to the inhibition of bradykinin breakdown and the preconditioning effect of the elevated endogenous bradykinin level. We have previously shown that in patients undergoing percutaneous coronary intervention, one 120-second balloon inflation is insufficient to precondition the heart. The objective of the present study was to examine whether the administration of enalaprilat to these patients results in protection. Twenty patients underwent two 120-second coronary artery occlusions separated by a reperfusion interval of 10 min. Ten patients were given 50 microg x min-1 enalaprilat in an intracoronary infusion between the balloon inflations, whereas the others received an infusion of saline. In the latter control patients, there were no significant differences in ST-segment elevation between the consecutive occlusions (peak ST: 1.61 +/- 0.17 vs. 1.61 +/- 0.16 mV; time to reach 0.5 mV ST elevation: 16 +/- 4 vs. 22 +/- 7 s; mean ST: 1.03 +/- 0.12 vs. 1.02 +/- 0.11 mV). In the patients who received enalaprilat before the second balloon inflation, the ST-segment elevation was significantly less pronounced and slower during the second inflation than during the first (peak ST: 1.80 +/- 0.18 vs. 1.41 +/- 0.19 mV; time to reach 0.5 mV ST elevation: 18 +/- 4 vs. 30 +/- 4 s; mean ST: 1.04 +/- 0.11 vs. 0.85 +/- 0.14 mV). We conclude that enalaprilat administered during percutaneous coronary intervention provides protection to patients who do not have a protective response to the initial balloon inflation.

Transanal delivery of angiotensin converting enzyme inhibitor prevents colonic fibrosis in a mouse colitis model: development of a unique mode of treatment.

BACKGROUND: We have previously shown that angiotensin converting enzyme-inhibitor (ACE-I) improved colonic inflammation and apoptosis in a dextran sodium sulfate (DSS)-induced colitis model. This study attempted to determine whether ACE-I could prevent the development of colonic fibrosis. METHODS: Colitis was induced in C57BL/6 mice with 2.5% DSS water for 7 days, followed by 7 days without DSS (fibrosis development). Study groups: Control (naive or non-treated), DSS+Placebo (polyethylene glycol (PEG), and DSS+ACE-I (using enalaprilat and PEG which are not absorbed through intact mucosa). Placebo and ACE-I were delivered daily via transanal route. Colonic mucosal fibrosis and inflammation were evaluated based on histological findings and cytokine expression. RESULTS: Transanal administration of ACE-I/PEG dose-dependently decreased the severity of fibrosis and pro-inflammatory cytokine expression. We next investigated if ACE-I acted on the TGF-beta/Smad signaling pathway as a mechanism of this anti-fibrosis action. Results showed a significant down-regulation of TGF-beta1 expression; as well, downstream signaling of the Smad family, known to mediate fibrosis, showed a decline in Smad 3 and 4 expression with ACE-I/PEG. CONCLUSION: ACE-I/PEG is effective in preventing colonic fibrosis and pro-inflammatory cytokine expression in a DSS colitis model, most likely by down-regulating the TGF-beta signaling pathway. ACE-I/PEG may be a potential new option for treating inflammatory bowel disease.

Enalaprilat induced acute parotitis.

Drug induced acute parotitis is a very uncommon complication reported with a few drugs only. There is no case of acute bilateral parotitis reported previously with i.v. enalaprilat. We present here a female patient who developed acute bilateral parotitis within minutes of i.v. enalaprilat injection and recovered within 24 hours of stopping the drug and with symptomatic treatment.

17Beta-estradiol increases basal but not bradykinin-stimulated release of active t-PA in young postmenopausal women.

Angiotensin-converting enzyme inhibition potentiates basal and bradykinin-stimulated tissue-type plasminogen activator (t-PA) release to a greater extent in women than in men. This study tested the hypothesis that 17beta-estradiol enhances the effect of angiotensin-converting enzyme inhibition on t-PA release in young postmenopausal women. We conducted a double-blind, prospective, crossover study in 14 young postmenopausal women (mean age 48.2+/-2.3 years) who were randomized to receive 17beta-estradiol (1 mg/d) or matching placebo for 4 weeks. At the end of each treatment period, we measured the effect of intraarterial infusion of bradykinin, methacholine, and nitroprusside on forearm blood flow and net t-PA release, before and during intraarterial enalaprilat (0.33 microg/min/100 mL forearm volume). 17Beta-estradiol significantly reduced baseline venous plasminogen activator inhibitor-1 antigen (4.4+/-1.4 versus 10.4+/-2.5 ng/mL, P=0.001) and t-PA antigen (5.5+/-0.6 versus 7.5+/-1.3 ng/mL, P=0.022) compared with placebo. 17Beta-estradiol increased basal forearm vascular release of active t-PA compared with placebo (1.2+/-0.3 IU/mL/min versus 0.4+/-0.1 IU/mL/min respectively, P=0.032), without increasing t-PA antigen release (P=0.761). Enalaprilat significantly increased basal net t-PA antigen release (from -0.8+/-1.0 to 3.2+/-1.2 ng/min/100 mL, P=0.012), but not the release of active t-PA, during either placebo or 17beta-estradiol. Enalaprilat potentiated bradykinin-stimulated vasodilation and t-PA antigen and activity release similarly during placebo and 17beta-estradiol treatment. 17Beta-estradiol treatment does not alter the effect of angiotensin-converting enzyme inhibition on basal t-PA antigen or on bradykinin-stimulated t-PA antigen or activity release. 17Beta-estradiol increases basal release of active t-PA in young postmenopausal women, consistent with enhanced vascular fibrinolytic function.

[Effects of single or combined administration of cedilanid and enalaprilat on visceral damages in early stage of severe scald in rats].

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Pretreatment with intracoronary enalaprilat protects human myocardium during percutaneous coronary angioplasty.

OBJECTIVES: We tested the hypothesis that enalaprilat induces preconditioning (PC)-mimetic actions in patients with stable coronary artery disease. BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors increase the bioavailability of bradykinin, which induces cardiac PC. METHODS: Twenty-two patients undergoing coronary angioplasty were randomized to an intracoronary infusion of enalaprilat or placebo, followed 10 min later by a PC protocol. RESULTS: In control patients, the ST-segment shift was greater during the first inflation than during the second and third inflations, both on the intracoronary electrocardiogram (ECG) (21.0 +/- 2.8 mm vs. 13.0 +/- 2.0 mm and 13.0 +/- 2.0 mm, p < 0.05) and the surface ECG (16.0 +/- 4.0 mm vs. 10.0 +/- 2.0 mm and 9.0 +/- 2.0 mm, p < 0.05). In contrast, enalaprilat-pretreated patients showed no change in ST-segment shift during inflations on either the intracoronary or the surface ECG. During the first inflation, the ST-segment shift was significantly smaller in treated versus control patients. The chest pain score during the first inflation was also significantly smaller in treated patients versus control patients (33.0 +/- 6.0 mm vs. 64.0 +/- 6.0 mm) and did not change in treated patients during the second and third inflations, whereas it decreased significantly in control patients. In a subset of 6 patients, enalaprilat increased coronary blood flow during infusion, but this effect dissipated before the beginning of angioplasty. CONCLUSIONS: Pretreatment with enalaprilat attenuates the manifestations of myocardial ischemia during angioplasty. This is the first in vivo evidence showing that an ACE inhibitor protects human myocardium, possibly via PC-mimetics actions, a novel property that might explain the cardioprotective actions of these drugs.

Effects of intracoronary low-dose enalaprilat on ventricular repolarization dynamics after direct percutaneous intervention for acute myocardial infarction.

BACKGROUND: Data from animal models suggest that inhibition of angiotensin converting enzymes result in an increased ventricular electrical stability after reperfusion in acute myocardial infarction (MI). As electrical stability is largely dependent on ventricular repolarization, we sought to determine the impact of low-dose intracoronary (i.c.) application of enalaprilat (EN) as an adjunct to direct primary coronary intervention (PCI) on QT dynamics in the acute phase of MI. METHODS: Twenty-two consecutive patients with a first acute MI who underwent successful direct PCI (TIMI 3 flow) were randomized to i.c. EN (50 microg) or placebo/saline (PL), given immediately after reopening of the infarct vessel. On hospital admission, a 24-hour-Holter-electrocardiogram (ECG) was initiated. Slopes of the linear QT/RR regression were determined for the time intervals before reperfusion and after reperfusion. RESULTS: A total of 7 patients in the EN group and 8 patients in the PL group had valid ECG recordings for beat-to-beat QT analysis. Mean RR interval and mean QT interval were not significantly different between the EN and the PL groups both before and after PCI. There were also no significant differences regarding QT/RR slopes between EN and PL groups before PCI. After PCI, QT/RR slopes significantly decreased in the EN group (0.169 +/- 0.04 to 0.121 +/- 0.03; P < 0.01), whereas there were no significant alterations in the PL group (0.175 +/- 0.04 to 0.171 +/- 0.03; P = ns). CONCLUSIONS: Intracoronary EN therapy as an adjunct to direct PCI significantly decreases QT/RR slopes, suggesting a normalization of the coupling between heart rate and repolarization by improving electrical restitution. Thus, our findings offer new insights into possible beneficial effects of ACE inhibition on cardiac electrical stability in acute MI.

Intracoronary enalaprilat during angioplasty for acute myocardial infarction: alleviation of postischaemic neurohumoral and inflammatory stress?

AIM: Reperfusion after myocardial ischaemia is associated with a distinct ischaemia/reperfusion injury. Since ACE-inhibition, beyond its influence on cardiac angiotensin II formation and kinin metabolism, has been shown to be cardioprotective by decreasing leucocyte adhesion and endothelin-1 (ET-1) release, we investigated the effects of intracoronary (i.c.) enalaprilat during primary angioplasty in acute myocardial infarction. METHODS AND RESULTS: Twenty-two patients were randomized to receive i.c. enalaprilat (50 micro g) or placebo immediately after reopening of the infarct-related artery (IRA). Plasma concentrations of soluble L-selectin, P-selectin, intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), ET-1 and nitric oxide metabolite concentrations (NOx) were measured in pulmonary arterial blood. Coronary blood flow was assessed using corrected thrombolysis in myocardial infarction (TIMI) frame counts (CTFC). During reperfusion, there was a significant increase in sL-selectin, sP-selectin and ET-1 in the placebo group, which was greatly diminished by enalaprilat. Levels of sVCAM-1 and sICAM-1 were not affected in either group. CTFC in the placebo group remained higher than normal in both the IRA and nonculprit vessels, whereas myocardial blood flow improved with enalaprilat. CONCLUSION: Enalaprilat as adjunct to primary angioplasty might be a protective approach to prevent leucocyte adhesion and the release of ET-1, thereby improving coronary blood flow.