Are Angiotensin-converting Enzyme Research Articles

The Correlation between Two Angiotensin-Converting Enzyme Inhibitor's Concentrations and Cognition.

Both lisinopril and enalapril are angiotensin-converting enzyme (ACE) drugs and widely used in the treatment of hypertension. Enalapril does not cross the blood-brain barrier, but lisinopril is centrally active. Our goal was to find out if there was a link between the actual concentration of ACE inhibitors and cognition and if there was a detectable difference between the two types of ACE inhibitors. Asymptomatic, non-treated patients were diagnosed by screening and the hypertension was confirmed by ambulatory blood pressure monitoring (ABPM). A battery of cognitive tests was used to assess the impact of randomly assigning participants to receive either lisinopril or enalapril. All neurocognitive functions were measured, especially the most affected by conditions of compromised perfusion pressures, such as hypertension, which are attention and executive functions. The lisinopril concentration showed a significant inverse correlation with mosaic test (coeff. = -0.5779) and seemed to have a significant negative effect on perceptual motor skills (coeff. = -0.5779), complex attention (coeff. = -0.5104) and learning (coeff. = -0.5202). Compared with enalapril, lisinopril is less successful in improving the components of cognitive functions.

IN SILICO ANALYSIS OF EDIBLE BIRD’S NEST PROTEINS AS POTENTIAL PRECURSORS FOR BIOACTIVE PEPTIDES

The present study aimed to perform an in silico evaluation of edible bird’s nest protein as potential precursors of bioactive peptides, as well as to determine whether such peptides can be released by selected proteolytic enzymes. Six edible bird’s nest (EBN) protein sequences from a previous study were chosen as potential precursors to produce bioactive peptides via in silico method using the BIOPEP database. AMCase protein sequences gave the highest number of bioactivities (16 to 18) and nucleobindin-2 protein gave the lowest number of bioactivities (9) among the other protein sequences. It was found that the most potential bioactive peptides from EBN proteins are angiotensin-converting enzyme (ACE) inhibitors and dipeptidyl peptidase-IV (DPPIV) inhibitors. Furthermore, in silico proteolysis using six selected enzymes was employed to release both dominant bioactivities in EBN proteins, which were ACE and DPP-IV inhibitors. This study shows that a combination of enzymes, chymotrypsin, and papain, produced the highest number of activities for both ACE and DPP-IV inhibitor peptides with the frequency of occurrence of bioactive peptides of 0.0968 and 0.1104, respectively. The toxic prediction tool, ToxinPred, found that all EBN peptides derived by in silico analysis were non-toxic. The current study proposed that EBN can serve as a potential source of bioactive peptides.

Asian management of hypertension: Current status, home blood pressure, and specific concerns in Vietnam

Hypertension and atherosclerotic diseases are becoming important public health issues in Vietnam. This is due, in part, to changing dietary patterns and lifestyles accompanying economic growth in the country. The most recent prevalence data suggest that 29% of the population has hypertension, and the rate of other cardiovascular risk factors is also high. Although use of home and ambulatory blood pressure monitoring (HBPM and ABPM) is increasing, Vietnamese physicians generally rely on office blood pressure (BP) for diagnosing and managing hypertension. A lack of availability and training are limiting factors. However, out-of-office BP monitoring is important to detect white-coat and masked hypertension, and define the 24-hour BP profile. This approach is recommended in current Vietnam Society of Hypertension and Vietnamese National Heart Association guidelines. Based on 2016 data, the most commonly used antihypertensive agents in Vietnam are angiotensin-converting enzyme (ACE) inhibitors, followed by calcium channel blockers (CCBs) and diuretics, with ß-blockers and angiotensin receptor blockers used less frequently. Combination therapy, usually with an ACE inhibitor plus CCB or diuretic, is quite common (used in 62% of patients). The participation of Vietnam in global hypertension initiatives and organizations has likely contributed to improved treatment and control rates over the last 10years. Nevertheless, the prevalence of hypertension remains high and additional strategies are needed to reduce this and prevent cardiovascular disease.

Limitations in using angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in the management of heart failure due to comorbidities: An Indian scenario

Background and Objectives: The essential drugs used in heart failure are angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers. Many trials had shown that these are the group of drugs with maximum benefits for the patients with heart failure. However, most of the patients were not receiving these drugs due to the negative impact of the comorbidities. Our study aims at identifying the limitations in giving ACE/angiotensin receptor blockers (ARBs) in chronic heart failure patients in our population. Methods: This is a prospective observational study conducted in a tertiary care center, over a period of 2 years from 2012. We selected 310 consecutive patients with the New York Heart Association (NYHA) Class 3 or 4 with various etiologies of heart failure. The patients with new-onset myocardial infarction, acute inflammatory conditions, septicemia, and end-stage renal disease with glomerular filtration rate (GFR)

Plasma concentrations and ACE-inhibitory effects of tryptophan-containing peptides from whey protein hydrolysate in healthy volunteers

The tryptophan-containing dipeptides isoleucine-tryptophan (IW) and tryptophan-leucine (WL) are angiotensin-converting enzyme (ACE)-inhibitors in vitro. These peptides are released by enzymatic hydrolysis of bovine whey protein. To exhibit ACE inhibition in vivo, peptides need to be absorbed into the circulatory system. This study aimed to determine the in vivo ACE-inhibitory potency of a whey protein hydrolysate (MPH), containing IW and WL, and to quantify plasma concentrations of these peptides after oral administration of MPH in healthy volunteers. Additionally, changes in blood pressure were investigated. After intake of 5 and 50g MPH, plasma ACE activity was reduced to 86.4 ± 5.9 and 75.1 ± 6.9% of baseline activity, respectively. Although a clear ACE inhibition was measured, no effect on blood pressure was seen. Basal plasma concentrations of the tryptophan-containing dipeptides were 2.8 ± 0.7nM for IW and 10.1 ± 1.8nM for WL. After intake of 5-50g MPH, peptide concentrations were dose dependently elevated to values between 12.5 ± 8.4 and 99.1 ± 58.7nM for IW and 15.0 ± 4.3-34.9 ± 19.4nM for WL. Administration of intact whey protein showed a minor ACE inhibition, probably caused by release of inhibitory peptides during gastrointestinal digestion. The increase of WL in plasma after intake of intact protein was similar to that determined after intake of MPH. In contrast, resulting IW concentrations were much lower after intake of intact whey protein when compared to MPH administration. After intake of MPH, plasma ACE activity decreased in parallel to the increase of IW and WL plasma concentrations. However, the resulting peptide concentrations cannot fully explain the reduction of ACE activity in plasma with a direct enzyme inhibition. Therefore, this study points to a gap in the understanding of the inhibitory action of these peptides in vivo. Thus, to further develop innovative food additives with ACE activity diminishing capabilities, it appears mandatory to better characterize the mode of action of these peptides.

Intrarenal Angiotensin-Converting Enzyme: the Old and the New.

The intrarenal renin-angiotensin-aldosterone system (RAS) is an independent paracrine hormonal system with an increasingly prominent role in hypertension and renal disease. Two enzyme components of this system are angiotensin-converting enzyme (ACE) and more recently discovered ACE2. The purpose of this review is to describe recent discoveries regarding the roles of intrarenal ACE and ACE2 and their interaction. Renal tubular ACE contributes to salt-sensitive hypertension. Additionally, the relative expression and activity of intrarenal ACE and ACE2 are central to promoting or inhibiting different renal pathologies including renovascular hypertension, diabetic nephropathy, and renal fibrosis. Renal ACE and ACE2 represent two opposing axes within the intrarenal RAS system whose interaction determines the progression of several common disease processes. While this relationship remains complex and incompletely understood, further investigations hold the potential for creating novel approaches to treating hypertension and kidney disease.

MILK PROTEINS DERIVED ACE-INHIBITORY PEPTIDES: FORMATION, IMPACT MECHANISM and BIOAVAILABILITY

Milk proteins are currently the main source of bioactive peptides which are inactive within thesequence of native protein but can be released by proteolysis during milk fermentation with lactic acidbacteria and by enzymatic hydrolysis. The most studied group of bioactive peptides in vivo and in vitroup until now are angiotensin-converting enzyme (ACE) inhibitory peptides. The main peptides whichhave been linked to this property are the tri peptides such as those having the amino acid sequence ofvalin-prolin-prolin (VPP) and izolosin-prolin-prolin (IPP). The peptides derived from milk proteins arenot as potent as the drugs used for hypertension treatment, but hold a promise as safer and naturaltherapeutic agents without any adverse effect. In this review, some studies related to with structure,formation and bioavailability of milk derived antihypertensive peptides were discussed

Polypharmacy Treatment of Hypertensionin Public Health Centers

Background : Hypertension is one of the most prominent global diseases. Despite the availability of effective therapies, hypertension remains poorly controlled in Indonesia. In many cases, patient’s noncompliance may be attributable to the low patients’ knowledge, attitude, and life-style practices such as polypharmacy. Polypharmacy is defined as the administration of many drugs at in one prescription. Polypharmacy increases expenses, possible adverse reaction to a single agent, incidence of drug interactions, and decreases patient’s compliance This study aimed to identify the practice of polypharmacy in hypertension treatment in primary health centers. Methods : A cross-sectional descriptive observational study was carried out on 60 patients from two primary health centers in Jatinangor, West Java, Indonesia in October 2013. Sociodemographic profile, degree of hypertension, types of antihypertensive drugs, concomitant drugs given together with antihypertensive drugs, and treatment compliance data were collected and presented in tables and figures. Results : The incidence of hypertension was more common among male patients compared to female patients. Thirty-three patients (55%) have low compliance to their medication. Twenty-nine patients (48%) received single drug and 31 patients (52%) received more than one drugs. Conclusions : The percentage of polypharmacy practice in treating hypertension in primary health centers is 52%. The most frequently prescribed anti-hypertensive are angiotensin-converting enzyme (ACE) inhibitors and calcium-channel blockers (CCB). Most of hypertensive patients have low compliance to therapy. [AMJ.2016;3(4):633–9] DOI: 10.15850/amj.v3n4.951

ACE and UCP2 gene polymorphisms and their association with baseline and exercise-related changes in the functional performance of older adults

Maintaining high levels of physical function is an important aspect of successful ageing. While muscle mass and strength contribute to functional performance in older adults, little is known about the possible genetic basis for the heterogeneity of physical function in older adults and in how older adults respond to exercise. Two genes that have possible roles in determining levels of muscle mass, strength and function in young and older adults are angiotensin-converting enzyme (ACE) and mitochondrial uncoupling protein 2 (UCP2). This study examined whether polymorphisms in these two individual genes were associated with baseline functional performance levels and/or the training-related changes following exercise in previously untrained older adults. Five-eight Caucasian older adults (mean age 69.8 years) with no recent history of resistance training enrolled in a 12 week program of resistance, balance and cardiovascular exercises aimed at improving functional performance. Performance in 6 functional tasks was recorded at baseline and after 12 weeks. Genomic DNA was assayed for the ACE intron 16 insertion/deletion (I/D) and the UCP2 G-866A polymorphism. Baseline differences among genotype groups were tested using analysis of variance. Genotype differences in absolute and relative changes in physical function among the exercisers were tested using a general linear model, adjusting for age and gender. The genotype frequencies for each of the studied polymorphisms conformed to the Hardy-Weinberg equilibrium. The ACE I/D genotype was significantly associated with mean baseline measures of handgrip strength (II 30.9 ± 3.01 v. ID 31.7 ± 1.48 v. DD 29.3 ± 2.18 kg, p < 0.001), 8ft Up and Go time (II 6.45 ± 0.48 v. ID/DD 4.41 ± 0.19 s, p < 0.001) and 6 min walk distance (II 458 ± 28.7 v. ID/DD 546 ± 12.1m, p = 0.008). The UCP2 G-866A genotype was also associated with baseline 8ft Up and Go time (GG 5.45 ± 0.35 v. GA 4.47 ± 0.26 v. AA 3.89 ± 0.71 s, p = 0.045). After 12 weeks of training, a significant difference between UCP2 G-886A genotype groups for change in 8ft Up and Go time was detected (GG −0.68 ± 0.17 v. GA −0.10 ± 0.14 v. AA +0.05 ± 0.31 s, p = 0.023). While several interesting and possibly consistent associations with older adults’ baseline functional performance were found for the ACE and UCP2 polymorphisms, we found no strong evidence of genetic associations with exercise responses in this study. The relative equivalence of some of these training-response findings to the literature may have reflected the current study’s focus on physical function rather than just strength, the relatively high levels of baseline function for some genotype groups as well as the greater statistical power for detecting baseline differences than the training-related changes.

Renin-angiotensin system: an old player with novel functions in skeletal muscle.

Skeletal muscle is a tissue that shows the most plasticity in the body; it can change in response to physiological and pathological stimuli. Among the diseases that affect skeletal muscle are myopathy-associated fibrosis, insulin resistance, and muscle atrophy. A common factor in these pathologies is the participation of the renin-angiotensin system (RAS). This system can be functionally separated into the classical and nonclassical RAS axis. The main components of the classical RAS pathway are angiotensin-converting enzyme (ACE), angiotensin II (Ang-II), and Ang-II receptors (AT receptors), whereas the nonclassical axis is composed of ACE2, angiotensin 1-7 [Ang (1-7)], and the Mas receptor. Hyperactivity of the classical axis in skeletal muscle has been associated with insulin resistance, atrophy, and fibrosis. In contrast, current evidence supports the action of the nonclassical RAS as a counter-regulator axis of the classical RAS pathway in skeletal muscle. In this review, we describe the mechanisms involved in the pathological effects of the classical RAS, advances in the use of pharmacological molecules to inhibit this axis, and the beneficial effects of stimulation of the nonclassical RAS pathway on insulin resistance, atrophy, and fibrosis in skeletal muscle.

Medical genetics-based drug repurposing for Alzheimer's disease.

Alzheimer's disease (AD) is a disease that threatens the elderly. No efficient therapeutic method is currently available to combat AD. Drug repurposing has provided a new route for AD drug discovery, and medical genetics has shown potential in target-based drug repurposing. We compared AD-associated genes with approved drug targets and found that three are targeted by 23 approved drugs. Thus, these drugs may be used to treat AD according to the medical genetic information of the targets. In vitro and in vivo experiments revealed that four drugs, all of which are angiotensin-converting enzyme (ACE) inhibitors, had potential to treat AD.

Modern possibilities of hypertension drug therapy. Candesartan and its place in the therapy

Arterial hypertension (AH) remains the one of the major cardiovascular diseases in the adult population and a major factor in cardiovascular and cerebrovascular morbidity and mortality. Drug therapy of hypertension leads to a reduction of cardiovascular risk by affecting blood pressure. Renin-angiotensin-aldosterone system (RAAS) plays a key role in the formation of hypertension, as the drug blockade of its components can significantly improve the prognosis of patients. The principal means of blocking the RAAS are angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists II (ARA II, sartans). Both classes of drugs have shown their high antihypertensive efficacy, with the ARA II having almost perfect portability. Recently, however, sartans’independent rolein the treatment of hypertension has been questioned. Date overview of the evidence base of sartans with a focus on modern antihypertensive drug called candesartan cilexetil was the following work’s objective.

State-of-the-art treatment of hypertension: established and new drugs

The treatment of essential hypertension is based essentially on the prescription of four major classes of antihypertensive drugs, i.e. blockers of the renin--angiotensin system, calcium channel blockers, diuretics and beta-blockers. In recent years, very few new drug therapies of hypertension have become available. Therefore, it is crucial for physicians to optimize their antihypertensive therapies with the drugs available on the market. In each of the classes of antihypertensive drugs, questions have recently been raised: are angiotensin-converting enzyme (ACE) inhibitors superior to angiotensin II receptor blockers (ARB)? Is it possible to reduce the incidence of peripheral oedema with calcium antagonists? Is hydrochlorothiazide really the good diuretic to use in combination therapies? The purpose of this review is to discuss these various questions in the light of the most recent clinical studies and meta-analyses. These latter suggest that ACE inhibitors and ARB are equivalent except for a better tolerability profile of ARB. Third generation calcium channel blockers enable to reduce the incidence of peripheral oedema and chlorthalidone is certainly more effective than hydrochlorothiazide in preventing cardiovascular events in hypertension. At last, studies suggest that drug adherence and long-term persistence under therapy is one of the major issues in the actual management of essential hypertension.

Vasoactive Hormones and the Diabetic Kidney

Diabetic nephropathy is the single most common cause of end-stage renal disease (ESRD) and accounts for significant morbidity and mortality. While the incidence of ESRD increased dramatically in the 1980s and 1990s, the U.S. Renal Data System (USRDS) 2005 Annual Data Report shows that 338 out of every million Americans had kidney failure in 2003, down slightly from 340 per million in 2002. This report shows that the numbers of people developing ESRD have stabilized despite the persistent increase in the number of people diagnosed with type 2 diabetes mellitus (T2DM). These data attest to both the efficacy of the currently available therapeutic regimens for the treatment of ESRD as well as better overall patient care. Unfortunately, these encouraging statistics do not apply to all patients. According to the USRDS report, the most marked ESRD decrease was seen in young Caucasian men (<40 years of age), while in other patient groups, particularly African Americans, ESRD has not changed much at all. These observations suggest that more in-depth studies, addressing specific issues, such as race, are needed to understand the disease process fully in order to create novel therapeutic strategies to eradicate the disease completely in all patient populations.The most commonly used therapeutic treatments for diabetic nephropathy are angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (Ang II) receptor blockers (ARBs), implicating the importance of the renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of diabetic nephropathy. The RAAS is not the only vasoactive hormonal system that is involved in the disease process. Over the past decade, studies have suggested that other vasoactive hormones, including endothelin, urotensin II, and the kallikrein-kinin system (KKS), are instrumental in mediating structural and functional alterations in the renal vasculature and parenchyma, leading to the development and progression of diabetic nephropathy. This review will summarize our current understanding of the contribution of vasoactive hormones in the pathophysiology of diabetic nephropathy with specific emphasis on the RAAS, especially the more recently identified components of this hormonal pathway.

Review: Dual blockade of the renin angiotensin system in diabetes — rationale and risks

Diabetic nephropathy is the most common cause of end stage renal failure (ESRF) in the developedof world and as the incidence of diabetes increases this trend will continue, although most of these patients will die of cardiovascular diseases. The renin-angiotensin system (RAS) is believed to play a central role in the development and progression of both micro- and macrovascular complications of diabetes and blocking this system in diabetic patients is critically important. Two widely used inhibitors of RAS are angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). These drugs affect the system at different levels and thus may have an additive effect. Use of drugs from one class may not be completely effective in blocking this system for several reasons. In this article we discuss issues surrounding the use of dual blockade (i.e. the use of ARB and ACE inhibitors together in patients with diabetic nephropathy responding insufficiently to previous antihypertensive treatment including either ARB or ACE inhibitors) in patients with diabet

Pharmacologic therapy for patients with chronic heart failure and reduced systolic function: review of trials and practical considerations

Heart failure (HF) is a complex clinical syndrome resulting from any structural or functional cardiac disorder impairing the ability of the ventricles to fill with or eject blood. The approach to pharmacologic treatment has become a combined preventive and symptomatic management strategy. Ideally, treatment should be initiated in patients at risk, preventing disease progression. In patients who have progressed to symptomatic left ventricular dysfunction, certain therapies have been demonstrated to improve survival, decrease hospitalizations, and reduce symptoms. The mainstay therapies are angiotensin-converting enzyme (ACE) inhibitors and β-blockers (bisoprolol, carvedilol, and metoprolol XL/CR), with diuretics to control fluid balance. In patients who cannot tolerate ACE inhibitors because of angioedema or severe cough, valsartan can be substituted. Valsartan should not be added in patients already taking an ACE inhibitor and a β-blocker. Spironolactone is recommended in patients who have New York Heart Association (NYHA) class III to IV symptoms despite maximal therapies with ACE inhibitors, β-blockers, diuretics, and digoxin. Low-dose digoxin, yielding a serum concentration <1 ng/mL can be added to improve symptoms and, possibly, mortality. The combination of hydralazine and isosorbide dinitrate might be useful in patients (especially in African Americans) who cannot tolerate ACE inhibitors or valsartan because of hypotension or renal dysfunction. Calcium antagonists, with the exception of amlodipine, oral or intravenous inotropes, and vasodilators, should be avoided in HF with reduced systolic function. Amiodarone should be used only if patients have a family history of sudden death, or a history of ventricular fibrillation or sustained ventricular tachycardia, and should be used in conjunction with an implantable defibrillator. Finally, anticoagulation is recommended only in patients who have concomitant atrial fibrillation or a previous history of cerebral or systemic emboli.

Biosensors for the Enantioselective Analysis of S-Enalapril and S-Ramipril

S-Enalapril, and S-ramipril are angiotensin-converting enzyme (ACE) inhibitors which are used for treatment of hypertension. Due to the fact that only the S enantiomer possesses the ACE inhibiting activity, it is necessary to develop an enantioselective analytical method for its discrimination from the less active R-enantiomer. An amperometric biosensor, based on L-amino acid oxidase, was developed and proved reliable for the analysis of the S-enantiomer of these ACE inhibitors. The working range of the biosensor for S-enalapril assay (A) is 0.4–120μmol/L, and for S-ramipril assay (B) is 0.2–100μmol/L, with a limit of detection of 163 nmol/L (A) and 107 nmol/L (B), respectively. It is of interest to mention that the biosensors demonstrated enantioselectivity versus D-proline (1.4 × 10−3 mol/L(A), 5.3 × 10−3 mol/L(B) and also the selectivity versus the polyvinylpyrolidone (3.0 × 10−3 mol/L(A), 3.2 × 10−3 mol/L(B), respectively. The working pH ranges are: 6.8 – 7.4 (A), and 6.2 – 7.0 (B), respectively. The RSD < 1% assured by using the amperometric biosensors for S enantiomers assay in raw materials, in tablet formulations, and their suitability for the analysis of these drug enantiomers.

Influence of ACE Inhibition on Fluid Metabolism in Chronic Heart Failure and Its Pathophysiologic Relevance

BACKGROUND: In congestive heart failure with water retention, subtraction of body fluid by ultrafiltration causes greater diuresis and clinical improvement in patients who are angiotensin-converting enzyme (ACE)-inhibited, suggesting an influence of ACE inhibitors on fluid metabolism. METHODS AND RESULTS: Patients with moderate congestive heart failure were subjected to ultrafiltration (around 2000 mL) and followed up for 3 months. Usual outpatient therapy, consisting of digoxin, furosemide, and ACE inhibitors (18 patients, group A) and of digoxin and furosemide only (18 patients, group B), was continued throughout the trial. Hemodynamics, renal function, body fluid and electrolytes, plasma norepinephrine, renin activity, aldosterone, and plasma volume were monitored. At 30 and 90 days after ultrafiltration, hormones, renal function, functional capacity (based on cardiopulmonary tests), and extravascular lung water (chest radiograph score) were determined. Soon after ultrafiltration, body weight, plasma volume, and diuresis were reduced (hypovolemia) and hormones were raised (reaction to hypovolemia). In the next 4 days, all these variables reverted to the pre-ultrafiltration values in group B; in group A diuresis and plasma volume recovered, body weight was still reduced, and hormones became lower than baseline. These changes persisted in the next 3 months. An early reduction of extravascular lung water continued long term in group A only, associated with increase of exercise tolerance time and oxygen uptake and decrease of the dead space/tidal volume ratio. CONCLUSIONS: In congestive heart failure, ACE inhibition persistently prevented fluid accumulation once the excess of body fluid had been withdrawn with a nonpharmacologic method, resulting in sustained improvement in functional capacity. Reduction in circulating norepinephrine, aldosterone, and renin did not seem to be the cause but the consequence of this action, whose mechanisms remain undefined.

Clinically important drug interactions with anticoagulants. An update.

Coumarin derivatives combine 3 unfavorable properties which make them prone to potentially life threatening drug-drug interactions: (i) high protein binding; (ii) cytochrome P450 dependent metabolism; and (iii) a narrow therapeutic range. An entire list of drugs which are supposed to interact with coumarins (mostly with warfarin) comprises about 250 different compounds. Noteworthy are the interactions with cardiovascular or antilipidaemic drugs which are often coadministered with coumarins: amiodarone, propafenone and fibrates. Cardiovascular drugs which are obviously devoid or proven to be devoid of an interaction are angiotensin converting enzyme (ACE) inhibitors, calcium antagonists, beta-blockers and cardiac glycosides. There are several other drugs which enhance the hypoprothrombinaemic response to coumarins by various mechanisms: inhibitors of the elimination of the eutomer S-(-)-warfarin (e.g. miconazole, phenylbutazone), combined with protein binding displacement (e.g., sulfinpyrazone, phenylbutazone), synergistic hypoprothrombinaemia (e.g. cefazoline). Furthermore, bleeding complications may occur with drugs affecting platelet function [aspirin (acetylsalicylic acid) and several nonsteroidal anti-inflammatories (NSAIDs)]. Strong inducers of coumarin metabolism are rifampicin (rifampin) and carbamazepine. Biphasic interactions may occur where a drug first enhances the hypoprothrombinaemic response to a coumarin but has a sustained inducing effect on coumarin metabolism (e.g. phenytoin or sulfinpyrazone). The complex response of coumarins to concomitant drug therapy makes it difficult to predict the occurrence and degree of a deterioration of anticoagulant control in individual patients. For clinical practice, it seems advisable that one should monitor for changes in prothrombin time when adding or deleting any newly approved drug or any drug suspected (e.g. on the basis of this review) to cause an interaction to patients on coumarin therapy. The onset of the adverse prothrombin time response might be from between 1 to 2 days up to 3 weeks (in case of phenprocoumon) after starting a concomitant drug regimen. With amiodarone, an adverse prothrombin time response might occur up to 2 months after initiating therapy. For heparins, only a drug interaction with aspirin or nitroglycerin seems clinically relevant due to the possibility of coadministration during acute cardiac events. Both drugs are shown to enhance the activated partial thromboplastin time response to heparin.

Activation of two angiotensin-generating systems in the balloon-injured artery

Participation of angiotensin II in the myointimal proliferation following a vascular injury was postulated. This study assessed the potential involvement of the local angiotensin II-forming enzymes in injured arteries of dogs. The potential angiotensin II-forming enzymes are angiotensin-converting enzyme (ACE) and chymostatin-sensitive angiotensin II-generating enzyme (CAGE) which is highly homologous to or could be identical to the mast cell chymase. Both ACE and CAGE catalyze the conversion of angiotensin I to angiotensin II. We found that the enzymatic activities of ACE and CAGE, and the mRNA levels of ACE and chymase were increased in the injury-induced hypertrophied vessels. The results suggest that ACE and CAGE participate in the hypertrophy through the production of angiotensin II which is a growth promoter for vascular smooth muscle cells.