BACKGROUND: The aim of this study was to evaluate the efficiency of captopril renography to detect renovascular hypertension (RVH) using the standardized test criteria established at the consensus conference in Santa Fe 1995. The evaluation was made prospectively and in a clinical situation. METHODS: Renal scintigraphy was performed with Tc-MAG3 according to a 2-day protocol in patients receiving 25 mg captopril 1 h before the test. A baseline study was added only in patients showing abnormal findings in the captopril-stimulated study. All tests were re-evaluated according to the consensus criteria by two nuclear medicine specialists who were unaware of the original evaluation that was made by different doctors on duty at the nuclear medicine section at the time. RESULTS: Using a 12-month clinical follow-up as a reference, 16 patients in a group of 164 hypertensive patients had RVH, that is, a prevalence of 10%. The re-evaluation and original evaluation indicated a sensitivity of 94 versus 100%, specificity of 97 versus 88%, accuracy of 97 versus 89%, positive predictive value of 83 versus 47%, and negative predictive value of 99 versus 100%. In 15 studies, results from the two evaluations were discordant and in 14 of these studies an originally false positive or intermediate study was re-evaluated as negative. The test result was highly decisive in the future management of patients, minimizing the number of renal angiograms that had to be performed and initiating a search for other causes of secondary hypertension. CONCLUSION: Captopril renography is a useful and reliable test in patients with suspicion of RVH. Strict adherence to the diagnostic criteria and recommendations from the 1995 consensus conference further improved the performance of the test compared with clinical follow-up.

Captopril is the first angiotensin-converting enzyme inhibitor for oral administration. In combination with continued digitalis and diuretic therapy it has been demonstrated to be effective in the management of severe heart failure refractory to optimal digitalis, diuretic and, in many patients, vasodilator treatment. Most studies to date have been open trials of several weeks or months duration, but a number of patients have received continued treatment, with sustained benefit, for up to 1 year or more. A placebo-controlled trial in a limited number of patients with less severe heart failure has confirmed the results of open trials. Captopril administration improves cardiac performance as a result of a reduction in systemic vascular resistance (afterload) and the various determinants of left ventricular filling pressure (preload). Improvements in exercise tolerance and functional classification, with associated reduction of clinical symptomatology, occur with simultaneous decreases in myocardial oxygen consumption. At present, captopril is worthy of a trial in patients refractory to more traditional medical management. Whether it should be considered a 'first-line' agent after failure of optimal digitalis and diuretic therapy, and before instituting other vasodilator therapy, is less clear. In patients with severe or resistant heart failure, a response to captopril is usually accompanied by a general improvement in the quality of life. The effect of captopril treatment on 1- and 2-year survival rates in patients with severe heart failure appears similar to that reported for other vasodilators. Most patients tolerate captopril treatment well, but hypotension, reduced renal function, skin rash, dysgeusia, and neutropenia have been reported.

Angiotensin (Ang) I converting enzyme (ACE) inhibitors represent a major advance in the treatment of congestive heart failure, and tissue, rather than circulating ACE, may be their major site of action. However, assessments of tissue ACE inhibition in treated patients has not always supported this contention. In these studies, ACE activity was measured in homogenates of sampled tissue by biochemical methods. In the present study, using a model system, we have examined the validity of these tissue-sampling methods. Functional ACE activity was determined by comparing positive inotropic responses to [Pro10]Ang I in either vehicle-pretreated or ACE inhibitor-pretreated papillary muscles.[Pro10]Ang I elicits a response, which is entirely dependent on ACE-mediated conversion to Ang II. The ACE inhibitors studied were captopril, enalaprilat, lisinopril, and quinaprilat. In a parallel study, papillary muscle ACE activity was also measured in homogenates using [125I]MK-351A (a radiolabeled ACE inhibitor) binding. The studies indicate that the tissue-sampling method significantly underestimated functional ACE inhibition in hamster papillary muscles (p < 0.001). Kinetic studies indicated that the half-time for the dissociation of [3H]enalaprilat and [3H]lisinopril from hamster ventricular ACE was 4.5 and 6.2 minutes, respectively. The dissociation of [3H]quinaprilat was biphasic (half-time, 47 and 90 minutes), indicating that the two active sites of somatic ACE differ in their ability to bind to this inhibitor. The rapid rate of ACE inhibitor dissociation suggests that, during the time taken to assay ACE activity biochemically, the enzyme becomes "disinhibited," leading to an underestimation of functional ACE inhibition. ACE inhibitor dissociation rates were partially predictive of the duration of functional ACE inhibition in papillary muscles; other factors that appeared to contribute were "tissue trapping" of the inhibitor and de novo synthesis of ACE in papillary muscles. Quantification of tissue ACE inhibition and its relation to drug efficacy must, therefore, involve a careful consideration of these factors to avoid artifacts in clinical decision making and in assessments of pathogenic mechanisms involved in congestive heart failure.

This report establishes the presence of mammalian-like proopiomelanocotropic hormone (POMC), and six of its peptides, including adrenocorticotropic hormone (ACTH) and melanocyte-stimulating hormone (MSH), in the immune tissues of the leech Theromyzon tessulatum. The 25.4-kDa protein was purified by high pressure gel permeation chromatography, anti-ACTH-affinity column, and reverse-phase HPLC. Its characterization was performed by Edman degradation, enzymatic treatments, and electrospray mass spectrometry. Leech POMC exhibits considerable amino acid sequence similarity to mammalian POMC. Of the six peptides, three showed high sequence similarity to their vertebrate counterparts met-enkephalin, alpha-MSH, and ACTH: 100, 84.6, and 70%, respectively; whereas gamma-MSH, beta-endorphin, and gamma-lipotropin hormone exhibited only 45, 20, and 10% sequence identity, respectively. No dibasic amino acid residues were found at the C terminus of the gamma- and beta-MSH peptides. In contrast, the leech alpha-MSH was flanked at its C-terminal by the Gly-Arg-Lys amidation signal. ACTH and corticotropin-like intermediary pituitary peptide were also C-terminally flanked by dibasic amino acid residues. The coding region of leech POMC was obtained by reverse transcription-PCR using degenerated oligonucleotide primers. Circulating levels of ACTH and MSH were 10 and 1 fmol/microl hemolymph, respectively. Morphine, in a dose-dependent manner, increased the levels of both peptides threefold; this effect was blocked by naloxone treatment. Similar results were found with the anandamide. Leech ACTH was processed to MSH by the enzymes neutral endopeptidase (24.11) and angiotensin-converting enzyme. Leech alpha-MSH had the same activity as authentic alpha-MSH in two bioasssay systems. Taken together, the study demonstrates that POMC is present in invertebrates and its immunoregulatory actions have been conserved during evolution.

Inhibitors of angiotensin converting enzyme may cause angio-oedema. To see if this might be due to potentiation of the tissue effects of bradykinin the thickness of weals raised by intradermal injection of saline or 1, 3, or 10 micrograms bradykinin was measured before and three times after single doses of captopril, enalapril, or placebo. The mean thickness increased with increasing doses of bradykinin. It did not change with time after the administration of placebo or captopril but increased from 0.61 mm before enalapril to 1.12 mm two and a half hours and 1.06 mm five hours after enalapril was given. Five subjects flushed when given bradykinin after captopril and four after enalapril, but none flushed when given bradykinin after placebo. It is concluded that angiotensin converting enzyme inhibitors potentiate the effects of intradermal bradykinin in vivo and that this may partially explain why they cause angio-oedema in susceptible patients.

[3H]Captopril autoradiography visualizes angiotensin-converting enzyme (ACE; EC 3.14.5.1) in the reproductive tract of male rats.[3H]Captopril binds to testicular slices with high affinity (Kd = 4.4 nM) and displays a pharmacological profile similar to that of ACE activity. High densities of [3H] captopril autoradiographic silver grains are found over spermatid heads and in the lumen of seminiferous tubules in stages I-VIII and XII-XIV. Tubules in stages IX-XI exhibit only one fifth the level of binding. The basal epithelium and interstitial tissue are not labeled. The initial segment of the epididymis contains very low levels of grains. The head of the epididymis demonstrates intense grain density at the luminal surface of the epithelium, with little luminal labeling. In a progression to the tail of the epididymis, epithelium labeling declines, and luminal grains increase. The lumen of the vas deferens is also labeled. ACE from testis and several regions of the epididymis has been categorized with respect to its particulate vs. soluble nature and its ability to be precipitated by an antirat lung ACE monoclonal antibody. Testicular ACE is particulate and not immunoprecipitable. The distribution of immunoprecipitable particulate ACE in the epididymis is similar to that of autoradiographic silver grains over the epithelium. The concentration of particulate but nonprecipitable ACE gradually rises from the initial segment to the tail of the epididymis, similar to the distribution of luminal [3H]captopril-associated grains. Soluble ACE activity, present in equal concentration throughout the epididymis and not immunoprecipitable, may not be detected by autoradiography of [3H]captopril.

The angiotensin converting enzyme inhibitors are an important therapeutic advance in the treatment of patients with hypertension and congestive heart failure. In addition, they are useful pharmacological probes to assess the contribution of the renin-angiotensin system to circulatory homeostasis. Captopril was the first angiotensin converting enzyme inhibitor approved for use in patients with hypertension and congestive heart failure. It is rapidly absorbed from the gastrointestinal tract, with detectable plasma concentrations apparent as early as 15 minutes. The extent of absorption is between 60 and 75% of an oral dose and peak plasma concentrations occur after approximately one hour. Captopril is primarily excreted by the kidneys via renal tubular secretion. Renal excretion is rapid, with 90% completed in the first 4 hours. The elimination half-life for unchanged captopril is about 1.7 hours and is markedly increased in the presence of renal insufficiency. Once absorbed, captopril is extensively metabolised to several forms, including a disulphide dimer of captopril, a captopril-cysteine disulphide, and other mixed disulphides with endogenous thiol compounds. It is probable that captopril and its pool of metabolites undergo reversible interconversions. Pharmacokinetic properties of captopril in patients with uncomplicated hypertension appear to be the same as in healthy subjects. However, long term administration of captopril leads to increased concentrations of total captopril, probably from the accumulation of captopril metabolites. Despite the number of potential influences on pharmacokinetic properties in patients with congestive heart failure, due to the many abnormalities in gastrointestinal tract oedema and reductions in splanchnic and renal blood flow, the available data suggest that its pharmacokinetic properties in patients with congestive heart failure resemble those in healthy subjects. However, additional data are necessary to confirm this. Enalapril is the second angiotensin converting enzyme inhibitor to become available. Enalapril is a prodrug that is well absorbed from the gastrointestinal tract, with 60 to 70% of an oral dose being absorbed. However, enalapril must be converted by hepatic esterases to the active form, enalaprilat. After the oral administration of enalapril, the tmax for enalapril is one hour, but for enalaprilat it is 4 hours. There is a prolonged terminal elimination phase with enalaprilat being detectable as late as 96 hours after dosing. Thus, enalapril has a much longer duration of action than captopril. Like captopril, enalapril is primarily excreted by the kidneys.(ABSTRACT TRUNCATED AT 400 WORDS)

By inhibiting ACE, captopril blocks the conversion of AI or AII and augments the effects of bradykinin both in vitro and in vivo. In rats, dogs, and monkeys with 2-kidney renal hypertension, orally administered captopril rapidly and markedly reduces blood pressure; this antihypertensive effect apparently occurs via a renin-dependent mechanism; that is, the inhibition of ACE. In 1-kidney renal hypertension studies in rats and dogs, it was determined that oral doses of captopril markedly lowered blood pressure, but only after several days of dosing; the mechanism is thought to be non-renin dependent. In SHR, daily oral doses of captopril progressively lowered blood pressure; normal levels were attained by the sixth month. In all species studied, the reduction in blood pressure resulted from a reduction in total peripheral resistance; cardiac output remained unchanged or increased. In humans, captopril reduces blood pressure in patients with essential hypertension with low, normal, and high renin levels, and in patients with renovascular hypertension and hypertension associated with chronic renal failure. In hypertensive patients with high plasma renin activity, captopril apparently exerts most of its pharmacologic effects through inhibition of ACE. The means by which captopril reduces high blood pressure associated with low or normal PRA is not known, but it is clear that captopril does not act on an overactive plasma renin-angiotensin system in these cases. The antihypertensive effect of captopril is enhanced when it is given in combination with a diuretic or after salt depletion. Captopril was rapidly and well absorbed in all species tested, including man. Studies in rodents indicated that ingestion of food caused a reduction in the extent of absorption and bioavailability of captopril. Captopril and/or its metabolites were distributed extensively and rapidly throughout most tissues of normal rats; no radioactivity was detected in the brain. In vitro and in vivo, captopril formed disulfide bonds with albumin and other proteins. This binding was reversible in nature. In vitro studies in blood indicates that the disulfide dimer of captopril and mixed disulfides of captopril with L-cysteine and glutathione were formed. In intact blood cells, captopril remained in the reduced form (sulfhydryl), whereas in whole blood or plasma, captopril was converted to its disulfide dimer and other oxidative products. Biotransformation of captopril may involve both enzymatic and nonenzymatic processes.(ABSTRACT TRUNCATED AT 400 WORDS)

The present study assesses the binding density of the selective angiotensin converting enzyme (ACE) radioligand [3H]ceranapril in brain tissue homogenates derived from patients with Alzheimer's disease and those from age-, sex- and post-mortem delay-matched neurologically normal patients. Saturation studies with [3H]ceranapril identified that the specific binding (defined by captopril, 10 microM) was homogenous and of high affinity. ACE inhibitor recognition site density was higher by some 70% in the temporal cortex (Brodmann area 22) from Alzheimer's patients whereas densities were similar in frontal cortex and cerebellum when compared to control tissue. It is unknown whether this apparently selective alteration in ACE density is directly related to, or a compensatory effect of the disease, but it provides additional support for the development of compounds which interact with the central angiotensin system as novel therapies for cognitive dysfunction.

The nature of protein breakdown products and peptidomimetic drugs such as beta-lactams is crucial for their transmembrane transport across apical enterocyte membranes, which is accomplished by the pH-dependent high-capacity oligopeptide transporter PEPT1. To visualize oligopeptide transporter-mediated uptake of oligopeptides, an ex vivo assay using the fluorophore-conjugated dipeptide derivative D-Ala-Lys-N(epsilon)-7-amino-4-methylcoumarin-3-acetic acid (D-Ala-Lys-AMCA) was established in the murine small intestine and compared with immunohistochemistry for PEPT1 in murine and human small intestine. D-Ala-Lys-AMCA was accumulated by enterocytes throughout all segments of the murine small intestine, with decreasing intensity from the top to the base of the villi. Goblet cells did not show specific uptake. Inhibition studies revealed competitive inhibition by the beta-lactam cefadroxil, the angiotensin-converting enzyme inhibitor captopril, and the dipeptide glycyl-glutamine. Controls were performed using either the inhibitor diethylpyrocarbonate or an incubation temperature of 4 degrees C to exclude unspecific uptake. Immunohistochemistry for PEPT1 localized immunoreactivity to the enterocytes, with the highest intensity at the apical membrane. This is the first study that visualizes dipeptide transport across the mammalian intestine and indicates that uptake assays using D-Ala-Lys-AMCA might be useful for characterizing PEPT1-specific substrates or inhibitors.