Involvement of the TRPV1 receptor in plasma extravasation in airways of rats treated with an angiotensin-converting enzyme inhibitor.

Angiotensin-converting enzyme inhibitors (ACEIs) are widely used in the treatment of hypertension, congestive heart failure and renal disease, and are considered relatively safe and generally well-tolerated drugs. However, adverse effects of ACEIs have been reported, including non-productive cough and angioedema, which can lead to poor adherence to therapy. The mechanisms by which ACEIs promote adverse effects are not fully elucidated, although increased bradykinin plasma levels following ACEI therapy seem to play an important role. Since bradykinin can sensitise the transient potential vanilloid receptor 1 (TRPV1), we investigated the role of TRPV1 in plasma extravasation in the trachea and bronchi of rats treated with the ACEI captopril. We observed that intravenous (i.v.) administration of captopril did not cause plasma extravasation in the trachea or bronchi of spontaneously breathing rats, but induced plasma extravasation in the trachea and bronchi of artificially ventilated rats. The intratracheal (i.t.) instillation of capsaicin or bradykinin also induced an increase in plasma extravasation in the trachea and bronchi of artificially ventilated rats. As expected, capsaicin-induced plasma extravasation was inhibited by i.t. pretreatment with the TRPV1 selective antagonist capsazepine (CPZ) while bradykinin-induced plasma extravasation was reduced by i.t. pretreatment with the selective B2 receptor antagonist Icatibant, originally known as HOE 140 (HOE). Interestingly, bradykinin-induced plasma extravasation was also inhibited by CPZ. The pretreatment with HOE and CPZ, singly or in combination and at doses which do not cause inhibitory effects per se, significantly inhibited the plasma extravasation induced by captopril treatment in artificially ventilated rats. In addition, treatment with a high dose of capsaicin in newborn rats, which induces degeneration of TRPV1-expressing sensory neurons, abolished both capsaicin and captopril-induced plasma extravasation in artificially ventilated rats. In conclusion, our study identified that captopril treatment promoted sensitisation of TRPV1, via B2 receptor activation, inducing plasma extravasation in the airways of mechanically ventilated rats. The present findings add a new view about the role of TRPV1 in the plasma extravasation induced by captopril and could to contribute to the elucidation of mechanisms by which ACEI induces adverse effects on airways.

Captopril's influence on Danio rerio embryonic development: Unveiling significant toxic outcomes at environmentally relevant concentrations.

Anticipating a global increase in cardiovascular diseases, there is an expected surge in the use of angiotensin-converting enzyme inhibitors, notably captopril (CAP). This heightened usage raises significant environmental apprehensions, mainly due to limited knowledge regarding CAP's toxic effects on aquatic species. In response to these concerns, the current study aimed to tackle this knowledge gap by evaluating the potential influence of nominal concentrations of CAP (0.2-2000 µg/L) on the embryonic development of Danio rerio. The findings revealed that CAP at all concentrations, even at concentrations considered environmentally significant (0.2 and 2 µg/L), induced various malformations in the embryos, ultimately leading to their mortality. Main malformations included pericardial edema, craniofacial malformation, scoliosis, tail deformation, and yolk sac deformation. In addition, CAP significantly altered the antioxidant activity of superoxide dismutase and catalase across all concentrations. Simultaneously, it elevated lipid peroxidation levels, hydroperoxides, and carbonylic proteins in the embryos, eliciting a substantial oxidative stress response. Likewise, CAP, at all concentrations, exerted significant modulatory effects on the expression of genes associated with apoptosis (bax, bcl2, p53, and casp3), organogenesis (tbx2a, tbx2b, and irx3b), and ion exchange (slc12a1 and kcnj1) in Danio rerio embryos. Both augmentation and reduction in the expression levels of these genes characterized this modulation. The Pearson correlation analysis indicated a close association between oxidative damage biomarkers and the expression patterns of all examined genes with the elevated incidence of malformations and mortality in the embryos. In summary, it can be deduced that CAP poses a threat to aquatic species. Nevertheless, further research is imperative to enhance our understanding of the environmental implications of this pharmaceutical compound.

Inhibitors of angiotensin I converting enzyme potentiate fibromyalgia-like pain symptoms via kinin receptors in mice.

Fibromyalgia is a potentially disabling chronic disease, characterized by widespread pain and a range of comorbidities such as hypertension. Among the mechanisms involved in fibromyalgia-like pain symptoms are kinins and their B1 and B2 receptors. Moreover, angiotensin I converting enzyme (ACE) inhibitors, commonly used as antihypertensive drugs, can enhance pain by blocking the degradation of peptides such as substance P and bradykinin, besides enhancing kinin receptors signalling. We investigated the effect of ACE inhibitors on reserpine-induced fibromyalgia-like pain symptoms and the involvement of kinins in this effect in mice. Nociceptive parameters (mechanical and cold allodynia and overt nociception) were evaluated after ACE inhibitors administration in mice previously treated with reserpine. The role of kinin B1 and B2 receptors was investigated using pharmacological antagonism. Additionally, bradykinin levels, as well as the activity of ACE and kininase I, were measured in the sciatic nerve, spinal cord and cerebral cortex of the mice. The ACE inhibitors enalapril and captopril enhanced reserpine-induced mechanical allodynia, and this increase was prevented by kinin B1 and B2 receptor antagonists. Substance P and bradykinin caused overt nociception and increased mechanical allodynia in animals treated with reserpine. Reserpine plus ACE inhibitors increased bradykinin-related peptide levels and inhibited ACE activity in pain modulation structures. Since hypertension is a frequent comorbidity affecting fibromyalgia patients, hypertension treatment with ACE inhibitors in these patients should be reviewed once this could enhance fibromyalgia-like pain symptoms. Thus, the treatment of hypertensive patients with fibromyalgia could include other classes of antihypertensive drugs, different from ACE inhibitors.

Sublethal effects induced by captopril on Cyprinus carpio as determined by oxidative stress biomarkers.

To our knowledge, this is the first study to evaluate captopril-induced oxidative stress in fish, and specifically in the common carp Cyprinus carpio. At present, very few studies in the international literature evaluate the sublethal effects of captopril on aquatic organisms such as fish, and available ones focus on determination of median lethal concentration in crustaceans and algae. Also, studies evaluating these effects do not make reference to the mechanism of action of this pharmaceutical or its toxicokinetics. This limits our knowledge of the characterization of the sublethal effects of this medication and of its potential ecological impact. The present study aimed to evaluate the sublethal effects induced by three different concentrations of captopril, on C. carpio), by determination of activity of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), as well as indicators of cellular oxidation: hydroperoxide content (HPC), lipid peroxidation (LPX) and protein carbonyl content (PCC). Specimens were exposed for 12, 24, 48, 72 and 96h to three different captopril concentrations: 1µgL-1, 1mgL-1 and 100mgL-1 (the first one has been detected environmentally, the other two have been associated with diverse toxic effects in aquatic species), and brain, gill, liver, kidney and blood samples were evaluated. Significant increases in HPC and LPX were observed mainly in kidney and gill, while PCC also increased in brain. Modifications were found in the activity of SOD (mostly in kidney, brain and blood), CAT (all organs) and GPx (kidney and gill). In conclusion, captopril induces oxidative stress in C. carpio.

Mitigation of radiation nephropathy after internal alpha-particle irradiation of kidneys.

PURPOSE: Internal irradiation of kidneys as a consequence of radioimmunotherapy, radiation accidents, or nuclear terrorism can result in radiation nephropathy. We attempted to modify pharmacologically, the functional and morphologic changes in mouse kidneys after injection with the actinium ((225)Ac) nanogenerator, an in vivo generator of alpha- and beta-particle emitting elements. METHODS AND MATERIALS: The animals were injected with 0.35 muCi of the (225)Ac nanogenerator, which delivers a dose of 27.6 Gy to the kidneys. Then, they were randomized to receive captopril (angiotensin-converting enzyme inhibitor), L-158,809 (angiotensin II receptor-1 blocker), spironolactone (aldosterone receptor antagonist), or a placebo. RESULTS: Forty weeks after the (225)Ac injection, the placebo-control mice showed a significant increase in blood urea nitrogen (BUN) (87.6 +/- 6.9 mg/dL), dilated Bowman spaces, and tubulolysis with basement membrane thickening. Captopril treatment accentuated the functional (BUN 119.0 +/- 4.0 mg/dL; p <0.01 vs. placebo controls) and histopathologic damage. In contrast, L-158,809 offered moderate protection (BUN 66.6 +/- 3.9 mg/dL; p = 0.02 vs. placebo controls). Spironolactone treatment, however, significantly prevented the development of histopathologic and functional changes (BUN 31.2 +/- 2.5 mg/dL; p <0.001 vs. placebo controls). CONCLUSIONS: Low-dose spironolactone and, to a lesser extent, angiotensin receptor-1 blockade can offer renal protection in a mouse model of internal alpha-particle irradiation.

Impairing effects of angiotensin-converting enzyme inhibitor Captopril on bone of normal mice.

There are contradicting results about the effects of angiotensin-converting enzyme inhibitors (ACEIs) on bones. This study was aimed to investigate the effect of ACEI, Captopril, on bone metabolism and histology as well as the action of Captopril on skeletal renin-angiotensin system (RAS) and bradykinin receptor pathway in normal male mice. The urine, serum, tibias and femurs from normal control mice and Captopril-treated (10mg/kg) mice were collected for biochemical, histological and molecular analyses after drug administration for eight weeks. The mice after the treatment with Captopril had a significant decrease of serum testosterone level. The histological measurements showed the loss of trabecular bone mass and trabecular bone number, and the breakage of trabecular bone network as well as the changes of chondrocyte zone at epiphyseal plate in Captopril-treated mice. The defect of Captopril on trabecular bone was reflected by the quantitative bio-parameters from micro-CT. The expression of renin receptor and bradykinin B2 receptor (B2R) was significantly up-regulated in tibia of mice upon to the Captopril treatment, which decreased the ratio of OPG/RANKL and the expression of osteoblastic factor RUNX2. Furthermore, Captopril treatment resulted in the increase of pAkt/Akt and pNFκB expression in tibia. The present study revealed the impairing effects of Captopril on bone via interfering with the circulating sex hormone level and B2R pathway, which suggests that the bone metabolism of patients need to be carefully monitored when being prescribed for ACEIs.

The contributions of adrenal hormones, hemodynamic factors, and the endotoxin-related stress reaction to stable prostaglandin analog-induced peripheral lymphopenia and neutrophilia.

Stable prostaglandin analogs are known to induce lymphopenia and neutrophilia in a dose-dependent fashion after subcutaneous injection in rats. The purpose of the present investigation is to determine whether the prostaglandin-induced changes in circulating leukocytes might be secondary to hypotension with the ensuing release of adrenal hormones. The adrenal medullary catecholamine epinephrine was found to induce neutrophilia in both intact and adrenalectomized rats, and the glucocorticosteroid analog dexamethasone induced a profound lymphopenia in rats as reported by previous investigators. A stable analog of PGF2 alpha (15-S-15-methyl PGF2 alpha; M-PGF2 alpha) at the dose of 1 mg/kg induced marked systemic hypotension 1 h after injection, with lymphopenia and neutrophilia 6 h after injection. The non-prostanoid hypotensive agent captopril, at a dose of 63 mg/kg, induced a hypotension of similar magnitude and kinetics to that induced by prostaglandin. Captopril also induced lymphopenia and neutrophilia at 6 h, although the neutrophilia was of lesser magnitude than that induced by prostaglandins. The prostaglandin-induced lymphopenia was found to be mediated, at least in part, by the hypotension-induced release of adrenal hormones, as evidenced by the abrogation of lymphopenia in prostaglandin-treated adrenalectomized rats. Captopril-treated adrenalectomized rats, however, did develop a significant lymphopenia, suggesting that hypotension can result in lymphopenia even in adrenalectomized rats. The M-PGF2 alpha-induced neutrophilia in adrenalectomized rats, by comparison to captopril-induced neutrophilia in adrenalectomized rats, was greater than the neutrophilia expected as the result of hypotension alone. Indeed, the M-PGF2 alpha-induced neutrophilia in adrenalectomized rats was greater than the captopril-induced neutrophilia in sham-adrenalectomized rats. Thus, a portion of the neutrophilia induced by M-PGF2 alpha in intact rats may be mediated through adrenal-independent, hemodynamic-independent mechanisms. The possibility that M-PGF2 alpha might be inducing neutrophilia via an endotoxin-like stress reaction was investigated by examining changes in circulating white blood cells in intact and adrenalectomized C3H/HeN (endotoxin-sensitive) and C3H/HeJ (endotoxin-resistant) mice after prostaglandin administration. No quantitative differences in the prostaglandin-induced neutrophilia were noted in C3H/HeJ mice as compared to the C3H/HeN mice.(ABSTRACT TRUNCATED AT 400 WORDS)

Angiotensin-converting enzyme inhibitors have no effect on ovulation and ovarian steroidogenesis in the perfused rat ovary.

The null hypothesis of this study was that the angiotensin-converting enzyme inhibitors, captopril and teprotide, would not reduce the number of ovulations in vivo and in vitro in the rat. Captopril (in three regimens) was administered continuously beginning prior to pregnant mare's serum gonadotropin and hCG to trigger ovulation. The number of in vivo ovulations were counted. Ovaries similarly primed with pregnant mare's serum gonadotropin were dissected and perfused in media with hCG and captopril (two regimens) or teprotide (one regimen). The number of in vitro ovulations and steroid production in the perfusions were evaluated. The results were evaluated by the Student's t test. Power calculations gave only a 20% chance of missing a 16% difference in ovulations or steroidogenesis. There was no inhibition of ovulation or change in steroid production in angiotensin-converting enzyme treated rats in vivo or in vitro. While angiotensin II has been shown to be an important mediator in the mechanism of ovulation, angiotensin-converting enzyme inhibition via captopril or teprotide does not result in angiotensin II antagonistic effects. Hypothetical mechanisms to explain this paradox are presented.

Acute and subacute toxicity and efficacy of S-nitrosylated captopril, an ACE inhibitor possessing nitric oxide activities.

The toxicity and efficacy of S-nitrosocaptopril (CapNO), a novel vasodilator possessing the capacities of both a nitric oxide donor and an angiotensin converting enzyme (ACE) inhibitor, were examined in rodents. In single-dose acute toxicity studies in ICR mice, the median lethal dose (LD(50)) for CapNO was 674+/-94 mg/kg (iv) and 2078+/-100 mg/kg (po), whereas for oral captopril was 4286+/-173 mg/kg. S-nitrosoglutathione, containing the same S-nitroso moiety as CapNO, showed an LD(50) equal to CapNO when the values were expressed by the mol/kg. The cause of acute death by the high doses of CapNO was lethal hypotension. In the subacute toxicity studies, oral CapNO was well tolerated in normotensive and hypertensive rats at doses up to 500 mg/kg/day for 3 months, except for considerable reductions in food consumption and growth rate observed in the 500 mg/kg/day group. Serum chemistry and hematology tests performed in the subacute toxicity studies revealed no adverse effects of oral CapNO except for a significant decrease in cholesterol levels in hypertensive SHR rat. At autopsy, no histopathological changes in major organs were observed over the subacute period. Administration of a therapeutic dose of CapNO (iv, 250 microg/kg which produced 25% decreases in blood pressure) revealed no changes in the hematological parameters. Subchronic treatment of SHR and SS/Jr rats with oral CapNO (50 mg/kg/day) significantly reduced mean arterial pressure to the normotensive level. Considering the absence of adverse effects of CapNO in the subchronic toxicity study, CapNO appears to be a safe drug for further clinical trials, but particular caution must be taken because it can cause hypotension when overdosed.

Hyperplasia of juxtaglomerular cells and renin localization in kidney of normotensive animals given captopril. Electron microscopic and immunohistochemical studies.

Captopril, a competitive inhibitor of angiotensin I-converting enzyme (ACE), is an orally potent antihypertensive agent. Light and electron microscopic studies of th kidneys of mice, rats, and monkeys given large oral doses of captopril for long duration were conducted. All mice and some rats and monkeys developed hyperplasia of the renin-secreting cells which appeared in several layers surrounding the vascular wall of the afferent arterioles. In the electron microscope, these epithelioid cells appeared heavily loaded with aggregates of homogeneous electron dense, osmiophilic amorphous granules filling distended spaces of the endoplasmic reticulum. The Golgi cisterns often included small, sharply outlined triangular or rhomboid osmiophilic granules. The use of specific renin antibodies and the application of the "three-layer bridge technique" for peroxidase-antiperoxidase defined and verified the accumulation of renin in the juxtaglomerular cells. After cessation of dosing, hyperplasia of the juxtaglomerular cells markedly regressed, and there was a significant reduction in the number and size of the renin granules in such cells.

[Acute toxicological studies of captopril in rats and mice].

The acute toxicity of captopril, a potential inhibitor of angiotensin converting enzyme, was studied in Sprague-Dawley rats and ICR mice. In the oral administration, a decrease of spontaneous motor activity, lacrimation, salivation and decline of body temperature was noted in the rats and mice. In the mice, tarry stool was also noted. The LD50 was estimated as: 4249 mg/kg in male mice, 5050 mg/kg in female mice, 4336 mg/kg in male rats and 4245 mg/kg in female rats, In the dead animals, a hemorrhagic erosion or ulcer was recognized in the glandular stomach. An intravenous captopril in mice, caused immediate death by dyspnea in some animals within 3 minutes, but delayed death was also occurred within 24 hours showing a decrease of spontaneous motor activity and decline of body temperature. The LD50 was estimated as 3154 mg/kg in male mice and 3225 mg/kg in female mice. A single intravenous administration of captopril in dose of 1600 mg/kg did not cause any death in the rats of both sexes. The mice of both sexes well tolerated a single subcutaneous administration of captopril in a dose of 2400 mg/kg. No death occurred in rats of both sexes received subcutaneously captopril in a dose of 1200 mg/kg. At an injection site, a necrotic ulcer was noted in the skin of rats and mice which received subcutaneously captopril in a dose of 1600 mg/kg or more and 1200 mg/kg, respectively.

[One month studies on the subacute toxicity of captopril in rats].

Subacute toxicity of captopril by daily oral administration at dose levels of 10 mg/kg, 30 mg/kg, 100 mg/kg, 300 mg/kg, 900 mg/kg and 2700 mg/kg for one month was studied in Sprague-Dawley rats. In the 2700 mg/kg group, 13 of 18 males and 17 of 18 females died with marked emaciation and abdominal distension. In the 900 mg/kg group, 1 of 18 males and 3 of 18 females died also during the administration period. In dead animals, a marked dilatation of gastrointestinal tract was noted showing multiple hemorrhagic erosions and/or ulcers in the glandular stomach. The remainder of these groups exhibited polydipsia and polyuria during the dosage period. In the 300 mg/kg and 100 mg/kg groups, all animals survived throughout the entire experimental period showing polydipsia and polyuria. In the 30 mg/kg and 10 mg/kg groups, all animals survived also throughout the entire dosage period without showing any toxic sign. Regarding plasma analysis, the BUN and creatinine concentration was significantly elevated in the group of 100 mg/kg or more. In the hematological examination, there was a decrease of erythrocyte counts, hemoglobin contents and hematocrit values in the group of 300 mg/kg or more. Pathological examinations revealed a marked thickening of the wall in afferent arterioles and interlobular arteries of the kidney in association with hypertrophy and hyperplasia of juxtaglomerular cells in 100 mg/kg, 300 mg/kg, 900 mg/kg and 2700 mg/kg groups. In these groups, multiple hemorrhagic erosions with or without ulcer were also noted in the glandular stomach. In the spleen, a slight increase of extramedullary hematopoiesis and hemosiderosis was noted in the 100 mg/kg, 300 mg/kg, 900 mg/kg and 2700 mg/kg groups, in which an increase of erythropoietic elements was also noted in the bone marrow. From these results, the maximum nontoxic dose was estimated as about 30 mg/kg/day by oral administration of captopril in the rats.

[Twelve month studies on the chronic toxicity of captopril in rats].

The chronic administration of captopril to Sprague-Dawley rats was performed under the barrier system by feeding ad libitum with mixed diet in various concentrations of captopril with 3 months recovery period. The number of animals was 180 female and 180 male including 5 groups of control, 30, 100, 300 and 900 mg/kg/day. The maximum nontoxic dose was estimated as about 30 mg/kg/day for male but a little more than this for female rats. Body weight increase was significantly reduced in male but for the first 3 months in female rats. No death was ascribed to the toxic effect of captopril. Polydipsia and polyuria in male, and the significant increase in values of BUN and inorganic phosphate in both sexes were observed. The reduction in erythrocyte count, values of hemoglobin and hematocrit, hemosiderosis in reticulum cells of the spleen and Kupffer cells in the liver and the increase of erythropoieses indicated hemolytic anemia. Heart weight reduced while kidney weight increased. Pathological examination revealed hypertrophia and hyperplasia of JG cells and thickening of walls of afferent arterioles with hyperplasia of vascular smooth muscle cells and increase of collagen fibers. Thickening of walls extended to walls of the interlobular arteries which remained after withdrawal of captopril for 3 months though JG granules attenuated. The age-related increases of incidences of proteinuria and myocardial fibrosis were attenuated dose-dependently which are probably due to hypotension induced by captopril.

[Three month subacute toxicity of captopril in beagle dogs].

Thirty four beagle dogs, male and female were orally given 10, 30, 100 and 200 mg/kg/day of captopril, an angiotensin converting enzyme inhibitor, for 3 months followed by a recovery test for 4 weeks. One of 4 female dogs which were treated with the highest dose of 200 mg/kg/day throughout the experimental period died of bronchial pneumonia. Hypersalivation and occasionally vomiting was observed in dogs treated with 100 and 200 mg/kg/day. Skin eruption such as erythema and papules was observed mostly at the ventral surface of the neck, chest and upper abdomen in dogs in these two experimental groups. Histological examination of the lesion revealed cellular infiltration with edema and expansion in the dermis and slight hyperkeratosis with parakeratosis and acanthosis. Changes in erythrocyte counts, hematocrit values and hemoglobin contents during the course of administration were variable among dogs but these were obvious in animals treated with higher doses. An increase in erythropoiesis of the bone marrow, extramedullary hematopoiesis and slight hemosiderosis in liver and spleen were revealed by histological examination. Above histological observations suggest that captopril may cause hemolysis. Hypertrophy and hyperplasia of juxtaglomerular cells with increased number of JG granules were shown in the highest dosage group even 4 weeks after suspension of captopril administration. A distinct plasma renin activity supported the morphological changes. From the results of three months administration of captopril to beagle dogs, the maximum non-toxic dose may be around 10 mg/kg/day and toxic dose 100 mg/kg/day.

Detection of hepatotoxicity potential with metabolite profiling (metabolomics) of rat plasma.

While conventional parameters used to detect hepatotoxicity in drug safety assessment studies are generally informative, the need remains for parameters that can detect the potential for hepatotoxicity at lower doses and/or at earlier time points. Previous work has shown that metabolite profiling (metabonomics/metabolomics) can detect signals of potential hepatotoxicity in rats treated with doxorubicin at doses that do not elicit hepatotoxicity as monitored with conventional parameters. The current study extended this observation to the question of whether such signals could be detected in rats treated with compounds that can elicit hepatotoxicity in humans (i.e., drug-induced liver injury, DILI) but have not been reported to do so in rats. Nine compounds were selected on the basis of their known DILI potential, with six other compounds chosen as negative for DILI potential. A database of rat plasma metabolite profiles, MetaMap(®)Tox (developed by metanomics GmbH and BASF SE) was used for both metabolite profiles and mode of action (MoA) metabolite signatures for a number of known toxicities. Eight of the nine compounds with DILI potential elicited metabolite profiles that matched with MoA patterns of various rat liver toxicities, including cholestasis, oxidative stress, acetaminophen-type toxicity and peroxisome proliferation. By contrast, only one of the six non-DILI compounds showed a weak match with rat liver toxicity. These results suggest that metabolite profiling may indeed have promise to detect signals of hepatotoxicity in rats treated with compounds having DILI potential.

Effects of zofenopril and ramipril on cough reflex responses in anesthetized and awake rabbits.

Cough is the most common symptom reported by patients in a primary care setting and is one of the most frequent secondary effects recorded during treatment with angiotensin-converting enzyme (ACE) inhibitors. The aim of the current study was to analyze potential differences in cough induction between 2 structurally different ACE inhibitors, namely zofenopril, which has a sulphydryl moiety, and ramipril, which has a carboxyl moiety. The cough reflex was induced by chemical (citric acid) and/or mechanical stimulation of the tracheobronchial tree in awake and anesthetized rabbits. Intravenous injection of the active compounds of the 2 ACE inhibitors, zofenoprilat (288 nmol/kg) and ramiprilat (129 nmol/kg), caused similar hypotensive effects in anesthetized rabbits. None of the studied cough-related variables changed in response to ACE inhibitor administration, with the exception of the number of coughs. Ramiprilat, but not zofenoprilat, increased the cough response induced by both mechanical and chemical stimulation (1 mol/L citric acid aerosol) of the tracheobronchial tree. In awake animals, zofenoprilat- or vehicle-treated rabbits did not show any significant changes in the number of coughs induced by 1 mol/L citric acid aerosol compared to their respective basal values (from 15.2 ± 2.3 to 13.1 ± 1.3 and from 16.1 ± 4.9 to 15.8 ± 4.3, respectively). Conversely, ramiprilat resulted in a significant increase in the number of coughs (from 21.1 ± 2.6 to 34.9 ± 3.5; P < .01). These findings confirm that there are differences in the cough potentiation effect induced by different ACE inhibitors. The low rate of cough seen with zofenoprilat may be related to its ability to induce a lower accumulation of bradykinin and prostaglandins at the lung level.

Hepatic necrosis and glutathione depletion in captopril-treated mice.

Captopril (CP) is an angiotensin-converting enzyme inhibitor whose metabolism involves endogenous thiols which may be depleted at high doses of CP. Following intraperitoneal administration of CP (50-300 mg/kg), dose-dependent depletion of hepatic glutathione, increased serum transaminase (SGPT) levels and hepatic necrosis were observed. The hepatic necrosis observed was either subcapsular or parenchymal in distribution. Both types of necrosis showed a dose-dependent increase in severity but with a large inter-animal variation. The patterns of necrosis observed with CP are different from the necrosis caused by paracetamol. Oral CP (300 mg/kg) caused parenchymal necrosis in only one animal. It is suggested that subcapsular necrosis may be due to the direct effect of i.p. captopril whereas parenchymal necrosis may be a consequence of hepatic GSH depletion.

Long-term effects of captopril on the morphology of normal rat adrenal zona glomerulosa. A morphometric study.

The effects of a long-term administration of captopril (Squib 14225) on the rat zona glomerulosa were investigated. Morphometry showed that this drug, which specifically inhibits angiotensin-converting enzyme, induces a notable atrophy of zona glomerulosa cells, which is principally due to the decrease in the volume of mitochondrial compartment and smooth endoplasmic reticulum. Radioimmunological assays disclosed that in the treated rats the plasma aldosterone concentration is significantly lowered. The suppressive effects of captopril were completely reserved by chronic treatment with angiotensin II. These findings confirm the view that the renin-angiotensin system is involved in the maintenance of the growth and steroidogenic capacity of the normal rat zona glomerulosa.

Toxicity study of the angiotensin converting enzyme inhibitor rentiapril in rats.

A three-months toxicity study of an angiotensin converting enzyme (ACE) inhibitor, rentiapril (CAS 80830-42-8), was performed in Sprague-Dawley rats by oral administration. The dose levels of 0, 30, 125, 500 and 1000 mg/kg were tested in both sexes, in which each experimental group comprised 10 rats. Another ACE inhibitor, captopril, was used as a reference compound. Rentiapril at the highest dose of 1000 mg/kg caused low food consumption and death of some animals with signs of bloody feces and anemia. In males and females receiving 500 and 1000 mg/kg, there were low body weight gain, increases in water intake, urine volume and serum BUN level, and decreases in levels of various erythrocytic parameters. Kidney weight was increased dose-dependently in both sexes. Histopathologically, renal changes in the 500 and 1000 mg/kg groups consisted of proximal tubular degeneration, juxtaglomerular cell hyperplasia and interstitial cell infiltration. Similar, but mild, changes in proximal tubules were present in the female 125 mg/kg group. Dead animals from the highest dose groups further showed gastrointestinal hemorrhagic erosion and/or ulcer, decreased bone marrow erythropoiesis and hepatocytic vacuolar degeneration. There was no pathological alteration in rats from other rentiapril-treated groups, as well as in controls. These results indicate that the no-effect dose of rentiapril in rats by three months oral administration is 30 mg/kg in female and 125 mg/kg in male, and suggest that, like other ACE-inhibitors, this compound also has a toxic potential to affect renal tissues.