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.

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.

Evaluation of the rat embryo culture system as a predictive test for human teratogens.

Ingestion of the anticonvulsant drug valproic acid and of the angiotensin converting enzyme inhibitor captopril during pregnancy has been associated with abnormal fetal outcome in humans. In contrast, the use of the antiinflammatory drug ibuprofen and the antihistamine diphenhydramine has not been documented to be embryotoxic in humans. We evaluated the rat embryo culture system as a predictive model of teratogenesis, using these four drugs as test agents. Valproic acid, ibuprofen, and diphenhydramine were embryotoxic, inducing concentration-dependent decreases in growth and a significant increase in anomalies. Valproic acid caused an increase in neural tube defects, ibuprofen increased the incidence of abnormal maxillary processes, and diphenhydramine increased the number of embryos with distorted body morphology. These abnormalities were induced at concentrations of valproic acid and diphenhydramine that are used clinically, but ibuprofen only induced toxicity at concentrations greatly exceeding the therapeutic range. Captopril was not embryotoxic up to 5 mM, the highest concentration tested. These results suggest that the rat embryo culture system produces both false positive and false negative data on the teratogenic potential of drugs. Although such an in vitro assay may be suitable to determine the mechanism of teratogenesis, it is not a sensitive indicator of potential human teratogens on its own. These data support the view that in vitro systems can only supplement clinical and epidemiological observations in humans, possibly as a method to determine mechanisms of actions of teratogens.