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.
Jia
L
L
Chinese Academy of Medical Sciences, Beijing, 100730, China. ljia@saci.org
Pei
R
R
Lin
M
M
Yang
X
X
D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use / Q000633:toxicity*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity*; D002423:Cause of Death; D004353:Drug Evaluation, Preclinical; D002149:Energy Intake / Q000187:drug effects; D005260:Female; D006128:Growth / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy*; D007022:Hypotension / Q000139:chemically induced / Q000401:mortality; D007275:Injections, Intravenous; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020030:Nitric Oxide Donors / Q000627:therapeutic use / Q000633:toxicity*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D018675:Toxicity Tests; D023382:Toxicity Tests, Acute; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000627:therapeutic use / Q000633:toxicity*
D000806:Angiotensin-Converting Enzyme Inhibitors; D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; C060039:S-nitrosocaptopril; D002216:Captopril