Captopril inhibits the 72 kDa and 92 kDa matrix metalloproteinases.
Gelatinases are metalloproteinases in the kidney which can cleave type IV collagen as well as gelatin. We partially purified the 72 kDa and 92 kDa gelatinases. The gelatinolytic activity was measured by zymography and a quantitative biotin-avidin assay. By zymography, captopril in concentrations of 20 mM and 40 mM added to the incubation buffer reduced the gelatinolytic activity in a dose-dependent manner. The addition of zinc in a concentration of 50 to 100 microM reversed most of the inhibitory effect of captopril. By the biotin-avidin assay, captopril in a concentration of 30 to 50 nM reduced half of either the 72 kDa or 92 kDa gelatinolytic activity. Zinc in a concentration of 50 microM completely reversed the inhibitory effect of 1 microM captopril on both gelatinases. Lisinopril, a non-sulfhydryl ACE inhibitor, similarly inhibited the gelatinases, but a 100-fold higher concentration of the drug was needed. These findings suggest that captopril reversibly inhibits the 72 kDa and 92 kDa metalloproteinases by interacting with the zinc ion at their active sites. This inhibitory effect is observed with captopril levels comparable to the concentrations needed to inhibit the angiotensin converting enzyme in vivo and may at least partially explain some of the renoprotective effects seen with this drug.
Sorbi
D
D
Department of Medicine, SUNY at Stony Brook.
Fadly
M
M
Hicks
R
R
Alexander
S
S
Arbeit
L
L
D000818:Animals; D002216:Captopril / Q000494:pharmacology*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005920:Glomerular Mesangium / Q000166:cytology / Q000201:enzymology*; D017706:Lisinopril / Q000494:pharmacology; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008722:Methods; D008970:Molecular Weight; D051381:Rats; D017207:Rats, Sprague-Dawley; D015032:Zinc
D002614:Chelating Agents; D004338:Drug Combinations; D002216:Captopril; D017706:Lisinopril; D008666:Metalloendopeptidases; D015032:Zinc