Peptidase activities in rats treated chronically with N(omega)-nitro-L-arginine methyl ester (L-NAME).
The chronic treatment of rats with N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) biosynthesis, results in hypertension. This inhibition of NO production results in activation of the renin-angiotensin system, with increased activity of the carboxypeptidase angiotensin I-converting enzyme (ACE). Since chronic NO inhibition increases ACE activity, we hypothesized that this inhibition could also affect the activities of other peptidases involved in cardiovascular functions. To test this possibility, we examined the activities of aminopeptidase M (APM), dipeptidyl peptidase IV (DPP IV), metalloendopeptidase 24.15 (MEP 24.15) and neutral endopeptidase 24.11 (NEP 24.11) in rat brain, heart, kidney, liver, lung and thoracic aorta. Male Wistar rats were treated chronically with L-NAME (80mgkg(-1) per day) administered in the drinking water for 4 weeks and their organs then removed and processed for the determination of peptidase activities. Treatment with L-NAME did not significantly alter the activities of the four peptidases in brain, heart, kidney, liver and lung. In contrast, in aorta, the activity of APM was slightly but significantly reduced whereas those of DPP IV and MEP 24.15 were markedly enhanced; NEP 24.11 was not detected in this tissue. Immunoblotting for DPP IV and MEP 24.15 showed increased expression in aortic tissue. Neither L-NAME (1-100microM) nor the NO donors sodium nitroprusside and 3-morpholinosydnonimine (SIN-1; 1-100microM) had any consistent effect on the activity of recombinant MEP 24.15 or renal DPP IV. The importance of MEP 24.15 in peptide metabolism was confirmed in pentobartibal-anesthetized rats pretreated with the MEP 24.15 inhibitor N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr-p-aminobenzoate (JA2), which significantly potentiated the hypotensive response to bradykinin. The altered peptidase activities seen in aorta may contribute to modulating vascular responses in this model of hypertension.
Linardi
Alessandra
A
Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil.
Panunto
Patricia Costa
PC
Ferro
Emer Suavinho
ES
Hyslop
Stephen
S
D000818:Animals; D001920:Bradykinin; D018826:CD13 Antigens / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D007022:Hypotension / Q000139:chemically induced / Q000201:enzymology; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D015260:Neprilysin / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D009569:Nitric Oxide; D010447:Peptide Hydrolases; D018826:CD13 Antigens; D018819:Dipeptidyl Peptidase 4; D007703:Peptidyl-Dipeptidase A; D008666:Metalloendopeptidases; D015260:Neprilysin; C022510:thimet oligopeptidase; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester