In vivo assessment of captopril selectivity of angiotensin I-converting enzyme inhibition: differential inhibition of acetyl-ser-asp-lys-pro and angiotensin I hydrolysis.
Angiotensin I-converting enzyme (ACE) is a zinc metallopeptidase that plays a major role in blood pressure regulation. The demonstration that the hemoregulatory peptide acetyl-Ser-Asp-Lys-Pro (AcSDKP) is a natural and specific substrate of the N-active site of ACE suggests that this enzyme may have a new physiological role such as the modulation of hematopoietic stem cells. In vitro studies have shown that ACE inhibitors displayed various potencies in inhibiting the degradation of different natural or synthetic substrates of ACE, among which captopril inhibits AcSDKP hydrolysis more potently than angiotensin I hydrolysis. To look for this selectivity in vivo, we investigated the pharmacodynamic effect of increasing doses of captopril (0.01-10 mg/kg) during the 90 min after i.v. administration to spontaneously hypertensive rats. Plasma and urinary AcSDKP levels were measured. The renin-angiotensin system was evaluated by measurements of ACE activity in plasma samples, using the synthetic substrate Hip-His-Leu, by determinations of plasma renin concentrations and measurements of arterial blood pressure. The results showed that captopril (0.01-0.3 mg/kg) selectively inhibited AcSDKP hydrolysis, with limited effects on the renin-angiotensin system. AcSDKP levels in plasma and urine rose to a plateau 4 times the basal level for doses more than 0.3 mg/kg. All of the parameters reflecting the renin-angiotensin system were significantly affected at doses of 1 and 10 mg/kg. The present study therefore confirms that captopril can be used to protect hematopoietic stem cells during antitumor chemotherapy while having only a limited effect on cardiovascular homeostasis.
Junot
C
C
Commissariat à l'Energie Atomique, Service de Pharmacologie et d'Immunologie, Saclay, Gif-sur-Yvette, France.
Menard
J
J
Gonzales
M F
MF
Michaud
A
A
Corvol
P
P
Ezan
E
E
D000803:Angiotensin I / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002216:Captopril / Q000008:administration & dosage / Q000494:pharmacology*; D006868:Hydrolysis; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D009842:Oligopeptides / Q000493:pharmacokinetics*; D007703:Peptidyl-Dipeptidase A / Q000097:blood*; D051381:Rats; D011918:Rats, Inbred SHR; D012083:Renin / Q000097:blood; D013379:Substrate Specificity; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D009842:Oligopeptides; D000803:Angiotensin I; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D012083:Renin; C058504:goralatide