Vol. 291, Issue 3, 982-987, December 1999

Effect of Angiotensin-Converting Enzyme Inhibition on Plasma, Urine, and Tissue Concentrations of Hemoregulatory Peptide Acetyl-Ser-Asp-Lys-Pro in Rats¹

Christophe Junot, Laurence Nicolet, Eric Ezan, Marie-Francoise Gonzales, Joel Menard and Michel Azizi

Commissariat à l'Energie Atomique, Service de Pharmacologie et d'Immunologie, Saclay, Gif-sur-Yvette (C.J., E.E.), Centre d'Investigations Cliniques 9201, Institut National de la Santé et de la Recherche Médicale (INSERM) et Assistance Publique des Hôpitaux de Paris, Hôpital Broussais, Paris (L.N., J.M., M.A.), and INSERM Unit 367, Paris, France (M.F.G., J.M.)

The hemoregulatory peptide Acetyl-Ser-Asp-Lys-Pro (AcSDKP) has been reported to accumulate in plasma and urine after the oral administration of angiotensin-converting enzyme (ACE) inhibitors in humans. It is unknown whether such an accumulation also occurs in tissues. We administered captopril (3, 10, or 30 mg/kg) orally for 2 weeks to Wistar rats. In a second experiment, captopril (10 mg/kg) was administered for 9 days and was followed by a 1-h i.v. infusion of either AcSDKP (0.1 or 2 mg/kg) or saline on day 9. Captopril alone dose-dependently increased plasma AcSDKP by a factor of 3 to 5 and urine AcSDKP by a factor of 3. It slightly increased renal and pulmonary AcSDKP concentrations but did not affect AcSDKP concentrations in bone marrow and spleen. The combination of AcSDKP (2 mg/kg) and captopril gave very high AcSDKP concentrations in plasma and urine and increases in AcSDKP concentration by factors of 27 in kidney, 5.5 in lung, and 6.9 in the extracellular fraction of bone marrow. In contrast, no change was observed in the AcSDKP concentration in spleen and in the intracellular fraction of bone marrow. In conclusion, during chronic ACE inhibition in rats, AcSDKP levels slightly increased in organs with high ACE contents. No such increase occurred in hematopoietic organs. AcSDKP had to be combined with captopril to significantly increase its concentration in tissues other than the spleen. The possibility of pharmacologically increasing AcSDKP levels in the extracellular fraction of bone marrow may be of value for protecting hematopoietic cells from the toxicity of cancer chemotherapy.