Inhibitory effects of aprotinin on kallikrein and kininases in dog's blood

Abstract

Summary The blood‐bathed organ technique was used in dogs to estimate kinin generation in the blood. Strips of cat jejunum were used as assay tissues. Infusions of kallikrein at 0·5–8 mu/ml into the blood in the extracorporeal circuit led to a generation of kinin at 0·6–10 ng/ml. The kinin generated was at the same concentration after incubation of kallikrein with blood for 15 s or 120 seconds. Intravenous infusions of kallikrein at (8–125 mu/kg)/min led to similar blood concentrations of kinin. These infusions induced substantial falls in blood pressure. Aprotinin inhibited the generation of kinin by kallikrein, but the concentration needed in vivo was 20,000 times higher than would be expected from the definition of the units. After intravenous injection of large doses of aprotinin, the kallikrein‐inhibiting activity passed off within 40–60 minutes. At the same time, there was a gradual reduction in kininase activity, so that the half life of bradykinin in blood increased from a mean of 13 s to 40 seconds. This effect reached a maximum 1–3 h after injection of aprotinin. It is suggested that a metabolite of aprotinin is responsible for the kininase inhibition and that this effect may limit the usefulness of aprotinin in man.

The inactivation of bradykinin in the pulmonary circulation of isolated lungs

“…This could not be accounted for by inactivation in blood alone. Bradykinin is also removed from the pulmonary circulation in the anaesthetized dog (Biron, 1968) and rat (Stewart & Roblero, 1967), and by perfused lungs from guinea-pigs and dogs (Pojda & Vane, 1971). Since cell-free extracts of dog lung readily inactivated bradykinin (Bakhle, 1968) it was considered likely that inactivation of bradykinin in the pulmonary circulation was due to enzymic degradation.…”