Physiologic, Pharmacologic, and Clinical Aspects of Proteinase Inhibitors

Abstract

It is generally assumed that the pharmacological action of a biologically active substance, which is synthesized by the body, is, in some way, paralleled by its physiological function. Provided that selective inhibition of distinct proteolyticesterolytic enzymes is the sole function of naturally occurring proteinase-inhibitors and that synthesis of these inhibitors is not merely a rudimental and now meaningless genetic cell-function, the physiological function of these inhibitors is selective inhibition of enzymatic-proteolytic processes. They probably also protect tissues against undue activation of proteolytic enzymes.Inhibitors, which only occur in certain species and, even in these, only in certain organs, and which do not occur in interstitial and other body fluids (TABLE l ) , probably inhibit and regulate enzymatic reactions at an intracellular level. This applies to the polyvalent trypsin-kallikrein-inhibitor from bovine organs, which occurs also in secretory organs like salivary glands and pancreas, but is not found in secretions of these organs nor in other body fluids (Frey et al., 1950). Stimulation-e.g., by pilocarpin-which usually results in an unphysiological high secretion rate, does not bring about any secretion of inhibitor. Following i.v. injection of pure preparations of trypsin-kallikrein-inhibitor from bovine organs up to 10,000 KIU/kg in cattle, dogs, and hogs, we could not demonstrate the inhibitor in saliva nor in pancreatic juice. Furthermore, the inhibitor reaching salivary glands and pancreas via the bloodstream did not accumulate in these organs. On isolated perfusion of dog pancreas, addition of Trasylol@ to the perfusion fluid does not. impair secretion of zymogens or insulin.From our former experiments, we know that intravenous Trasylol is distributed to the various organs according to their blood supply (FIGURE 1 ) . Following injection of 12,000 KIU/kg in rats and 3500 KIU/kg in dogs, inhibitor concentration in the liver attains a temporary maximum after 30 min. After a latent interval of about 10 min, inhibitor concentrations begins to increase in the kidneys. One hour after injection, the inhibitor content in renal tissue is higher than in the liver (50% and 36% respectively of the total amount). The blood still contains less than 10% of the injected inhibitor amount. About five hours after injection, almost the entire amount of inhibitor administered is to be found in an active form in the kidneys. The results suggest that the inhibitor undergoes structural change in the liver which condition it for fixation in the kidney. Using tritiumlabeled Trasylol, we could show that, before excretion, the bulk of inhibitor is degraded and is demonstrable in urine as tritium activity only (FIGURE 2) (Traut- schold et ul., 1964).As the trypsin-kallikrein-inhibitor occurs selectively in cattle and perhaps more generally in ruminants, a physiological function can be discussed for this species only. From the information available to us, we believe this inhibitor is identical with the inhibito...

Interrelations of the renal kallikrein-kinin system and renal prostaglandins in the conscious rat. Influence of mineralocorticoids.

“…Conversely, aprotinin which inhibits kidney and urinary kallikrein 10 may decrease the activity of the kallikrein-kinin system by reducing renal production of kinins, which in turn results in diminished release of prostaglandins. Aprotinin occurs in the kidney and to a lesser extent in the urine of rats injected with the enzyme inhibitor, 26 and this may account for our finding of reduced kidney and urinary kallikrein activity in such rats. However, measurement of urinary kallikrein activity in vitro may not accurately reflect the effectiveness of aprotinin as an inhibitor of kallikrein in vivo.…”

Obstructive nephropathy in the rat: possible roles for the renin-angiotensin system, prostaglandins, and thromboxanes in postobstructive renal function.

“…levels was performed in the rats in group XII. In these animals, again after an initial period without pharmare infused with an cological manipulation, and a second period of Captod to dissolve the pril treatment, the rats were treated during a third pe-I CPAH were sig-riod with the kallikrein inhibitor, Trasylol, to block vith Captopril than the production of the kinins (16,17 (14). Thereion which followed ted from decreased :reased production :wo further groups I those of group X ter release of UUO 'first period), then n (second period).…”

“…In 11 rats (group XII) the production of bradykinin and other kinins was suppressed by infusing the kallikrein inhibitor (16,17), Trasylol (registered trademark Bayer A. G., kindly supplied by Professor Dr. Gurt L. Haberland, Farbenfabriken, Bayer A. G., Wuppertal-Elberfeld, Germany). The Trasylol was prepared by dissolving 10.4 mg in 1.0 ml of a 0.9% solution of NaCl (69,000 KIU/ml).…”

Relationship of Plasma Peptides to the Myocardial Depressant Factor in Hemorrhagic Shock in Cats

“…For example, MDF formation has been shown to be prevented by cortisol (10), and in this study by Trasylol. Both of these agents are known to inhibit the formation of a variety of proteases which can release peptides (16)(17)(18)(19). MDF is a peptide with a molecular weight in the range of the known peptides released by proteases, such as kinins (about 800 to 1000).…”

“…Since Trasylol is an antagonist of kallikrein and other proteases (16,17), and since it appeared to block the production of MDF in shock, MDF was thought to be a peptide produced by proteases. In an attempt to obtain further data on this point, synthetic bradykinin and eledoisin were added to cat papillary muscles to determine whether these peptides possessed any negative inotropic activity.…”