Studies on vasoactivity of fibrin(ogen) derived peptides

Abstract: Fibrin accumulation is a common fmding in many pathological conditions, such as in inflammatory processes, e.g. in the lungs in pneumonia or pulmonary insufficiency after sepsis. During lysis of the fibrin by plasmin or leukocyte elastase, peptides are released that may contribute to the pathophysiological changes. Peptide 6A, Ala-Arg-Pro-Aia-Lys, released duting plasmin degradation of fibrin( ogen) induced dilation of bovine mesenteric arteries in vitro, increased cAMP in the vessels and released prostacyclin. It also increased coronary and femoral artery blood flow in the dog, probably due to release of prostacyclin and nitric oxide. L-arginine increased femoral blood flow in the dog, but was less potent than peptide 6A, indicating that properties beside the arginine content are important for the vasoactive effect of the peptide. D-arginine had much less effect than Laiginine, indicating that the effect of lrarginine is related to its utilization for synthesis of nitric oxide. Peptide 6A was an effective inhibitor of pulmonary angiotensin converting enzyme (ACE) in vivo in rabbits. It also potentiated the hemodynamic responses to bradykinin, an ACE substrate, and elicited bradykinin responses from normally subeffective circulating bradykinin levels. Peptide 6A showed an endothelium-dependent relaxant effect on rat aorta. Two different ACE inhibitors, one with and one without sulfhydryl groups, both enhanced this effect, indicating that the mechanism underlying the potentiation effect is inhibition of ACE and not related to sulhydryl supplementation.Peptide Bp 30-43, Arg-Pro-Ala-Pro-Pro-Pro-lle-Ser-Gly-Gly-Gly-Tyr-Arg-Ala, caused vasodilation of bovine mesenteric arteries, an increase m both cAMP and cGMP in the vessels and an increased release of prostacyclin. It also induced polymorphonuclear leukocyte emigration in rabbit skin in vivo. A contributory cause of this effect may be release of the vasodilator prostacyctin.In summary, these investigations showed that certain peptides released during degradation of human fibrin(ogen) have vasoactive properties and that the effects are mediated by prostacyclin, nitric oxide and inhibition of ACE. Endogenously released such peptides might contribute to the pathophysiology in inflammation or thrombolysis via the mechanisms described. In addition analogues to these peptides might be of therapeutic interest in the future, e.g. in thrombolysis or critical limb ischemia.