Effects of novel synthetic serine protease inhibitors on postoperative blood loss, coagulation parameters, and vascular relaxation after cardiac surgery

Szabó, Gábor; Veres, Gábor; Radovits, Tamás; Haider, Humaira; Krieger, Nelli; Bährle, Susanne; Miesel-Gröschel, Christiane; Niklisch, Silke; Kretzler, Matthias; Locht, Andreas van de

doi:10.1016/j.jtcvs.2009.09.019

Cited by 16 publications

(22 citation statements)

References 22 publications

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“…37,38 Similarly, other plasma kallikrein inhibitors have also shown to have antithrombotic properties in vitro or in animal models of venous and arterial thrombosis ( Table 1). [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55] These studies provide strong evidence that although components of the plasma KKS are dispensable for normal hemostasis, they play a central role in pathological thrombus formation.…”

Section: Plasma Kallikrein: Synthesis Structure and Functionsmentioning

confidence: 99%

Plasma Kallikrein Inhibitors in Cardiovascular Disease

Kolte

Shariat‐Madar

2016

Cardiology in Review

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Plasma prekallikrein is the liver-derived precursor of the trypsin-like serine protease plasma kallikrein, and circulates in plasma bound to high molecular weight kininogen. Plasma prekallikrein is activated to plasma kallikrein by activated factor XII or prolylcarboxypeptidase. Plasma kallikrein regulates the activity of multiple proteolytic cascades in the cardiovascular system such as the intrinsic pathway of coagulation, the kallikrein-kinin system, the fibrinolytic system, the renin-angiotensin system, and the complement pathways. As such, plasma kallikrein plays a central role in the pathogenesis of thrombosis, inflammation, and blood pressure regulation. Under physiological conditions, plasma kallikrein serves as a cardioprotective enzyme. However, its increased plasma concentration or hyperactivity perpetuates cardiovascular disease (CVD). In this article, we review the biochemistry and cell biology of plasma kallikrein and summarize data from preclinical and clinical studies that have established important functions of this serine protease in CVD states. Finally, we propose plasma kallikrein inhibitors as a novel class of drugs with potential therapeutic applications in the treatment of CVDs.

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Section: Plasma Kallikrein: Synthesis Structure and Functionsmentioning

confidence: 99%

Plasma Kallikrein Inhibitors in Cardiovascular Disease

Kolte

Shariat‐Madar

2016

Cardiology in Review

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“…Considering its interesting inhibition profile, CU‐2010 half‐life was studied and found to be 20 min in dogs and rats following intravenous administration, which increases to 45 min for its pegylated analog CU‐2020 . But pegylation had variable effect on inhibition potencies of factor XIIa (4.5‐fold increase), plasmin (fourfold loss), kallikrein (fourfold decrease), and factor XIa (31‐fold decrease), while retaining factor Xa and thrombin inhibition potential . Both CU‐2010 and CU‐2020 reduced blood loss by approximately threefold relative to the vehicle (149 ± 24 mL) after cardiopulmonary bypass surgery in a canine model, which was similar to that observed for aprotinin .…”

Section: Plasmin Inhibitors As Antifibrinolyticsmentioning

confidence: 99%

Recent Advances on Plasmin Inhibitors for the Treatment of Fibrinolysis‐Related Disorders

Al‐Horani

Desai

2014

Medicinal Research Reviews

101

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Growing evidence suggests that plasmin is involved in a number of physiological processes in addition to its key role in fibrin cleavage. Plasmin inhibition is critical in preventing adverse consequences arising from plasmin overactivity, e.g., blood loss that may follow cardiac surgery. Aprotinin was widely used as an antifibrinolytic drug before its discontinuation in 2008. Tranexamic acid and ε-aminocaproic acid, two small molecule plasmin inhibitors, are currently used in the clinic. Several molecules have been designed utilizing covalent, but reversible, chemistry relying on reactive cyclohexanones, nitrile warheads, and reactive aldehyde peptidomimetics. Other major classes of plasmin inhibitors include the cyclic peptidomimetics and polypeptides of the Kunitz and Kazal-type. Allosteric inhibitors of plasmin have also been designed including small molecule lysine analogs that bind to plasmin's kringle domain(s) and sulfated glycosaminoglycan mimetics that bind to plasmin's catalytic domain. Plasmin inhibitors have also been explored for resolving other disease states including cell metastasis, cell proliferation, angiogenesis, and embryo implantation. This review highlights functional and structural aspects of plasmin inhibitors with the goal of advancing their design.

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“…Moreover, there is a diverse range of serine protease inhibitors, including synthetic chemical inhibitors, and natural proteinaceous inhibitors, available for research or therapeutic purposes. Szabo et al reported that synthetic serine protease inhibitors have an effect on vascular relaxation after cardiac surgery [18]. Chao et al reported that kallistatin, a natural serine protease inhibitor, is a potent vasodilator which operates via a vascular smooth muscle mechanism [19].…”

Section: Introductionmentioning

confidence: 99%

Nafamostat mesilate promotes endothelium-dependent vasorelaxation via the Akt-eNOS dependent pathway

Choi

Kwon

Song

et al. 2016

Korean J Physiol Pharmacol

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Nafamostat mesilate (NM), a synthetic serine protease inhibitor, has anticoagulant and anti-inflammatory properties. The intracellular mediator and external anti-inflammatory external signal in the vascular wall have been reported to protect endothelial cells, in part due to nitric oxide (NO) production. This study was designed to examine whether NM exhibit endothelium dependent vascular relaxation through Akt/endothelial nitric oxide synthase (eNOS) activation and generation of NO. NM enhanced Akt/eNOS phosphorylation and NO production in a dose- and time-dependent manner in human umbilical vein endothelial cells (HUVECs) and aorta tissues obtained from rats treated with various concentrations of NM. NM concomitantly decreased arginase activity, which could increase the available arginine substrate for NO production. Moreover, we investigated whether NM increased NO bioavailability and decreased aortic relaxation response to an eNOS inhibitor in the aorta. These results suggest that NM increases NO generation via the Akt/eNOS signaling pathway, leading to endothelium-dependent vascular relaxation. Therefore, the vasorelaxing action of NM may contribute to the regulation of cardiovascular function.

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Effects of novel synthetic serine protease inhibitors on postoperative blood loss, coagulation parameters, and vascular relaxation after cardiac surgery

Abstract: CU-2010 and CU-2020 significantly reduced blood loss after cardiac surgery, with prolonged partial thromboplastin and activated clotting times, demonstrating improved antithrombotic profile. Neither aprotinin nor the novel serine protease inhibitors influenced vascular relaxation.

Cited by 16 publications

References 22 publications

Plasma Kallikrein Inhibitors in Cardiovascular Disease

Plasma Kallikrein Inhibitors in Cardiovascular Disease

Recent Advances on Plasmin Inhibitors for the Treatment of Fibrinolysis‐Related Disorders

Nafamostat mesilate promotes endothelium-dependent vasorelaxation via the Akt-eNOS dependent pathway

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