Antithrombotic Properties of Water-Soluble Carbon Monoxide-Releasing Molecules

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 32; no. 9; pp. 2149 - 2157
• Main Authors: Kramkowski, Karol, Leszczynska, Agnieszka, Mogielnicki, Andrzej, Chlopicki, Stefan, Fedorowicz, Andrzej, Grochal, Elzbieta, Mann, Brian, Brzoska, Tomasz, Urano, Tetsumei, Motterlini, Roberto, Buczko, Wlodzimierz
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.09.2012; Lippincott Williams & Wilkins
• Subjects: Animals; Arterial Occlusive Diseases - blood; Arterial Occlusive Diseases - etiology; Arterial Occlusive Diseases - physiopathology; Arterial Occlusive Diseases - prevention & control; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood Coagulation - drug effects; Blood Gas Analysis; Blood Platelets - drug effects; Blood Platelets - metabolism; Blood Pressure - drug effects; Boranes - administration & dosage; Boranes - chemistry; Boranes - metabolism; Boranes - pharmacology; Carbon Monoxide - metabolism; Carbonates - administration & dosage; Carbonates - chemistry; Carbonates - metabolism; Carbonates - pharmacology; Cardiology. Vascular system; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dose-Response Relationship, Drug; Fibrin - metabolism; Fibrinogen - metabolism; Fibrinolysis - drug effects; Fibrinolytic Agents - administration & dosage; Fibrinolytic Agents - chemistry; Fibrinolytic Agents - metabolism; Fibrinolytic Agents - pharmacology; Green Fluorescent Proteins - biosynthesis; Green Fluorescent Proteins - genetics; Injections, Intravenous; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Confocal; Organometallic Compounds - administration & dosage; Organometallic Compounds - chemistry; Organometallic Compounds - metabolism; Organometallic Compounds - pharmacology; Plasminogen Activator Inhibitor 1 - blood; Platelet Aggregation - drug effects; Prothrombin Time; Rats; Rats, Wistar; Solubility; Thrombosis - blood; Thrombosis - etiology; Thrombosis - physiopathology; Thrombosis - prevention & control; Time Factors; Venous Thrombosis - blood; Venous Thrombosis - etiology; Venous Thrombosis - physiopathology; Venous Thrombosis - prevention & control; Water - chemistry; carbon monoxide-releasing molecules; intravital microscopy; Hemostatic; Rat; fibrin generation; Rodentia; Cardiovascular disease; green fluorescent protein mice; Thrombosis; platelet aggregation; Vascular disease; Aggregation; Fibrin; Plasminogen activator inhibitor 1; Vertebrata; Platelet; Mammalia; plasminogen activator inhibitor-1; Microscopy; Mouse; Animal; Atherosclerosis; Carbon monoxide
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.112.253989

OBJECTIVE—We compared the antithrombotic effects in vivo of 2 chemically different carbon monoxide–releasing molecules (CORM-A1 and CORM-3) on arterial and venous thrombus formation and on hemostatic parameters such as platelet activation, coagulation, and fibrinolysis. The hypotensive response to CORMs and their effects on whole blood gas analysis and blood cell count were also examined. METHODS AND RESULTS—CORM-A1 (10–30 µmol/kg, i.v.), in a dose-dependent fashion, significantly decreased weight of electrically induced thrombus in rats, whereas CORM-3 inhibited thrombosis only at the highest dose used (30 µmol/kg). CORM-A1 showed a direct and stronger inhibition of platelet aggregation than CORM-3 in healthy rats, both in vitro and in vivo. The antiaggregatory effect of CORM-A1, but not CORM-3, correlated positively with weight of the thrombus. Concentration of active plasminogen activator inhibitor-1 in plasma also decreased in response to CORM-A1, but not to CORM-3. Neither CORM-A1 nor CORM-3 had an effect on plasma concentration of active tissue plasminogen activator. CORM-3, but not CORM-A1, decreased the concentration of fibrinogen, fibrin generation, and prolonged prothrombin time. Similarly, laser-induced venous thrombosis observed intravitally via confocal system in green fluorescent protein mice was significantly decreased by CORMs. Although both CORM-A1 and CORM-3 (30 µmol/kg) decreased platelets accumulation in thrombus, only CORM-A1 (3–30 µmol/kg) inhibited platelet activation to phosphatidylserine on their surface. CONCLUSION—CORM-3 and CORM-A1 inhibited thrombosis in vivo, however CORM-A1, which slowly releases carbon monoxide, and displayed a relatively weak hypotensive effect had a more pronounced antithrombotic effect associated with a stronger inhibition of platelet aggregation associated with a decrease in active plasminogen activator inhibitor-1 concentration. In contrast, the fast CO releaser CORM-3 that displayed a more pronounced hypotensive effect inhibited thrombosis primarily through a decrease in fibrin generation, but had no direct influence on platelet aggregation and fibrynolysis.