The fibrinolytic system attenuates vascular tone: effects of tissue plasminogen activator (tPA) and aminocaproic acid on renal microcirculation

• Published in: British journal of pharmacology Vol. 141; no. 6; pp. 971 - 978
• Main Authors: Heyman, Samuel N, Hanna, Zohair, Nassar, Taher, Shina, Ahuva, Akkawi, Sa'ed, Goldfarb, Marina, Rosen, Seymour, Higazi, Abd‐Al Roof
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-03-2004; Nature Publishing
• Subjects: aminocaproic acid; Aminocaproic Acid - pharmacology; Animals; Aorta; Biological and medical sciences; calcium; Calcium - metabolism; Cells, Cultured; Fibrinolytic Agents - pharmacology; Hemodynamics; Humans; In Vitro Techniques; Isometric Contraction - drug effects; Kidney; Kidney Medulla - blood supply; Kidney Medulla - drug effects; laser Doppler; Medical sciences; medulla; microcirculation; Microcirculation - drug effects; Muscle, Smooth, Vascular - physiology; Perfusion; Pharmacology. Drug treatments; Plasminogen Inactivators - pharmacology; rat; Rats; Rats, Sprague-Dawley; Renal Circulation - drug effects; reteplase; tissue plasminogen activator; Tissue Plasminogen Activator - pharmacology; vascular smooth muscle; Vasoconstriction - drug effects; medulla; Calcium; Hemostatic; Rat; tissue plasminogen activator; Smooth muscle; Aminocaproic acid; Inorganic element; Kidney; t-Plasminogen activator; Microcirculation; Laser dopplerometry; Blood vessel; Antifibrinolytic; laser Doppler; vascular smooth muscle; Serine endopeptidases; Enzyme; Rodentia; Pharmacology; Fibrinolysis; Peptidases; Vertebrata; Mammalia; Urinary system; Animal; Reteplase; Hydrolases; Circulatory system; Hemodynamics; Fibrinolytic
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0705714

The renal medulla is a major source of plasminogen activators (PA), recently shown to induce vasodilation in vitro. Treatment with PA inhibitors has been associated with renal dysfunction, suggesting compromised renal microvasculature. We investigated the impact of the PA inhibitor epsilon amino‐caproic acid (EACA) upon vascular tone in vitro, and studied the effect of both tPA and EACA upon intrarenal hemodynamics in vivo.
In vitro experiments were carried out in isolated aortic rings and with cultured vascular smooth muscle cells. Studies of renal microcirculation and morphology were conducted in anesthetized Sprague–Dawley rats.
In isolated aortic rings, EACA (but not the other inhibitors of the fibrinolytic system PAI‐1 or α‐2 antiplasmin) reduced the half‐maximal effective concentration of phenylephrine (PE) required to induce contraction (from 32 nM in control solution to 2 and 0.1 nM at EACA concentrations of 1 and 10 μM, respectively). Using reteplase (retavase) in the same model, we also provide evidence that the vasoactivity of tPA is in part kringle‐dependent. In cultured vascular smooth muscle cells, Ca2+ internalization following PE was enhanced by EACA, and retarded by tPA.
In anesthetized rats, EACA (150 mg kg−1) did not affect systemic blood pressure, total renal or cortical blood flow. However, the outer medullary blood flow declined 12±2% below the baseline (P<0.03). By contrast, tPA (2 mg kg−1), transiently increased outer medullary blood flow by 8±5% (P<0.02). Fibrin microthrombi were not found within the renal microvasculature in EACA‐treated animals.
In conclusion, both fibrinolytic and antifibrinolytic agents modulate medullary renal blood flow with reciprocal effects of vasodilation (PA) and vasoconstriction (EACA). In vitro studies suggest that these hemodynamic responses are related to direct modulation of the vascular tone.
British Journal of Pharmacology (2004) 141, 971–978. doi:10.1038/sj.bjp.0705714