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Alpha- and beta-adrenergic influences on the tissue and urokinase plasminogen activator systems

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Author: Larsson, P.T. · Wallén, N.H. · Wiman, B. · Dooijewaard, G.
Type:article
Date:1999
Institution: Gaubius instituut TNO
Source:Fibrinolysis and Proteolysis, 4-5, 13, 169-175
Identifier: 235353
Keywords: adrenalin · isoprenaline · noradrenalin · phentolamine · phentolamine mesylate · plasminogen activator inhibitor 1 · propranolol · tissue plasminogen activator · urokinase · controlled study · dose response · drug potentiation · fibrinolysis · heart rate · human · human experiment · intravenous drug administration · male

Abstract

Objective: To study the influence of α- and β-adrenoceptor stimulation in vivo on fibrinolysis in healthy male volunteers. Design: Infusions were given in a single blind fashion and in a randomized order if placebo infusions were included. Setting: University Department (Karolinska Hospital). Subjects: Thirty-four healthy, non-smoking male volunteers aged 21-38 years. Interventions: Study 1 - The volunteers participated in two or three separate experiments; 30 min infusions of saline placebo, phentolamine (500 μg/min) or propranolol (bolus dose of 140 μg/kg + 0.5 μg/kg/min) followed by the addition of a 30 min adrenaline infusion (0.4 nmol/kg/min), n=10 in each group. Study 2 - Infusion of a low and an intermediate-high dose of noradrenaline (0.15 and 0.75 nmol/kg/min; 20 min at each dose level), n=11. Study 3 - Infusion of a low and high dose of isoprenaline (5 and 20 ng/kg/min), each during 20 min, n=10. Main outcome measures: Venous plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigen and activity levels, and plasma levels of urokinase (u-PA) antigen. Results: t-PA activity and antigen levels were markedly increased during adrenaline infusion (by 309±35 and 81±16% respectively, both P<0.01) with a concomitant decrease in PAI-1 activity. U-PA antigen levels increased to a lesser extent. Propranolol, but not phentolamine, attenuated or blunted the effects of adrenaline. Non-selective β-adrenoceptor stimulation by isoprenaline caused smaller, but similar and dose-dependent alterations in fibrinolytic parameters as observed during adrenaline infusions, except for u-PA antigen levels that remained unaltered. A small increase in t-PA activity (by 55±13%, P<0.001) was observed during noradrenaline infusion, whereas t-PA antigen levels only tended to increase, PAI-1 activity decreased and u-PA antigen levels were not affected. Conclusion: Catecholamine-induced increases in plasma levels of t-PA, and to some extent u-PA, are mainly β-adrenoceptor mediated, whereas α-adrenoceptors are of minor importance.