SummaryThe aim of this study was to investigate the anti-thrombotic effects of an inhibitor of the plasminogen activator inhibitor-1 (PAI-1) in rats given endotoxin. In studies in vitro, PRAP-1, a Fab-fragment of a polyclonal antibody against human PAI-1, was shown to inhibit PAI-1 activity in rat plasma as well as to stimulate clot-lysis of the euglobulin fraction derived from rat plasma. Endotoxin administered to anaesthetised rats produced a marked increase in plasma PAI-1 activity. To study fibrin formation and lysis in vivo after intravenous (i. v.) injection of the coagulant enzyme batroxobin, 125I-fibrinogen was administered to the animals. The thrombi formed by batroxobin were rapidly lysed in control animals, while the rate of lysis was markedly attenuated in rats given endotoxin. PRAP-1 was administered i.v. (bolus + infusion) to rats given endotoxin and batroxobin and the PAI-1 inhibitor caused a dose-dependent decrease in the 125I-fibrin deposition in the lungs. An immunohistochemical technique was used to confirm this decrease in density of fibrin clots in the tissue. Furthermore, PRAP-1 decreased plasma PAI-1 activity in the rats and this reduction was correlated to the decrease in lung 125I-fibrin deposition at the corresponding time point. It is concluded that in this experimental model the PAI-1 antibody PRAP-1 may indeed inhibit thrombosis in animals exposed to endotoxin.
The use of in vitro models for the study of cardiovascular effects of drugs may not be representative for the in vivo therapeutic effects. However, drug effects in vivo are often difficult to assess because of counteracting reflexes and auto-regulatory rearrangements. To solve this dilemma, the present study presents a two-step method using both in vivo and in vitro techniques to investigate vascular versus myocardial selectivity of three dihydropyridine calcium antagonists: amlodipine, felodipine and nifedipine. The ratio between intravenous drug doses causing 25% reduction in mean arterial blood pressure (vascular potency) and in heart rate (cardiac chronotropic potency) was determined in anaesthetised spontaneously hypertensive rats during autonomic cardiac blockade. In isolated hearts from spontaneously hypertensive rats, the inotropic versus chronotropic potency ratio was determined between the two drug concentrations producing a 25% reduction in cardiac contractility (dP/dt max) and in heart rate, respectively. The vascular versus chronotropic selectivity in vivo was higher for felodipine (121) than for nifedipine (47) and amlodipine (15). The inotropic versus chronotropic potency ratios obtained from the in vitro studies were: felodipine (1), amlodipine (2) and nifedipine (20). The in vitro results were used to extrapolate the vascular versus cardiac chronotropic selectivity obtained in vivo to a vascular versus myocardial selectivity drug ratio, being 20 and 60 times higher for felodipine than for amlodipine and nifedipine, respectively.
Basic fibroblast growth factor (bFGF), is a heparin-binding factor with potent angiogenic properties in vitro and in vivo. bFGF is involved in tumour growth, but it has also been shown to reduce infarct size in experimentally induced acute myocardial infarction. Platelets are also believed to have an important role in both tumour growth and myocardial infarction.We have studied bFGF binding to platelets by flow cytometry. Platelet activation by ADP induces bFGF binding to platelets. bFGF bound to activated platelets will result in a locally high concentration of bFGF in patients with myocardial infarctions and malignant tumours. Addition of recombinant bFGF to platelet rich plasma reduced the percentage of fibrinogen positive platelets. bFGF may thus have an inhibitory effect on platelet aggregation.
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