So far pharmacological consequences of inhibition of
thromboxane A2 (TXA2) synthase by
imidazole derivatives (e.g.,
camonagrel or
dazoxiben) were linked to suppression of platelet activity. Here we report that in patients with peripheral
atherosclerosis or in cats with extracorporeal thrombogenesis treatment with
camonagrel is associated with activation of fibrinolysis or thrombolysis. These phenomena seem to be related to the
camonagrel-induced shift in metabolism of
prostaglandin endoperoxides from TXA2 to
prostacyclin (PGI2), although in an in vitro model the involvement of the
L-arginine/
nitric oxide pathway cannot be excluded. In cats
camonagrel (10 mg/kg i.v.) produced not only a fall in TXB2 but also a rise in
6-keto-PGF1 alpha and no change in
cyclic-GMP plasma levels. This points to PGI2 rather than to
nitric oxide as an in vivo mediator of
camonagrel-induced thrombolysis. The crucial role of endogenous PGI2 in the thrombolytic response to
camonagrel in cats was evidenced by its blockade following pretreatment of animals with a megadose of
aspirin (50 mg/kg i.v.) and lack of any effect on pretreatment with
L-NAME (100 micrograms/kg/min, i.v.). Obviously TXA2 synthase inhibitors (e.g.,
camonagrel) and
cyclo-oxygenase inhibitors (e.g.,
aspirin) antagonize each other in their anti-thrombotic actions and must not be administered at the same time. Furthermore, in patients
camonagrel (800 mg orally) suppressed TXA2 generation by 99.5% and doubled the plasma level of
6-keto-PGF1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)