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Trapidil and some other 5,7-disubstituted s-triazolo(1,5-a)pyrimidine derivatives (TPDs) which were shown to have potent actions against platelet aggregation also inhibited in vitro platelet thromboxane A2 (TXA2) biosynthesis in clotting human and rabbit whole blood as well as in arachidonic acid-activated platelet-rich human plasma. The inhibitory potency of TPDs on TXB2 formation paralleled the antiaggregatory effectiveness to a certain extent and decreased in the following order: AR 12456 greater than AR 12463 approximately AR 12464 approximately AR 12465 greater than trapidil. When TPDs were administered orally to rabbits and blood was taken 2 hours later, no changes of serum TXB2 level were observed. After i.v. injection of TPDs in rabbits, the most active TPDs AR 12456 and AR 12463 led to a short-lasting reduction of serum TXB2 by 61.4 and 49.4% resp.. The TXB2 levels returned nearly to pre-treatment level after 80 min. The possibility is discussed that TPDs mainly prevent platelet TXA2 formation by inhibiting phosphodiesterase activity.

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Five selected trapidil derivatives (12456, 12460, 12463, 12464, 12465) inhibited the arachidonic acid(AA)- and prostaglandin endoperoxide analogue(U-46619)- induced platelet aggregation as well as the AA- induced thromboxane A2(TXA2) formation. These effects of the derivatives were generally more markedly expressed than those of trapidil.

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The effects of four beta-adrenoceptor blocking agents on arachidonic acid (AA)-induced platelet aggregation and thromboxane (TX) formation in human and rabbit platelet-rich plasma (PRP) as well as their influence on prostaglandin endoperoxide analogue (U-46619)-induced aggregation in human PRP were studied. The potency against AA-induced aggregation decreased in the following sequence: pindolol greater than propranolol greater than talinolol greater than practolol (without effect). Pindolol (0.1-1.0 mmol/l) inhibited both AA-induced aggregation and TX formation. The cyclooxygenase activity in ram seminal vesicle microsomes was suppressed by both pindolol isomers. Propranolol was without effect on the cyclooxygenase. This supports the assumption that the inhibitory activity of pindolol on AA-induced platelet aggregation is mediated by its inhibiting effect on platelet cyclooxygenase as the first step of the TX formation. Propranolol (IC50:0.2 mmol/l), talinolol (IC50:0.7 mmol/l) and pindolol (IC50:1.3 mmol/l) inhibited the U-46619-induced aggregation, whereas practolol remained without effect. The spectrum of the reported data with propranolol, talinolol and practolol may be assumed to allow the correlation of the results to both the membrane stabilizing effects and to lipophilicity of the drugs.

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Ten healthy volunteers daily received 30 ml linseed oil for 4 weeks in addition to the "normal" diet. The influence of linseed oil diet on the fatty acid pattern of plasma phospholipids and thromboxane formation in platelets was investigated. The fatty acid pattern was analysed by gas liquid chromatography. The alpha-linolenic, eicosapentaenoic and docosahexaenoic acids were increased (p less than 0.01), whereas linoleic and arachidonic acids were decreased (p less than 0.05) after 4 weeks of the linseed oil diet. The thromboxane formation of platelets were unchanged. Additionally the influence of HDL and LDL on PGI2 biosynthesis in pig aortic microsomes (PAM) was investigated. HDL taken from serum before and after 3 weeks of linseed oil diet and LDL taken after 3 weeks of diet stimulated the PGI2 formation in PAM, whereas LDL taken from serum before the diet period inhibited the PGI2 formation in PAM.

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All vasodilatory drugs reported in this chapter possess an antiaggregatory effect on platelets, some of them with a synergistic effect on prostacyclin-induced inhibition of aggregation. Thus, the question seems valid whether the antiaggregatory effect represents one part of their antianginal and antihypertensive action. Some vasodilators stimulate the biosynthesis of prostacyclin and/or other vasodilating prostaglandins. This stimulation could be linked not only to the antiaggregatory but also to the vasodilating action. The influence on prostaglandin biosynthesis, however, is not obligatory for all vasodilators, as nitroglycerin proves. Trapidil inhibits the biosynthesis and the effect of thromboxane A2, as our own experiments and those by Ohnishi et al. (7) have shown. This effect could be favorable in patients with heart infarction. Lefer et al. (5) have demonstrated a fivefold increase in thromboxane release after experimental ligation of the coronary artery in the cat. Pinane thromboxane, a thromboxane antagonist, almost completely abolished all deleterious consequences of ischemia. Whether trapidil is also able to inhibit thromboxane biosynthesis and activity under clinical conditions of heart infarction will be the topic of further investigations.

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The influence of the antianginal drug trapidil on the biosynthesis of thromboxane A2 (TXA2) and/or prostacyclin (PGI2), metabolites of arachidonic acid (AA), was investigated in rabbit and human platelet rich plasma (PRP), in homogenates of rabbit spleen and of rat lung and in aortic preparations of rats and rabbits, respectively. Trapidil showed a marked inhibition of the AA-induced aggregation and TXA2 biosynthesis in rabbit and human PRP. The TXA2 inhibition by trapidil was not demonstrable in damaged platelets and seems to require intact cells. In homogenates of rat lungs, trapidil remained without effect on the TXA2 and PGI2 synthesis. In rabbit spleen homogenates the drug induced an inhibition of the formation of both AA metabolites. In contrast to Japanese authors we could not observe any increase in PGI2 release in rat aortic preparation. The PGI2 release from isolated perfused guinea pigs hearts was enhanced; on the other hand, the PGI2 efflux from rabbit hearts remained unchanged. The antiaggregatory effect of PGI2 on the ADP-induced aggregation was strengthened by trapidil, showing an overadditive effect in rabbit PRP. The aggregation inducing effect of the prostaglandin endoperoxide analog U-46619 was inhibited by trapidil. A possible clinical significance of the inhibitions of the synthesis and effect of TXA2 for therapy of ischemic heart disease is discussed.

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N-Carboxy-3-morpholinosydnone imine ethyl ester (molsidomine) and its main metabolite 3-morpholinosydnone imine (SIN-1) were investigated in rabbit platelet-rich plasma (PRP) for antiaggregatory activity and inhibition of thromboxane A2 (TXA2) generation (arachidonic acid (AA)-induced) as well as in human PRP regarding prostaglandin endoperoxide analogue (U-46 619)- and AA-induced aggregation and TXB2 formation. The results were compared with the effects of nictindole. In rabbit PRP the inhibitory effects of molsidomine on aggregation and TXA2 generation were 20fold lower than that of SIN-1. The IC50-values of SIN-1, which is the pharmacologically active biotransformation product of molsidomine, were about 1 mumol/l in the experimental models used. The inhibitory effects of nictindole were about 50 times higher than those of SIN-1. In human PRP the inhibitory potency of SIN-1 decreased in the following sequence: U-46 619-induced aggregation (IC50 = 0.9 mumol/l) greater than AA-induced aggregation (IC50 = 1.4 mumol/l) greater than TXB2 formation (IC50 = 2.9 mumol/l). Molsidomine was nearly without effect in human PRP. Our own preliminary results and findings obtained by other authors seem to exclude a direct effect of SIN-1 on cyclooxygenase and thromboxane synthetase. The possible clinical significance of our findings in different types of angina pectoris and for myocardial infarction is discussed.

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The influence of reserpine, alpha-methyldopa and clonidine on the activity of lipoprotein lipase (LPL) of the rabbit heart and the effect of reserpine on the LPL activity of the cardiac tissue of normotonic and spontaneously hypertensive rats was investigated by a modified method of Robinson, Reserpine and alpha-methyldopa caused in the rabbit heart muscle a pronounced increase in LPL activity by 74 and 35%, respectively. Stimulation by clonidine was not statistically verified. Application of reserpine increases the LPL activity in the hearts both of normotonic and spontaneously hypertensive rats. The enzyme activity in the hypertrophied hearts of spontaneously hypertensive rats is not enhanced. The results are discussed in connection with changes of the catecholamine level.

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