thromboxane-b2 and embramine

The effects of bromadryl, dithiaden, chloroquine and propranolol on thrombin-stimulated rat platelet aggregation (measured turbidimetrically) and thromboxane B2 generation (detected by an RIA method) were compared with four selected physico-chemical parameters of these drugs. Platelet aggregation was inhibited in the rank order of potency: bromadryl > dithiaden > propranolol > chloroquine, which corresponded with the decrease in the net charge of the terminal methyl-(or ethyl-) groups in the side chain and with the increase of the dipole moment of drug molecules. On the other hand, the rank order of potency in which the drugs tested inhibited thromboxane B2 formation (chloroquine > dithiaden > bromadryl > propranolol) correlated well with the decline in molar refractivity of the drugs. No relationship was found between inhibitory effects of drugs and their partition coefficients. The results presented indicate that inhibition of platelet functions might consist of several types of drug-cell interactions, depend on the structure and physico-chemical properties of the drugs and cannot be estimated simply on the basis of partition coefficients.

Topics: Animals; Benzothiepins; Blood Platelets; Chemical Phenomena; Chemistry, Physical; Chloroquine; Diphenhydramine; Dose-Response Relationship, Drug; Platelet Aggregation Inhibitors; Platelet Function Tests; Propranolol; Radioimmunoassay; Rats; Software; Structure-Activity Relationship; Thrombin; Thromboxane B2

The histamine receptor H1-antagonists of cationic amphiphilic drug (CAD) structure BromadrylR (BRO) and DithiadenR (DIT) were investigated on stimulated functions of blood platelets in vitro. Both drugs dose-dependently decreased platelet aggregation. BRO significantly decreased aggregation in concentrations of 20 and 200 mumol/l in thrombin and ADP stimulated platelets, respectively. DIT was 10 times less active as compared with BRO. A dose-dependent inhibitory effect of BRO and DIT was demonstrated on thrombin stimulated production of malondialdehyde (MDA) and thromboxane (TXB2) generation in platelets. A significant decrease in MDA production and TXB2 generation was measured with BRO and DIT in 10 mumol/l concentration. Results showed that the antihistaminic drugs BRO and DIT inhibited stimulated aggregation in relation to membrane phospholipid peroxidation and arachidonic cascade activation in platelets. These data, along with results from studies on the effect of other CAD on platelets, revealed that antihistaminic drugs interfere with stimulated aggregation by inhibiting phospholipase A2 rather than the intraplatelet histamine receptor.

Topics: Adenosine Diphosphate; Benzothiepins; Blood Platelets; Diphenhydramine; Dose-Response Relationship, Drug; Histamine H1 Antagonists; Humans; Malondialdehyde; Platelet Aggregation; Platelet Aggregation Inhibitors; Thrombin; Thromboxane B2

The H1-receptor antagonist bromadryl dose-dependently inhibited stimulated rat platelet aggregation in vitro. Bromadryl was 10 times more effective on the secondary aggregation of thrombin-stimulated platelets compared with its inhibition of ADP-stimulated primary platelet aggregation in plasma. The inhibition of aggregation was accompanied by a dose-dependent inhibition of thrombin-stimulated malondialdehyde formation and thromboxane B2 production. The results indicate that bromadryl may interfere intracellularly with membrane phospholipid peroxidation and the arachidonic acid metabolism of stimulated platelets. Bromadryl, like other cationic amphiphilic drugs, may inhibit stimulated platelet functions by decreasing the stimulus-induced activation of phospholipase A2. Our results support the possible interference of bromadryl with histamine as an intraplatelet messenger responsible for aggregation.

Topics: Adenosine Diphosphate; Animals; Blood Platelets; Diphenhydramine; Dose-Response Relationship, Drug; Histamine H1 Antagonists; In Vitro Techniques; Male; Malondialdehyde; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Thrombin; Thromboxane B2