Hispidulin, a natural flavone, inhibits human platelet aggregation by increasing cAMP levels.

Hispidulin, a natural flavone, and theophylline inhibited platelet aggregation triggered by adenosine-5'-monophosphate, arachidonic acid, paf-acether and collagen. Hispidulin was 100-fold more potent than theophylline. A threshold concentration of PGE1 did not modify the anti-aggregatory effect of hispidulin but potentiated the effect of theophylline. A threshold concentration of hispidulin had no effect on the inhibitory action of theophylline. Hispidulin (100 microM) and theophylline (10 mM) increased the control cAMP level in platelets 4-fold. A threshold concentration of PGE1 had a small effect on hispidulin-induced cAMP levels but increased the theophylline-induced cAMP levels 3-fold. Theophylline (10 mM)-induced cAMP levels were not modified by hispidulin. We demonstrate a correlation between the inhibition of platelet aggregation and the increase in cAMP levels induced by hispidulin. These data suggest that hispidulin could inhibit platelet aggregation by elevating cAMP levels by a mechanism different from that of theophylline or PGE1.

Relaxation of isolated human pulmonary muscle preparations with prostacyclin (PGI2) and its analogs.

The effects of PGI2 and two analogs Iloprost and ZK 96480 were examined on isolated human pulmonary muscle preparations. High concentrations of these agents reduced the basal tone in all types of preparations. In addition, they relaxed tissues which had been maximally contracted with histamine (50 microM). PGI2 was more potent on pulmonary arterial muscle preparations (pD2 value: 6.33, n = 3) than on bronchial muscles. The relaxations induced by PGI2 in bronchial preparations were quite variable, that is, some tissues relaxed while others did not. The analogs also relaxed arterial preparations and the pD2 values were approximately the same (Iloprost: 7.42, n = 4 and ZK 96480: 7.48, n = 4). The isolated human pulmonary vascular preparations were approximately 10-fold more sensitive to the analogs than bronchial muscle preparations. In bronchial tissues we noted that the PGI2 relaxant effect was spontaneously reversed with time, an activity not observed with both analogs. A pretreatment of the bronchial tissues with indomethacin (1.7 microM) did not reduce the variations observed with PGI2 nor modify the transient relaxation observed with this agent. These data demonstrate that vascular tissues from the human lung are considerably more sensitive to these relaxant agonists than bronchial preparations.

Effects of various pharmacological agents on isolated human bronchial and pulmonary arterial and venous muscle preparations contracted by leukotriene D4.

The response of isolated human bronchial muscle preparations to leukotriene D4 (LTD4, 0.1 microM; 0.22 +/- 0.03 g/mm2) was similar to that of histamine (50 microM; 0.21 +/- 0.02 g/mm2). Isolated pulmonary venous preparations also contracted to these same concentrations of both agonists (LTD4, 0.32 +/- 0.19 g/mm2; and histamine, 0.36 +/- 0.07 g/mm2). However, pulmonary arterial preparations responded to histamine (50 microM, 0.59 +/- 0.10 g/mm2) but exhibited a reduced response to LTD4 (0.3 microM, 0.06 +/- 0.01 g/mm2). Bronchial and pulmonary venous muscle preparations from the human lung had the same sensitivities to LTD4 (pD2 values: bronchus, 7.95 +/- 0.08 and vein, 7.76 +/- 0.07). When bronchial or pulmonary venous muscle preparations were incubated for 30 min with either diltiazem (10 microM), indomethacin (1.7 microM) or L-cysteine (3 microM), the LTD4 cumulative concentration-effect curves following these drug treatments were similar to controls. However, FPL-55712 (10 microM) significantly shifted the LTD4 concentration-effect curves produced in bronchial preparations to the right. In isolated pulmonary arterial preparations none of these drug treatments enhanced the LTD4 response. These results show that isolated human pulmonary arterial preparations are less responsive to LTD4 than bronchial or venous preparations. In addition, the data obtained subsequent to the various drug treatments indirectly suggest that the LTD4 contraction is not modified by a calcium channel blocker or by inhibition of the endogenous products of the cyclooxygenase pathway.