15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and sergolexole

Platelet aggregation at sites of vascular injury releases both peptide growth factors and vasoactive compounds. Although significant attention has been focused on peptide growth factors, very little is known about the mitogenic effect of vasoactive compounds. We evaluated the effect of serotonin (5-HT) and thromboxane A2 (TXA2) mimetic U46619 alone and in combination on aortic endothelial cells. Stimulation of endothelial cells by 5-HT resulted in an increase in tritiated thymidine uptake and an increase in cell number, whereas U46619 did not have any significant effect. However, when endothelial cells were exposed to both compounds, U46619 potentiated the mitogenic effect of 5-HT on endothelial cells. When endothelial cells were preincubated with LY281067 (a 5-HT2 receptor antagonist) or ridogrel (a combined TXA2 synthase inhibitor and receptor antagonist), LY281067 blocked the mitogenic effect of 5-HT and ridogrel blocked the potentiating effect of U46619 on 5-HT2-induced tritiated thymidine incorporation. When endothelial cells were preincubated with both antagonists, the effects of both 5-HT and U46619 were blocked. Recent studies have indicated that regenerating endothelial cells at sites of vascular injury may release growth factors for vascular smooth muscle cells, leading to smooth muscle cell proliferation and development of neointima. This study suggests that the combined use of 5-HT and TXA2 receptor antagonists may inhibit the growth of endothelial cells at sites of vascular injury and attenuate the formation of neointima.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Cell Division; Cells, Cultured; Disease Models, Animal; Endothelium, Vascular; Lysergic Acid; Male; Muscle, Smooth, Vascular; Pentanoic Acids; Platelet Aggregation; Pyridines; Rabbits; Serotonin; Serotonin Antagonists; Thromboxane A2; Thromboxane-A Synthase; Thymidine; Vasoconstrictor Agents

Restenosis is a major complication that limits the long-term efficacy of coronary angioplasty. Migration and proliferation of activated medial smooth muscle cells (SMCs) is considered an important mechanism in this process. Because at sites of vascular injury, aggregating platelets release both serotonin (5-HT) and thromboxane A2 (TXA2), we examined whether 5-HT and TXA2 can induce SMC proliferation and whether there is synergistic interaction between these two mediators.. The mitogenic effects of 5-HT and TXA2 either alone or in combination was examined in serum-free medium on canine aortic SMCs by [3H]thymidine incorporation into DNA and by cell counting. 5-HT induced SMC proliferation at a concentration of 100 nmol/L, whereas the effect of TXA2 (U46619, a stable TXA2 mimetic) on inducing proliferation of SMCs was observed at a concentration of 100 nmol/L. When these two mediators were added together, there was a synergistic interaction on inducing SMC proliferation even at subthreshold concentrations. The mitogenic effect of 5-HT and its synergistic interaction with TXA2 on SMC proliferation was abolished by a 5-HT2 receptor antagonist, LY281067, without affecting the contribution of TXA2. Similarly, the TXA2 synthase inhibitor/receptor antagonist ridogrel abolished the mitogenic effect of TXA2 and the interaction between 5-HT and TXA2 without affecting the response to 5-HT. When LY281067 and ridogrel were used together, they abolished the mitogenic effects of 5-HT and TXA2.. At sites of vascular injury, platelet-induced SMC proliferation may also be modulated by nonpeptide growth mediators. A combination of a 5-HT2 receptor antagonist and TXA2 synthase inhibitor/receptor may be useful for attenuation of restenosis after angioplasty.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta; Cell Division; Cells, Cultured; DNA; Dogs; Drug Synergism; Lysergic Acid; Muscle, Smooth, Vascular; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Thromboxane A2; Thymidine