Synergistic potentiation of 5-hydroxytryptamine secretion by platelet agonists and phorbol myristate acetate despite inhibition of agonist-induced arachidonate/thromboxane and β-thromboglobulin release and Ca2+ mobilization by phorbol myristate acetate

S Joseph; S Krishnamurthi; V V Kakkar

摘要

pPrevious studies have demonstrated an inhibition of agonist-induced inositol phospholipid breakdown and intracellular Ca2+ ([Ca2+]i) mobilization by phorbol esters in platelets. In this study, we have examined the effect of phorbol 12-myristate 13-acetate (PMA) on agonist-induced granule secretion and correlated it with agonist-induced [Ca2+]i mobilization, arachidonate and thromboxane (Tx) release in human platelets. With increasing times of incubation with PMA (10 s-5 min), the rise in [Ca2+]i induced by thrombin and the TxA2 mimetic, U46619, was increasingly inhibited (90-100% with 5 min incubation) and, correlating with this, thrombin-induced [3H]arachidonate, TxB2 and beta-thromboglobulin (beta TG) release were also inhibited. In addition, the conversion of exogenously added arachidonate to TxB2 was inhibited (50-80%) by a 10 s-5 min pretreatment with PMA. However, secretion of 5-hydroxy[14C]tryptamine (5HT) induced by thrombin or U46619 was not inhibited by 10 s-2 min incubations with PMA and, on the contrary, with low agonist concentrations, was potentiated by PMA in the absence of a significant rise in [Ca2+]i or endogenous Tx formation, to levels significantly greater than or equal to the sum of that obtained when agonist and PMA were added separately. With longer times of incubation with PMA (5 min), these synergistic effects became less pronounced as inhibitory effects of PMA on agonist-induced [14C]5HT secretion became apparent. The results indicate that, while PMA may cause an inhibition of agonist-induced [Ca2+]i mobilization resulting in an inhibition of agonist-induced arachidonate, TxB2 and beta TG release, its effects on agonist-induced 5HT secretion may be complicated by [Ca2+]i-independent synergistic effects of agonist and PMA./p

机译：>以前的研究表明，佛波酯可抑制激动剂诱导的肌醇磷脂分解和细胞内Ca2 +（[Ca2 +] i）动员。在这项研究中，我们检查了佛波醇12-肉豆蔻酸酯13-醋酸酯（PMA）对激动剂诱导的颗粒分泌的影响，并将其与激动剂诱导的[Ca2 +] i动员，花生四烯酸和血栓烷（Tx）释放相关。随着与PMA孵育时间的增加（10 s-5分钟），凝血酶和TxA2模拟物U46619诱导的[Ca2 +] i的升高受到越来越多的抑制（孵育5分钟时90-100％），并且与此相关，凝血酶诱导的[3H]花生四烯酸盐，TxB2和β-血球蛋白（βTG）的释放也受到抑制。此外，外源添加的花生四烯酸酯向TxB2的转化通过PMA预处理10 s-5分钟被抑制（50-80％）。然而，凝血酶或U46619诱导的5-羟基[14C]色胺（5HT）的分泌在与PMA孵育10 s-2 min时不会受到抑制，相反，在激动剂浓度较低的情况下，PMA在不存在PM的情况下会增强分泌[Ca2 +] i或内源性Tx形成的显着增加，使其水平显着大于或等于分别添加激动剂和PMA时获得的水平之和。随着与PMA孵育时间的延长（5分钟），随着PMA对激动剂诱导的[14C] 5HT分泌的抑制作用变得明显，这些协同作用变得不那么明显。结果表明，虽然PMA可能会抑制激动剂诱导的[Ca2 +] i动员，从而抑制激动剂诱导的花生四烯酸酯，TxB2和βTG的释放，但其对激动剂诱导的5HT分泌的作用可能会因[Ca2 +激动剂和PMA的] i独立性协同作用。

Synergistic potentiation of 5-hydroxytryptamine secretion by platelet agonists and phorbol myristate acetate despite inhibition of agonist-induced arachidonate/thromboxane and β-thromboglobulin release and Ca2+ mobilization by phorbol myristate acetate

摘要

著录项

相关主题

期刊订阅