Thromboxane A2 and prostaglandin F2α mediate inflammatory tachycardia

Systemic inflammation induces various adaptive responses including tachycardia. Although inflammation-associated tachycardia has been thought to result from increased sympathetic discharge caused by inflammatory signals of the immune system(1), definitive proof has been lacking. Prostanoids, including prostaglandin (PG) D-2, PGE(2), PGF(2 alpha), PGI(2) and thromboxane (TX) A(2), exert their actions through specific receptors: DP, EP (EP1, EP2, EP3, EP4), FP, IP and TP, respectively(2). Here we have examined the roles of prostanoids in inflammatory tachycardia using mice that lack each of these receptors individually. The TXA(2) analog I-BOP and PGF(2 alpha) each increased the beating rate of the isolated atrium of wild-type mice in vitro through interaction with TP and FP receptors, respectively. The cytokine- induced increase in beating rate was markedly inhibited in atria from mice lacking either TP or FP receptors. The tachycardia induced in wild-type mice by injection of lipopolysaccharide (LPS) was greatly attenuated in TP-deficient or FP-deficient mice and was completely absent in mice lacking both TP and FP. The beta-blocker propranolol did not block the LPS-induced increase in heart rate in wildtype animals. Our results show that inflammatory tachycardia is caused by a direct action on the heart of TXA(2) and PGF(2 alpha) formed under systemic inflammatory conditions.