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_<2α>, PGI_2, and thromboxane (TX) A_2-exert their actions through specific receptors: DP, EP (EP_1, EP_2, EP_3, EP_4), FP, IP, and TP, respectively^2. Here we have examined the roles of prostanoids in inflammatory tachycardia with the use of mice lacking each of these receptors individually. The TXA_2 analog I-BOP and PGF_<2α> each increased the beating rate of the isolated atrium of wild-type (WT) mice in vitro through interaction with TP and FP, respectively. The cytokine-induced increase in beating rate was markedly inhibited in atria from mice lacking either TP or FP. The tachycardia induced in WT mice by injection of lipopolysaccharide (LPS) was greatly attenuated in TP-/- or FP-/- mice and was completely absent in mice lacking both TP and FP. Propranolol failed to block the LPS-induced increase in heart rate in WT animals. Our results show that inflammatory tachycardia is caused by a direct action on the heart of TXA_2 and PGF_<2α> formed under systemic inflammatory conditions.
