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Thromboxane A2 and prostaglandin F2α mediate inflammatory tachycardia

Nature Medicine volume 11, pages 562–566 (2005)Cite this article

Abstract

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 system1, definitive proof has been lacking. Prostanoids, including prostaglandin (PG) D2, PGE2, PGF2α, PGI2 and thromboxane (TX) A2, exert their actions through specific receptors: DP, EP (EP1, EP2, EP3, EP4), FP, IP and TP, respectively2. Here we have examined the roles of prostanoids in inflammatory tachycardia using mice that lack each of these receptors individually. The TXA2 analog I-BOP and PGF2α 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 β-blocker propranolol did not block the LPS-induced increase in heart rate in wild-type animals. Our results show that inflammatory tachycardia is caused by a direct action on the heart of TXA2 and PGF2α formed under systemic inflammatory conditions.

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Figure 1: Effects of exogenous prostanoids on the beating rate of the isolated right atrium.
Figure 2: Distinct sites of action of PGF2α and I-BOP within the right atrium.
Figure 3: Role of endogenous prostanoids in cytokine-stimulated increase in the beating rate of the right atrium.
Figure 4: Role of endogenous prostanoids in LPS-induced tachycardia in vivo.

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Acknowledgements

We thank K. Nakaya and T. Yokoyama for help in breeding and maintenance of mice. We also thank K. Nakanishi and Y. Takashima for experimental and secretarial assistance, respectively. This work was supported by a Grant in Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan, by a Research Grant for Cardiovascular Disease (14A-1) from the Ministry of Health and Welfare of Japan, and by grants from Ono Pharmaceutical Co., the Smoking Research Foundation, the Hokkaido Heart Association, the Mochida Memorial Foundation, Japan Research Foundation for Clinical Pharmacology, and Japan Foundation of Cardiovascular Research.

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Authors and Affiliations

  1. Department of Pharmacology, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan

    Koji Takayama, Koh-ichi Yuhki, Takayuki Fujino, Akiyoshi Hara, Takehiro Yamada, Shuhko Kuriyama, Hideji Karibe, Yuji Okada & Fumitaka Ushikubi

  2. Department of Anesthesiology, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan

    Koji Takayama, Osamu Takahata & Hiroshi Iwasaki

  3. Department of Pharmacology, Akita University School of Medicine, Hondou 1-1-1, Akita, 010-8543, Japan

    Kyoichi Ono & Toshihiko Iijima

  4. Department of Biochemistry, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan

    Takanobu Taniguchi

  5. Department of Pharmacology, Kyoto University Faculty of Medicine, Sakyo-ku, 606-8315, Kyoto, Japan

    Shuh Narumiya

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Correspondence to Fumitaka Ushikubi.

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Supplementary information

Supplementary Fig. 1

Effects of exogenous prostanoids on the beating rate of the isolated right atrium. (PDF 1115 kb)

Supplementary Fig. 2

Effects of epinephrine and acteylcholine on the beating rate of the isolated right atrium. (PDF 483 kb)

Supplementary Fig. 3

Effect of LPS on blood pressure. (PDF 124 kb)

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Takayama, K., Yuhki, Ki., Ono, K. et al. Thromboxane A2 and prostaglandin F2α mediate inflammatory tachycardia. Nat Med 11, 562–566 (2005). https://doi.org/10.1038/nm1231

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