Reversal of hemorrhagic shock in rats using the metabolically stable thyrotropin-releasing hormone analog taltirelin hydrate.

Abstract

We investigated the effect of taltirelin hydrate ((−)-N-[(S)-hexahydro-1-methyl- 2,6-dioxo-4-pyrimidinyl-carbonyl]-L-histidyl-L-prolinamide tetrahydrate; taltirelin), a metabolically stable thyrotropin-releasing hormone (TRH) analog, on circulatory function, respiratory function, and viable time after bleeding in urethane-anesthetized rats. Massive volume-controlled bleeding caused marked reductions in mean arterial pressure (MAP) and respiratory rate (RR). The vital signs of control rats were lost within an average of 23 min after bleeding. Intravenous administration of taltirelin (0.03−0.3 mg/kg) and TRH (1 and 3 mg/kg) immediately after bleeding accelerated recovery of MAP and RR, and prolonged viable time in a dose-dependent manner. The potency of taltirelin in accelerating MAP and RR recovery and prolonging viable time was higher when compared with that of TRH. In addition, recovery of MAP and RR and the extension of viable time by taltirelin were inhibited by preintraperitoneal administration of atropine sulfate, which is a centrally acting muscarinic antagonist, but not by that of atropine methylbromide, which is a peripherally acting muscarinic antagonist. Taltirelin also recovered decreased arterial pH, bicarbonate ions, and base excess, and prevented a decrease in arterial oxygen saturation. In conclusion, the anti-shock effect of taltirelin was more potent than that of TRH. Taltirelin activity was mediated by the central muscarinic cholinergic system. In addition, taltirelin also corrected metabolic acidosis. These results suggest that taltirelin could be useful in the treatment of hypovolemic shock.

• Authors: Hidetoshi Asai, Yumi Watanabe, Rikako Yamauchi-Kohno, Osamu Doi
• Journal: Journal of receptor and signal transduction research (J Recept Signal Transduct Res) Vol. 31 Issue 6 Pg. 416-22 (Dec 2011) ISSN: 1532-4281 [Electronic] England
• PMID: 22044177 (Publication Type: Journal Article)

Chemical References

• Receptors, Muscarinic
• Receptors, Thyrotropin-Releasing Hormone
• TA 0910
• Thyrotropin-Releasing Hormone
• Atropine

Topics

• Animals
• Atropine (administration & dosage, pharmacology)
• Blood Gas Analysis
• Blood Pressure (drug effects)
• Hypovolemia (etiology, prevention & control)
• Rats
• Rats, Sprague-Dawley
• Receptors, Muscarinic (drug effects)
• Receptors, Thyrotropin-Releasing Hormone (metabolism)
• Respiratory Rate (drug effects)
• Shock, Hemorrhagic (complications, drug therapy)
• Thyrotropin-Releasing Hormone (analogs & derivatives, therapeutic use)