Lafutidine increases hepatic blood flow via potentiating the action of central thyrotropin-releasing hormone in rats.
BACKGROUND
Lafutidine, (+/-)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyridyl]oxy-(Z)-2 butenyl]acetamide, is a newly synthesized histamine H2 receptor antagonist and possesses a cytoprotective efficacy, which comprises mucin biosynthesis and stimulation of gastric blood flow mediated through capsaicin-sensitive sensory neurons and endogenous calcitonin gene-related peptide (CGRP). In the present study, an effect of lafutidine on hepatic blood flow was investigated in rats that received an intracisternal injection of a subthreshold dose of thyrotropin-releasing hormone (TRH) analog, RX 77368.


METHODS
Change in hepatic blood flow was determined by laser Doppler flowmetry. Male Wistar rats were anesthetized with urethane (1.5 g/kg, i.p.), and positioned on a stereotaxic apparatus. An abdominal incision was made, and a probe of laser Doppler flowmeter was placed on the surface of the liver. After a 60-min stabilization, basal hepatic blood flow was measured for 30 min, and lafutidine (0.5, 1, 3, 5 or 10 mg/kg) or vehicle was injected into the portal vein and a subthreshold dose (1.5 ng) of RX 77368 was injected intracisternally. Hepatic blood flow was monitored for 120 min postinjection. To investigate a role of capsaicin-sensitive sensory neurons and endogenous CGRP, systemic capsaicin treatment (125 mg/kg, s.c., 10-14 days before) and intravenous infusion of a CGRP receptor antagonist, human CGRP-(8-37) (15 micro g/kg as a bolus, followed by infusion at 3 micro g/kg/h) were performed, respectively.


RESULTS
Intracisternal injection of RX 77368 (1.5 ng) or intraportal lafutidine (10 mg/kg) by itself did not affect hepatic blood flow, but co-injection of intracisternal RX 77368 (1.5 ng) and intraportal lafutidine (5 mg/kg) increased it with peak response at 30 min postinjection. The effect of lafutidine on hepatic blood flow in rats given RX 77368 was dose-related over the range 1-5 mg/kg. By contrast, intracisternal injection of RX 77368 (1.5 ng) did not change hepatic blood flow in rats injected with another histamine H2 receptor antagonist, famotidine (5 mg/kg), intraportally. The stimulatory effect of co-injection of TRH analog and lafutidine was abolished by systemic capsaicin-treatment and CGRP antagonist.


CONCLUSIONS
These data suggest that lafutidine increases hepatic blood flow by sensitizing the liver to the action of central TRH via both capsaicin-sensitive sensory neurons and endogenous CGRP in urethane-anesthetized rats.
Yoneda
Masashi
M
Department of Gastroenterology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. yoneda@dokkyomed.ac.jp
Kurosawa
Mieko
M
Watanobe
Hajime
H
Terano
Akira
A
D000081:Acetamides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D004338:Drug Combinations; D004357:Drug Synergism; D005753:Gastric Mucosa / Q000098:blood supply*; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D017078:Laser-Doppler Flowmetry; D008099:Liver / Q000187:drug effects / Q000294:innervation; D008102:Liver Circulation / Q000502:physiology*; D008297:Male; D009475:Neurons, Afferent / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D051381:Rats; D017208:Rats, Wistar; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000008:administration & dosage; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000081:Acetamides; D004338:Drug Combinations; D006635:Histamine H2 Antagonists; D010880:Piperidines; D011725:Pyridines; D018015:Receptors, Calcitonin Gene-Related Peptide; C076948:lafutidine; D013973:Thyrotropin-Releasing Hormone; C027979:L-pyroglutamyl-L-histidyl-3,3-dimethylprolinamide; D002211:Capsaicin; D011761:Pyrrolidonecarboxylic Acid