See article in J. Gastroenterol. Hepatol. 2003; 18: 177–184.

Lafutidine is a new type of anti-ulcer drug possessing an antisecretory effect exerted via a histamine H2 receptor blockade,1 as well as gastroprotective activity against several necrotizing agents independent of its antisecretory action.2,3 It also increases the gastric mucosal blood flow.2 The gastroprotective action of lafutidine was abolished by treatment with a calcitonin-gene related peptide (CGRP) antagonist, CGRP8-37, or by the chemical defunctionalization of afferent nerves by systemic capsaicin,2 indicating that capsaicin-sensitive nerves contribute to the mechanisms underlying the actions of lafutidine. Nishihara et al. very recently reported that capsaicin dose-dependently increased CGRP release from the rat gastric corpus mucosa into the incubation medium, while lafutidine itself did not change basal CGRP release from the rat stomach.4 However, lafutidine accelerated CGRP release, which was induced by a low dose of capsaicin, and this potentiating effect was reversed by treatment with capsazepine, a vanilloid receptor antagonist. In addition, a receptor-binding assay indicated that lafutidine unlikely binds to vanilloid receptor subtype 1, which binds capsaicin. They speculated that lafutidine would sensitize the CGRP-containing sensory nerves that were stimulated by back-diffused acid or other noxious chemicals in the stomach.4

In issue 2 of the Journal, a presented paper is the first to demonstrate that lafutidine (1–10 mg/kg), administered via a portal vein, has an ability to increase hepatic blood flow.5 This increment was only observed under a thyrotropin-releasing hormone (TRH) analog injected intracisternally at a subthreshold dose (1.5 ng) to stimulate hepatic blood flow in anesthetized rats. This dose of TRH analog has been reported to have a gastric cytoprotective action against several kinds of necrotizing agents such as ethanol, by increasing gastric mucosal blood flow in rats.6–8 In fact, the gastric cytoprotective effect of a lower dose of TRH analog was originally demonstrated in another study.9 Unlike the action of central TRH on the stomach, an intracisternal injection of the TRH analog dose-dependently protected against carbon tetrachloride (CCl4)-induced liver damage mediated via a hepatic branch of the vagus.10

The blockade of the stimulatory effect of intraportal administration with lafutidine on hepatic blood flow by both systemic ablation of capsaicin-sensitive afferent neurons and antagonism for endogenous CGRP release from the capsaicin-sensitive neurons suggests that lafutidine might act on CGRP containing capsaicin-sensitive sensory neurons, resulting in an increase in blood flow in the liver.5 However, the actual action site of lafutidine to modify CGRP remains unknown, although capsaicin-sensitive primary afferent neurons, which contain CGRP, innervate the portal area where hepatic artery and portal vein exist.11,12 A lack of data on portal or peripheral CGRP release after lafutidine administration also fails to discuss the molecular mechanisms underlying lafutidine-induced upregulation of hepatic blood flow. A recent human study demonstrated that a single oral administration of lafutidine (20 mg) increases plasma CGRP levels at 40–120 min after administration in healthy male volunteers.13

No changes in mean arterial blood pressure under the co-injection of lafutidine and TRH might imply that alternation in arterial blood flow unlikely affects hepatic blood flow, and that an increase in peripheral CGRP levels to decrease blood pressure was unlikely present. The TRH analog at higher doses (5–100 ng) injected into the cisterna magna dose-dependently increased hepatic blood flow with a peak response at 15 min after TRH administration.14 From the sets of evidence that electrical vagal stimulation produces dilatation of the sinusoids,15 and that hepatic branch vagotomy abolished the central TRH-induced stimulation of hepatic blood flow, the authors speculated that the liver sinusoid dilatation is the most likely mechanism underlying central TRH-induced hepatic blood flow.14 Which types of nerve and vessel are involved under central TRH stimulation and portal lafutidine should be further examined to clarify the mechanisms and implications of the co-injection-induced increase in hepatic blood flow.

The novel function of lafutidine on hepatic blood flow seems beneficial in patients with liver dysfunction accompanied by a decrease in hepatic blood flow, because some H2 receptor antagonists decrease blood flow in the liver.16 Very recently, the administration of capsaicin and CGRP has been reported to significantly enhance ischemia/reperfusion-induced increases in hepatic tissue blood flow after reperfusion, resulting in a reduction in liver injury.17 Higher levels of plasma CGRP in patients with fulminant hepatic failure compared with liver cirrhosis18 may imply the host reaction to repair the damaged liver by increasing the hepatic blood flow. It appears worthwhile to investigate the effect of lafutidine on liver function in patients with severe liver dysfunction.

Lafutidine-induced hepatic blood flow upregulation was observed under the excitation of the vagus hepatic branch, elicited by the subthreshold dose of central TRH. Taking the result that lafutidine accelerated CGRP release, which was induced by a low dose of capsaicin, into consideration, lafutidine might sensitize the CGRP-containing capsaicin-sensitive afferent nerve terminals. Which situation might account for mild excitation of the vagus induced by central TRH? Some kinds of stress such as cold climate and food intake are known to stimulate vagal output.19 The increase in plasma CGRP levels after a single administration of lafutidine was demonstrated 2 h after lunch.13 Therefore, the investigation of the effect of stress or nutrients in the stomach on lafutidine action towards hepatic blood flow might indicate the beneficial strategy of lafutidine administration in humans.


  1. Top of page
  • 1
    Shibata M, Yamaura T, Inaba N, Onodera S, Chida Y, Ohnishi H. Gastric antisecretory effect of FRG-8813, a new histamine H2 receptor antagonist, in rats and dogs. Eur. J. Pharmacol. 1993; 235: 24553.
  • 2
    Onodera S, Shibata M, Tanaka M et al. Gastroprotective mechanism of lafutidine, a novel anti-ulcer drug with histamine H2-receptor antagonistic activity. Arzneimittelforschung 1999; 49: 51926.
  • 3
    Onodera S, Shibata M, Tanaka M, Inaba N, Yamaura T, Ohnishi H. Gastroprotective activity of FRG-8813, a novel histamine H2-receptor antagonist, in rats. Jpn J. Pharmacol. 1995; 68: 16173.
  • 4
    Nishihara K, Nozawa Y, Nakano M, Ajioka H, Matsuura N. Sensitizing effects of lafutidine on CGRP-containing afferent nerves in the rat stomach. Br. J. Pharmacol. 2002; 135: 148794.
  • 5
    Yoneda M, Kurosawa M, Watanobe H, Terano A. Lafutidine increases hepatic blood flow via potentiating the action of central thyrotropin-releasing hormones in urethane-anesthetized rats. J. Gastroenterol. Hepatol. 2003; 18: 177184.
  • 6
    Taché Y, Yoneda M. Central action of TRH to induce vagally mediated gastric cytoprotection and ulcer formation in rats. J. Clin. Gastroenterol. 1993; 17 (Suppl. 1): S5863.
  • 7
    Taché Y, Yoneda M, Kato K, Kiraly Á , Sütó G, Kaneko H. Intracisternal thyrotropin-releasing hormone-induced vagally mediated gastric protection against ethanol lesions: central and peripheral mechanisms. J. Gastroenterol. Hepatol. 1994; 9 (Suppl.): S2935.
  • 8
    Kaneko H, Taché Y, Kusugami K. Importance of medullary thyrotropin-releasing hormone in brain-gut circuits regulating gastric integrity: preclinical studies. J. Gastroenterol. 2002; 37 (Suppl. XIV): 12832.
  • 9
    Yoneda M, Taché Y. Central thyrotropin-releasing factor analog prevents ethanol-induced gastric damage through prostaglandins in rats. Gastroenterology 1992; 102: 156874.
  • 10
    Sato Y, Yoneda M, Yokohama S, Tamori K, Nakamura K, Makino I. Protective effect of central thyrotropin-releasing hormone (TRH) on CCl4-induced liver damage in rats. Gastroenterology 1996; 110: 1312 (Abstract).
  • 11
    Goehler LE, Sternini C. Calcitonin gene-related peptide innervation of the rat hepatobiliary system. Peptides 1996; 17: 20917.
  • 12
    Esteban FJ, Jimenez A, Fernandez AP et al. Neuronal nitric oxide synthase immunoreactivity in the guinea-pig liver: distribution and colocalization with neuropeptide Y and calcitonin gene-related peptide. Liver 2001; 21: 3749.
  • 13
    Itoh H, Naito T, Takeyama M. Lafutidine changes levels of somatostatin, calcitonin gene-related peptide, and secretin in human plasma. Biol. Pharm. Bull. 2002; 25: 37982.
  • 14
    Tamori K, Yoneda M, Nakamura K, Makino I. Effect of intracisternal thyrotropin-releasing hormone on hepatic blood flow in rats. Am. J. Physiol. 1998; 274: G27782.
  • 15
    Koo A, Liang IY. Microvascular filling pattern in rat liver sinusoids during vagal stimulation. J. Physiol. (Lond.) 1979; 295: 1919.
  • 16
    Onodera S, Shibata M, Tanaka M et al. Gastroprotective mechanism of a newly developed H2 receptor antagonist, FRG-8813. Ulcer Res. 1994; 21: 547.
  • 17
    Harada N, Okajima K, Uchiba M, Katsuragi T. Ischemia/reperfusion-induced increase in the hepatic level of prostacyclin is mainly mediated by activation of capsaicin-sensitive sensory neurons in rats. J. Lab. Clin. Med. 2002; 139: 21826.
  • 18
    Strauss GI, Edvinsson L, Larsen FS, Moller K, Knudsen GM. Circulating levels of neuropeptides (CGRP, VIP, NPY) in patients with fulminant hepatic failure. Neuropeptides 2001; 35: 17480.
  • 19
    Yang H, Wu SV, Ishikawa T, Taché Y. Cold exposure elevates thyrotropin-releasing hormone gene expression in medullary raphe nuclei: relationship with vagally mediated gastric erosions. Neuroscience 1994; 61: 65563.