Role of capsaicin-sensitive nerves and histamine H1, H2, and H3 receptors in the gastroprotective effect of histamine against stress ulcers in rats.
It is assumed that an overproduction of gastric acid is the most important factor in the development of peptic ulcer. However, it has been also demonstrated that gastric defense mechanisms, which prevent mucosal injury, are enhanced by the same factors that increase acid secretion. The aim of this study was to examine the role of capsaicin-sensitive sensory nerves and histamine H1, H2, and H3 receptors in histamine-induced gastroprotection against stress ulcers. Studies were performed on rats with intact or ablated sensory nerves. Ablation of sensory nerves was induced by neurotoxic doses of capsaicin. Gastric ulcers were induced by water immersion and restrain stress. Before exposure to stress, rats were pretreated with saline (control), histamine (10 micromol/kg), histamine H1 receptor antagonist pyrilamine (100 micromol/kg), histamine H2 receptor antagonist ranitidine (100 micromol/kg), histamine H3 receptor antagonist thioperamide (100 micromol/kg), or a combination of histamine with these histamine receptor antagonists.


RESULTS
Histamine alone reduced ulcer area evoked by stress and this effect was accompanied by an increase in gastric mucosal blood flow and mucosal DNA synthesis, as well as a decrease in serum pro-inflammatory interleukin-1beta concentration. Treatment with combination of pyrilamine plus histamine caused an increase in gastric ulcer area and serum interleukin-1beta above the value observed in animals treated with saline, and this effect was accompanied by a decrease in gastric mucosal DNA synthesis. Ranitidine, in combination with histamine, reduced the ulcer area and serum interleukin-1beta to a minimal value, whereas gastric mucosal blood flow and DNA synthesis reached a maximal value. Pretreatment with thioperamide before histamine administration abolished the histamine-evoked reduction in gastric ulcer area. Ablation of sensory nerves increased the ulcer area in animals treated with saline or histamine, or histamine in combination with pyrilamine or ranitidine. In animals with sensory nerves ablation combined with administration of thioperamide plus histamine, the ulcer area was similar to that in saline-treated animals with intact sensory nerves. We conclude that: (1) histamine exhibits protective effect against stress-induced gastric ulcer and that this gastroprotection is related to stimulation of histamine H1 and H3 receptors; (2) blockade of histamine H2 receptors exhibited beneficial effect on gastric mucosa against stress-induced gastric ulcers; and (3) ablation of sensory nerves aggravates stress-induced gastric ulcer and reduces histamine-evoked gastroprotection related to stimulation of histamine H3 receptors.
Dembiński
Artur
A
Department of Physiology, Jagiellonian University Medical School, 16 Grzegórzecka Street, Kraków 31-531, Poland. mpdembin@cyf-kr.edu.pl
Warzecha
Zygmunt
Z
Ceranowicz
Piotr
P
Brzozowski
Tomasz
T
Dembiński
Marcin
M
Konturek
Stanisław J
SJ
Pawlik
Wiesław W
WW
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects / Q000294:innervation; D006632:Histamine / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D007101:Immersion / Q000009:adverse effects; D007375:Interleukin-1 / Q000097:blood; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011968:Receptors, Histamine / Q000502:physiology*; D011969:Receptors, Histamine H1 / Q000502:physiology; D011970:Receptors, Histamine H2 / Q000502:physiology; D018100:Receptors, Histamine H3 / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects; D012149:Restraint, Physical / Q000009:adverse effects; D013276:Stomach Ulcer / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013312:Stress, Physiological / Q000209:etiology / Q000503:physiopathology
D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D007375:Interleukin-1; D010880:Piperidines; D011968:Receptors, Histamine; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; D006632:Histamine; D004247:DNA; D011738:Pyrilamine; C052075:thioperamide; D002211:Capsaicin