fibrosis.Such individuals may be 100-to 1000-fold more sensitive to histamine (and methacholine)than are normal subjects.Curiously,a few species (eg,rabbit)respond to histamine with bronchodilation,reflecting the dominance of the H2 receptor in their airways. 4.Gastrointestinal tract smooth muscle Histamine causes contraction of intestinal smooth muscle,and histamine-induced contraction of guinea pig ileum is a standard bioassay for this amine.The human gut is not as sensitive as that of the guinea pig,but large doses of histamine may cause diarrhea,partly as a result of this effect.This action of histamine is mediated by Hi receptors. 5.Other smooth muscle organs In humans,histamine generally has insignificant effects on the smooth muscle of the eye and genitourinary tract.However,pregnant women suffering anaphylactic reactions may abort as a result of histamine-induced contractions,and in some species the sensitivity of the uterus is sufficient to form the basis for a bioassay. 6.Secretory tissue Histamine has long been recognized as a powerful stimulant of gastric acid secretion and,to a lesser extent,of gastric pepsin and intrinsic factor production.The effect is caused by activation of H2 receptors on gastric parietal cells and is associated with increased adenylyl cyclase activity,cAMP concentration,and intracellular Ca2 concentration.Other stimulants of gastric acid secretion such as acetylcholine and gastrin do not increase cAMP even though their maximal effects on acid output can be reduced but not abolished by H2-receptor antagonists. Histamine also stimulates secretion in the small and large intestine.In contrast, H3-selective histamine agonists inhibit acid secretion stimulated by food or pentagastrin in several species. Histamine has much smaller effects on the activity of other glandular tissue at ordinary concentrations.Very high concentrations can cause adrenal medullary discharge. 7.Metabolic effects Recent studies of H3-receptor knockout mice demonstrate that absence of this receptor results in animals with increased food intake,decreased energy expenditure,and obesity.They also show insulin resistance and increased blood levels of leptin and insulin.It is not yet known whether the H3 receptor has a similar role in humans. 8.The"triple response"Intradermal injection of histamine causes a characteristic red spot,edema,and flare response that was first described over 60 years ago.The effect involves three separate cell types:smooth muscle in the microcirculation, capillary or venular endothelium,and sensory nerve endings.At the site of injection,a reddening appears owing to dilation of small vessels,followed soon by an edematous wheal at the injection site and a red irregular flare surrounding the wheal.The flare isfibrosis. Such individuals may be 100- to 1000-fold more sensitive to histamine (and methacholine) than are normal subjects. Curiously, a few species (eg, rabbit) respond to histamine with bronchodilation, reflecting the dominance of the H2 receptor in their airways. 4. Gastrointestinal tract smooth muscle Histamine causes contraction of intestinal smooth muscle, and histamine-induced contraction of guinea pig ileum is a standard bioassay for this amine. The human gut is not as sensitive as that of the guinea pig, but large doses of histamine may cause diarrhea, partly as a result of this effect. This action of histamine is mediated by H1 receptors. 5. Other smooth muscle organs In humans, histamine generally has insignificant effects on the smooth muscle of the eye and genitourinary tract. However, pregnant women suffering anaphylactic reactions may abort as a result of histamine-induced contractions, and in some species the sensitivity of the uterus is sufficient to form the basis for a bioassay. 6. Secretory tissue Histamine has long been recognized as a powerful stimulant of gastric acid secretion and, to a lesser extent, of gastric pepsin and intrinsic factor production. The effect is caused by activation of H2 receptors on gastric parietal cells and is associated with increased adenylyl cyclase activity, cAMP concentration, and intracellular Ca2+ concentration. Other stimulants of gastric acid secretion such as acetylcholine and gastrin do not increase cAMP even though their maximal effects on acid output can be reduced but not abolished by H 2-receptor antagonists. Histamine also stimulates secretion in the small and large intestine. In contrast, H3-selective histamine agonists inhibit acid secretion stimulated by food or pentagastrin in several species. Histamine has much smaller effects on the activity of other glandular tissue at ordinary concentrations. Very high concentrations can cause adrenal medullary discharge. 7. Metabolic effects Recent studies of H3-receptor knockout mice demonstrate that absence of this receptor results in animals with increased food intake, decreased energy expenditure, and obesity. They also show insulin resistance and increased blood levels of leptin and insulin. It is not yet known whether the H3 receptor has a similar role in humans. 8. The "triple response" Intradermal injection of histamine causes a characteristic red spot, edema, and flare response that was first described over 60 years ago. The effect involves three separate cell types: smooth muscle in the microcirculation, capillary or venular endothelium, and sensory nerve endings. At the site of injection, a reddening appears owing to dilation of small vessels, followed soon by an edematous wheal at the injection site and a red irregular flare surrounding the wheal. The flare is