In the brain, H1 and H2 receptors are located on postsynaptic membranes, whereas H3 receptors are predominantly presynaptic. Activation of H1 receptors, which are present in endothelium, smooth muscle cells, and nerve endings, usually elicits an increase in phosphoinositol hydrolysis and an increase in inositol trisphosphate (IP3) and intracellular calcium. Activation of H2 receptors, present in gastric mucosa, cardiac muscle cells, and some immune cells, increases intracellular cyclic adenosine monophosphate (cAMP) via Gs. Like the β2 adrenoceptor, under certain circumstances the H2 receptor may couple to Gq, activating the IP3-DAG (inositol 1,4,5-trisphosphate-diacylglycerol) cascade. Activation of H3 receptors decreases transmitter release from histaminergic and other neurons, probably mediated by a decrease in calcium influx through N-type calcium channels in nerve endings. H4 receptors are found mainly on leukocytes in the bone marrow and circulating blood. H4 receptors appear to have very important
TABLE 16–1 Histamine receptor subtypes.
CHAPTER 16 Histamine, Serotonin, & the Ergot Alkaloids 279 chemotactic effects on eosinophils and mast cells. In this role, they seem to play a part in inflammation and allergy. They may also modulate production of these cell types and they may mediate, in part, the previously recognized effects of histamine on cytokine production.
B. Tissue and Organ System Effects of Histamine
Histamine exerts powerful effects on smooth and cardiac muscle, on certain endothelial and nerve cells, on the secretory cells of the stomach, and on inflammatory cells. However, sensitivity to histamine varies greatly among species. Guinea pigs are exquisitely sensitive; humans, dogs, and cats somewhat less so; and mice and rats very much less so.
1.
Nervous system—Histamine is a powerful stimulant of sensory nerve endings, especially those mediating pain and itching. This H1-mediated effect is an important component of the urticarial response and reactions to insect and nettle stings. Some evidence suggests that local high concentrations can also depolarize efferent (axonal) nerve endings (see Triple Response, item 8 in this list). In the mouse, and probably in humans, respiratory neurons signaling inspiration and expiration are modulated by H1 receptors. H1 and H3 receptors play important roles in appetite and satiety; antipsychotic drugs that block these receptors cause significant weight gain (see Chapter 29). These receptors may also participate in nociception. Presynaptic H3 receptors play important roles in modulating release of several transmitters in the nervous system. H3 agonists reduce the release of acetylcholine, amine, and peptide transmitters in various areas of the brain and in peripheral nerves. An investigational inverse H3 agonist, pitolisant (BF2649), appears to reduce drowsiness in patients with narcolepsy.
2.
Cardiovascular system—In humans, injection or infusion of histamine causes a decrease in systolic and diastolic blood pressure and an increase in heart rate. The blood pressure changes are caused by the vasodilator action of histamine on arterioles and precapillary sphincters; the increase in heart rate involves both stimulatory actions of histamine on the heart and a reflex tachycardia. Flushing, a sense of warmth, and headache may also occur during histamine administration, consistent with the vasodilation. Vasodilation elicited by small doses of histamine is caused 1Inverse agonist. cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol trisphosphate.