Explore the vast range of titles available.

This article reviews the development of our knowledge of the actions of histamine which have taken place during the course of the 20th century. Histamine has been shown to have a key physiological role in the control of gastric acid secretion and a pathophysiological role in a range of allergic disorders. The synthesis of, and pharmacological studies on, selective agonists and antagonists has established the existence of four types of histamine receptor and histamine receptor antagonists have found very important therapeutic applications. Thus, in the 1940s, H1‐receptor antagonists (‘the antihistamines’) yielded and still provide valuable treatment for allergic conditions such as hay fever and rhinitis. In the late 1970s and 1980s, H2‐receptor antagonists (in the discovery of which the two authors were personally involved) revolutionised the treatment of peptic ulcer and other gastric acid‐related diseases. The H3‐receptor antagonists, although available since 1987, have been slower to find a therapeutic role. However, the discovery of nonimidazole derivatives such as brain‐penetrating H3 antagonists has provided drugs that are in early‐phase clinical trials, possibly for application in obesity, and a variety of central nervous system disorders, such as memory, learning deficits and epilepsy. Finally, the most recently (1999) discovered H4 receptor promises the potential to provide drugs acting on the immunological system with possible applications in asthma and inflammation. British Journal of Pharmacology (2006) 147, S127–S135. doi:10.1038/sj.bjp.0706440

This study examined the role of histamine H 3 receptors in vagal and sympathetic autonomic reflexes in the conscious rabbit, and in rabbit and guinea‐pig isolated right atria. The baroreceptor‐heart rate reflex (baroreflex), Bezold‐Jarisch‐like and nasopharyngeal reflexes were assessed after these treatments (i.v.; with H 1 and H 2 receptor block): (i) vehicle (saline; n =11); (ii) H 3 receptor agonist, ( R )‐ α ‐methylhistamine ( R ‐ α ‐MH) 100 μ g kg −1 +100 μ g kg −1 h −1 ( n =9); (iii) H 3 receptor antagonist, thioperamide 1 mg kg −1 +1 mg kg −1 h −1 ( n =11); (iv) R ‐ α ‐MH and thioperamide ( n =6); and (v) H 2 and H 3 antagonist, burimamide 6.3 mg kg −1 +6.3 mg kg −1 h −1 ( n =4). R ‐ α ‐MH caused a thioperamide‐sensitive fall in mean arterial pressure (MAP) of 8±1 mmHg and tachycardia of 18±2 bpm ( P <0.0005). Burimamide was without effect, however thioperamide elicited an increase in MAP of 4±1 mmHg ( P <0.01), but no change in heart rate (HR). R ‐ α ‐MH caused a 44% decrease in the average gain of the baroreflex ( P =0.0001); this effect was antagonised by thioperamide. Thioperamide caused a parallel rightward shift in the barocurve with an increase in MAP of 5 mmHg ( P <0.05). Burimamide had no effect on the baroreflex. The vagally mediated bradycardia elicited by the Bezold‐Jarisch and nasopharyngeal reflexes was unaffected by H 3 receptor ligand administration. R ‐ α ‐MH (10 μ M ) caused a thioperamide‐sensitive depression of both sympathetic and vagal responses in guinea‐pig atria, but had no effect in rabbit atria. As H 3 receptor activation caused a significant decrease in baroreflex gain without affecting HR range, the former is unlikely to be simply due to peripheral sympatholysis (supported by the lack of effect in isolated atria). Central H 3 receptors may have a tonic role in the baroreflex as thioperamide caused a rightward resetting of the barocurve. In contrast, the peripherally acting H 3 antagonist burimamide was without effect. These findings suggest a role for central histamine H 3 receptors in cardiovascular homeostasis in the rabbit. British Journal of Pharmacology (2003) 139 , 1023–1031. doi: 10.1038/sj.bjp.0705322

This study examined the role of histamine H3 receptors in vagal and sympathetic autonomic reflexes in the conscious rabbit, and in rabbit and guinea‐pig isolated right atria. The baroreceptor‐heart rate reflex (baroreflex), Bezold‐Jarisch‐like and nasopharyngeal reflexes were assessed after these treatments (i.v.; with H1 and H2 receptor block): (i) vehicle (saline; n=11); (ii) H3 receptor agonist, (R)‐α‐methylhistamine (R‐α‐MH) 100 μg kg−1+100 μg kg−1 h−1 (n=9); (iii) H3 receptor antagonist, thioperamide 1 mg kg−1+1 mg kg−1 h−1 (n=11); (iv) R‐α‐MH and thioperamide (n=6); and (v) H2 and H3 antagonist, burimamide 6.3 mg kg−1+6.3 mg kg−1 h−1 (n=4). R‐α‐MH caused a thioperamide‐sensitive fall in mean arterial pressure (MAP) of 8±1 mmHg and tachycardia of 18±2 bpm (P<0.0005). Burimamide was without effect, however thioperamide elicited an increase in MAP of 4±1 mmHg (P<0.01), but no change in heart rate (HR). R‐α‐MH caused a 44% decrease in the average gain of the baroreflex (P=0.0001); this effect was antagonised by thioperamide. Thioperamide caused a parallel rightward shift in the barocurve with an increase in MAP of 5 mmHg (P<0.05). Burimamide had no effect on the baroreflex. The vagally mediated bradycardia elicited by the Bezold‐Jarisch and nasopharyngeal reflexes was unaffected by H3 receptor ligand administration. R‐α‐MH (10 μM) caused a thioperamide‐sensitive depression of both sympathetic and vagal responses in guinea‐pig atria, but had no effect in rabbit atria. As H3 receptor activation caused a significant decrease in baroreflex gain without affecting HR range, the former is unlikely to be simply due to peripheral sympatholysis (supported by the lack of effect in isolated atria). Central H3 receptors may have a tonic role in the baroreflex as thioperamide caused a rightward resetting of the barocurve. In contrast, the peripherally acting H3 antagonist burimamide was without effect. These findings suggest a role for central histamine H3 receptors in cardiovascular homeostasis in the rabbit. British Journal of Pharmacology (2003) 139, 1023–1031. doi:10.1038/sj.bjp.0705322

Histamine H2 receptors transfected in Chinese hamster ovary (CHO) cells are time- and dose-dependently upregulated upon exposure to the H2 antagonists cimetidine and ranitidine. This effect appears to be H2 receptor-mediated as no change in receptor density was observed after H1 or H3 antagonist treatment or after incubation with the structural analogue of cimetidine, VUF 8299, which has no H2 antagonistic effects. By using transfected CHO cells expressing different densities of wild-type H2 receptors or an uncoupled H2Leu124Ala receptor, the histamine H2 receptor was found to display considerable agonist-independent H2 receptor activity. Cimetidine and ranitidine, which both induce H2 receptor upregulation, actually functioned as inverse agonists in those cell lines displaying spontaneous agonist-independent H2 receptor activity. Burimamide, on the other hand, was shown to act as a neutral antagonist and did as expected not induce H2 receptor upregulation after long-term exposure. The displayed inverse agonism of H2 antagonists appears to be a mechanistic basis for the observed H2 antagonist-induced H2 receptor upregulation in transfected CHO cells. These observations shed new light on the pharmacological classification of the H2 antagonists and may offer a plausible explanation for the observed development of tolerance after prolonged clinical use.