H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects.

This review addresses novel concepts of histamine H1-receptor function and attempts to relate them to the anti-inflammatory effects of H1-antihistamines. Furthermore, the molecular mechanisms underlying the cardiotoxic effects of H1-antihistamines are discussed. H1-receptors are G-protein-coupled-receptors (GPCRs), the inactive and active conformations of which coexist in equilibrium. The degree receptor activation in the absence of histamine is its 'constitutive activity'. In this two-state model, histamine acts as an agonist by combining with and stabilizing the activated conformation of the H1-receptor to shift the equilibrium towards the activated state. Drugs classified previously as antagonists act as either inverse agonists or neutral antagonists. Inverse agonists combine with and stabilize the inactive conformation of the receptor to shift the equilibrium towards the inactive state. Thus, they may down-regulate constitutive receptor activity, even in the absence of histamine. Neutral antagonists combine equally with both conformations of the receptor, do not affect basal receptor activity but do interfere with agonist binding. All H1-antihistamines examined to date are inverse agonists. As the term 'H1-receptor antagonists' is obviously erroneous, we suggest that it be replaced by 'H1-antihistamines'. The observations that H1-receptors modulate NF-kappaB activation and that there are complex interactions between GPCRs, has allowed us to postulate receptor dependent-mechanisms for some anti-inflammatory effects of H1-antihistamines, e.g. inhibition of ICAM-1 expression and the effects of bradykinin. Finally, the finding that blockade of HERG1 K+ channels is the mechanism by which some H1-antihistamines may cause cardiac arrhythmias has allowed the development of preclinical tests to predict such activity.