NEW ASPECTS OF THE ROLE OF HISTAMINE IN CARDIOVASCULAR FUNCTION - IDENTIFICATION, CHARACTERIZATION, AND POTENTIAL PATHOPHYSIOLOGICAL IMPORTANCE OF H-3 RECEPTORS

As a result of intensive research during several decades, the distribu tion, function, and pathophysiological role of cardiovascular H-1 and H-2 receptors are well known, whereas reports on the occurrence and fu nction of H-3 receptors in blood vessels and the heart have not become available before the last 7 years (i.e., 4 years after the first desc ription of these receptors in the central nervous system in 1983). The development of selective and potent H-3 receptor agonists and antagon ists was a prerequisite for convenient investigations of cardiovascula r Hg receptors, which like H, and H, receptors are G-protein coupled b ut unlike them have not yet been cloned. Both in blood vessels and the heart, H, receptors are located on noradrenergic nerve endings and up on stimulation mediate an inhibition of noradrenaline release. Whereas it remains to be clarified under which conditions the vascular H-3 re ceptors may be stimulated by endogenous histamine, those in the heart become activated in the early phases of myocardial ischemia characteri zed by an increased histamine spillover. The H-3 receptors in the cent ral nervous system also appear to be of importance for the control of vascular function. Inhibitory presynaptic H-3 receptors occur on trige minal sensory C fibres supplying blood vessels in the dura mater. Rele ase of neuropeptides from these fibres induces a neurogenic inflammati on, which has been suggested to be involved in the pathogenesis of mig raine. An interaction, involving presynaptic H-3 receptors, between se nsory C fibres and mast cells in close apposition to these fibres play s a role in the control of histamine synthesis in the dura mater. By i nfluencing this regulatory process, H-3 receptor agonists may limit th e extent of the neurogenic inflammation involved in the pathophysiolog y of migraine.