INHIBITORY H-3 RECEPTORS ON SYMPATHETIC-NERVES OF THE PITHED RAT - ACTIVATION BY ENDOGENOUS HISTAMINE AND OPERATION IN SPONTANEOUSLY HYPERTENSIVE RATS

Our previous results demonstrate the occurrence of presynaptic inhibit ory histamine H-3 receptors on sympathetic neurons innervating resista nce vessels of the pithed rat. The present study, in which new H-3 rec eptor ligands with increased potency and selectivity (imetit, clobenpr opit) were used, was designed to further explore the role of H-3 recep tors in the regulation of the rat cardiovascular system. In particular we were interested whether these receptors may be activated by endoge nous histamine and whether they are detectable in an experimental mode l of hypertension. All experiments were performed on pithed and vagoto mized rats treated with rauwolscine 1 mu mol/kg. In normotensive Wista r rats the electrical (1 Hz, 1 ms, 50 V for 20 s) stimulation of the p reganglionic sympathetic nerve fibres increased diastolic blood pressu re by about 35 mmHg. Two H-3 receptor agonists, R-(-)-alpha-methylhist amine and imetit, inhibited the electrically induced increase in diast olic blood pressure in a dose-dependent manner. The maximal effect (ab out 25%) was obtained for R-(-)-alpha-methylhistamine at about 10 mu m ol/kg and for imetit at about 1 mu mol/kg. Two H-3 receptor antagonist s, thioperamide 1 mu mol/kg and clobenpropit 0.1 mu mol/kg, attenuated the inhibitory effect of imetit. The neurogenic vasopressor response was increased by about 15% by thioperamide 1 mu mol/kg and clobenpropi t 0.1 mu mol/kg and decreased by 25% by the histamine methyltransferas e inhibitor metoprine 37 mu mol/kg. R-(-)-alpha-Methylhistamine, imeti t, thioperamide, clobenpropit and metoprine did not affect the vasopre ssor response to exogenously added noradrenaline 0.01 mu mol/kg (which increased diastolic blood pressure by about 40 mmHg). Metoprine had o nly a very low affinity for H-3 binding sites (labelled by H-3-N-alpha -methylhistamine; pK(i) 4.46). In pithed Wistar Kyoto (WKY) and sponta neously hypertensive (SHR) rats, electrical (1 Hz, 1 ms, 50 V for 10 s ) stimulation increased diastolic blood pressure by 28 and 37 mmHg, re spectively. Imetit inhibited the neurogenic vasopressor response to ab out the same extent in WKY and SHR rats (maximal effect of about 30%). The inhibitory influence of imetit was diminished by thioperamide 1 m u mol/kg to about the same degree in rats of either strain. The presen t study confirms the occurrence of presynaptic H-3 receptors on sympat hetic nerve fibres involved in the inhibition of the neurogenic vasopr essor response. Moreover, it demonstrates that these H-3 receptors are probably activated by endogenous histamine and appear to be operative in hypertension.