Inhibitory H3 receptors on sympathetic nerves of the pithed rat: activation by endogenous histamine and operation in spontaneously hypertensive rats

Abstract

Our previous results demonstrate the occurrence of presynaptic inhibitory histamine H₃ receptors on sympathetic neurons innervating resistance vessels of the pithed rat. The present study, in which new H₃ receptor ligands with increased potency and selectivity (imetit, clobenpropit) were used, was designed to further explore the role of H₃ receptors in the regulation of the rat cardiovascular system. In particular we were interested whether these receptors may be activated by endogenous histamine and whether they are detectable in an experimental model of hypertension.

All experiments were performed on pithed and vagotomized rats treated with rauwolscine 1 μmol/kg. In normotensive Wistar rats the electrical (1 Hz, 1 ms, 50 V for 20 s) stimulation of the preganglionic sympathetic nerve fibres increased diastolic blood pressure by about 35 mmHg. Two H₃ receptor agonists, R-(–)-α-methylhistamine and imetit, inhibited the electrically induced increase in diastolic blood pressure in a dose-dependent manner. The maximal effect (about 25%) was obtained for R-(–)-α-methylhistamine at about 10 μmol/kg and for imetit at about 1 μmol/kg. Two H₃ receptor antagonists, thioperamide 1 μmol/kg and clobenpropit 0.1 μmol/kg, attenuated the inhibitory effect of imetit. The neurogenic vasopressor response was increased by about 15% by thioperamide 1 μmol/kg and clobenpropit 0.1 μmol/kg and decreased by 25% by the histamine methyltransferase inhibitor metoprine 37 μmol/kg. R-(-)-α-Methylhistamine, imetit, thioperamide, clobenpropit and metoprine did not affect the vasopressor response to exogenously added noradrenaline 0.01 μmol/kg (which increased diastolic blood pressure by about 40 mmHg). Metoprine had only a very low affinity for H₃ binding sites (labelled by ³H-N^α-methylhistamine; pK_i 4.46). In pithed Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats, electrical (1 Hz, 1 ms, 50 V for 10 s) stimulation increased diastolic blood pressure by 28 and 37 mmHg, respectively. Imetit inhibited the neurogenic vasopressor response to about the same extent in WKY and SHR rats (maximal effect of about 30%). The inhibitory influence of imetit was diminished by thioperamide 1 μmol/kg to about the same degree in rats of either strain.

The present study confirms the occurrence of presynaptic H₃ receptors on sympathetic nerve fibres involved in the inhibition of the neurogenic vasopressor response. Moreover, it demonstrates that these H₃ receptors are probably activated by endogenous histamine and appear to be operative in hypertension.