Inhibitory H3 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 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 mumol/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-(-)-alpha-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-(-)-alpha-methylhistamine at about 10 mumol/kg and for imetit at about 1 mumol/kg. Two H3 receptor antagonists, thioperamide 1 mumol/kg and clobenpropit 0.1 mumol/kg, attenuated the inhibitory effect of imetit. The neurogenic vasopressor response was increased by about 15% by thioperamide 1 mumol/kg and clobenpropit 0.1 mumol/kg and decreased by 25% by the histamine methyltransferase inhibitor metoprine 37 mumol/kg. R-(-)-alpha-Methylhistamine, imetit, thioperamide, clobenpropit and metoprine did not affect the vasopressor response to exogenously added noradrenaline 0.01 mumol/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 alpha-methylhistamine; pKi 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 mumol/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.
Godlewski
G
G
Zaklad Farmakodynamiki, Akademia Medyczna, Bialystok, Poland.
Malinowska
B
B
Buczko
W
W
Schlicker
E
E
D000320:Adrenergic Fibers / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003655:Decerebrate State; D004558:Electric Stimulation; D006632:Histamine / Q000502:physiology*; D017442:Histamine Agonists / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011739:Pyrimethamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000502:physiology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014628:Vagotomy; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology
D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D008761:Methylhistamines; D010880:Piperidines; D018100:Receptors, Histamine H3; C006308:metoprine; C077430:imetit; C069357:alpha-methylhistamine; D006632:Histamine; D013890:Thiourea; C052075:thioperamide; C086108:clobenpropit; D011739:Pyrimethamine