methylatropine and metoprine

An increase in endogenous central histamine concentration after inhibition of histamine N-methyltransferase (HNMT) activity reverses critical hypotension and improves the survival of rats in haemorrhagic shock. The purpose of the study was to examine the involvement of the sympathetic nervous system in this endogenous central histamine-induced resuscitation. Experiments were carried out in ethylurethane-anaesthetised male Wistar rats subjected to haemorrhagic hypotension (mean arterial pressure MAP 20-25 mmHg), which led to the death of all control animals within 30 min. The HNMT inhibitor metoprine (20 micro g; i.c.v.) administered 5 min after establishing the critical hypotension increased the endogenous histamine concentration, measured 20 min after treatment, in the hypothalamus (534.33+/-67.52 vs. 423.98+/-54.17 ng/g wet tissue; P<0.05) and medulla oblongata (53.12+/-9.78 vs. 39.58+/-11.16 ng/g wet tissue; P<0.05). These responses were accompanied by plasma levels of noradrenaline and adrenaline 2.7 and 1.7 times higher respectively than in the control group ( P<0.01). Metoprine evoked dose-dependent (5, 10, 20 micro g; i.c.v.) rises in MAP and heart rate (HR) that were significantly higher than those in normotensive animals, and resulted in a 100% survival rate at 2 h after treatment (20 micro g; i.c.v.). The resuscitative effect was associated with rises in renal, hindquarters and mesenteric blood flows. The nicotinic cholinoceptor antagonist hexamethonium (3 mg/kg; i.v.) attenuated the MAP and HR changes, whereas the muscarinic cholinoceptor blocker methylatropine (2 mg/kg; i.v.) attenuated only the pressor effect. Metoprine-induced MAP and regional haemodynamic effects were also reduced by alpha(1)- and alpha(2)-adrenoceptor antagonists prazosin (0.5 mg/kg; i.v.) and yohimbine (1 mg/kg; i.v.), while the beta-adrenoceptor blocker propranolol (1 mg/kg; i.v.) diminished only HR changes. Ganglionic transmission inhibitors and adrenoceptor antagonists did not influence the survival rate at 2 h in the metoprine-treated groups. Bilateral adrenal demedullation diminished the pressor effect of metoprine, however, without influence on HR and survival at 2 h after treatment. In conclusion, the study demonstrates the activation of the sympathetic nervous system elicited by endogenous central histamine in haemorrhage-shocked rats and confirms its involvement in histamine-induced resuscitation.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Animals; Atropine Derivatives; Blood Pressure; Brain; Dose-Response Relationship, Drug; Epinephrine; Heart Rate; Hexamethonium; Histamine; Histamine N-Methyltransferase; Hypotension; Male; Muscarinic Antagonists; Nicotinic Antagonists; Pyrimethamine; Rats; Rats, Wistar; Regional Blood Flow; Shock, Hemorrhagic; Sympathetic Nervous System