Abstract: The histaminergic system consists of neurons concentrated in the tuberomammillary nucleus of the posterior hypothalamus and send innervation to almost all parts of the brain, including the cardiovascular complex. Recent hypotheses suggest that the system is implicated in the response to adverse or potentially dangerous stimuli, including dehydration, changes in blood pressure, nociceptive stimuli and other kinds of stress. In these conditions, there is an increase in the release or turnover of neuronal histamine leading to activation of compensatory mechanisms. The purpose of the study was to examine cardiovascular effects of endogenous central histamine in haemorrhage-shocked rats. Moreover, compensatory mechanisms activated by histamine were investigated. Studies were carried out in anaesthetized male Wistar rats subjected to a critical irreversible hypotension (mean arterial pressure [MAP] 20-25 mmHg). The protocol was approved by local ethics committee. Both histamine precursor L-histidine (intraperitoneally [ip]) and histamine N-methyltransferase (HNMT) inhibitors - SKF 91488 and metoprine (intracerebroventricularly [icv]) led to an increase in endogenous histamine concentrations in the cerebral cortex by 20-23%, hypothalamus by 25-27% and medulla oblongata by 23-29% in comparison to the control groups. L-histidine produced dose-dependent increases in MAP, heart rate (HR) and a survival rate of 2 h, whereas in normotensive animals it did not influence cardiovascular parameters. The effect was inhibited by (S)-á-fluoromethylhistidine, an irreversible inhibitor of L-histidine decarboxylase. SKF 91488 and metoprine evoked dose-dependent rises in MAP and HR, which were significantly higher than those in normotensive animals, and the improvement of survival rates at 2 h after treatment. The action was inhibited by H1 receptor antagonist chlorpheniramine (icv), while neither ranitidine (icv) nor thioperamide (icv), H2 and H3/H4 receptor blockers, respectively, influenced the effect. Metoprine-induced resuscitating action was accompanied by 2.7- and 1.7-fold higher plasma levels of noradrenaline and adrenaline, 2.5-fold higher concentration of arginine vasopressin (AVP), 2.9-fold higher level of angiotensin II, 3.3-fold higher level of ACTH and 1.7-fold higher level of á-MSH. In metoprine-treated animals, nicotinic cholinoceptor antagonist hexamethonium (intravenously [iv]) decreased MAP and HR changes, whereas muscarinic cholinoceptor blocker methylatropine (iv) inhibited only the pressor effect. Metoprine-induced MAP and regional haemodynamic effects were also reduced by á1- and á2-adrenoceptor antagonists prazosin (iv) and yohimbine (iv), while â-adrenoceptor blocker propranolol (iv) diminished only HR changes. V1a receptor antagonist [â-mercapto-â,â-cyclopentamethylenepropionyl1,O-me-Tyr2,Arg8]AVP (iv), but not V1b and V2 receptor blockers - SSR149415 (ip) and [adamantaneacetyl1,O-Et-D-Tyr2,Val4,aminobutyryl6,Arg8,9]AVP (iv), respectively, inhibited metoprine-induced haemodynamic effects, without influence on survival at 2 h. Moreover, angiotensin type 1 (AT1) receptor antagonist ZD 7155 (iv) and angiotensin-converting enzyme inhibitor captopril (iv) decreased regional vascular resistance and inhibited metoprine-induced increase in MAP, whereas AT2 receptor blocker PD 123319 (iv) had no effect. Finally, melanocortin type 4 (MC4) receptor antagonist HS014 (icv) inhibited metoprine-induced increase in MAP, which resulted from decreased regional vascular resistance; however, it did not affect HR and the survival at 2 h. In conclusion, an increase in endogenous central histamine concentrations after loading with L-histidine or inhibition of HNMT activity leads to rises in central histamine concentration and the reversal of haemorrhagic hypotension. The resuscitating action of central histamine results from H1 receptor activation. The study demonstrates an involvement of the sympathetic nervous system, AVP, the renin-angiotensin system and proopiomelanocortin-derived peptides in endogenous central histamine-induced resuscitating action. Present data confirm the hypothesis concerning the role of the histaminergic system in regulation of central homeostatic mechanisms in haemorrhagic shock.

Brief Biography of the Speaker:
Jerzy Jochem (MD, PhD) is an associate professor at Department of Basic Medical Sciences, Medical University of Silesia, Katowice, Poland, where he is also the Institutional Coordinator of the LLP-Erasmus Program. He is a specialist in internal medicine and cardiology. His main research interests concern cardiovascular physiology and cardiology, especially the central and peripheral mechanisms involved in the cardiovascular regulation in hypotension. In these fields, he authored or co-authored over 70 scientific papers published in reviewed journals and over 80 communications presented at international conferences. Dr. Jochem has received Polish Prime Minister Habilitation Award (2006) and the National Education Committee Award (2007). Since 2005 he is a vice-president of the Polish Histamine Research Society.