Endogenous central histamine-induced reversal of critical hemorrhagic hypotension in rats: studies with L-histidine.
Activation of the histaminergic system is characteristic of response to the action of adverse or potentially dangerous stimuli that disturb circulatory homeostasis, such as dehydration and changes in blood pressure. Previous study demonstrates that inhibition of histamine N-methyltransferase, which catabolizes histamine released from neurons, leads to the increase in endogenous central histamine concentrations and to the reversal of critical hemorrhagic hypotension. In the present study, the influence of intraperitoneal loading with histamine precursor L-histidine on central cardiovascular regulation was studied in a model of irreversible pressure-controlled hemorrhagic shock. Experiments were carried out in male Wistar rats anesthetized with ketamine/xylazine subjected to critical hemorrhagic hypotension of 20 to 25 mmHg, which resulted in the death of all control saline-treated animals within 30 min. L-histidine administered in 5 min of critical hypotension produced dose-dependent increases in mean arterial pressure and heart rate (100-500 mg/kg), and a 100% survival rate of 2 h (500 mg/kg), whereas in normotensive animals, it did not influence cardiovascular parameters. The resuscitating effect of L-histidine (500 mg/kg) was associated with increases in histamine concentrations in the cerebral cortex (0.97 +/- 0.11 nmol/g of wet tissue vs. 0.67 +/- 0.22 nmol/g of wet tissue; P<0.05), hypothalamus (4.78 +/- 0.58 nmol/g of wet tissue vs. 4.08 +/- 0.43 nmol/g of wet tissue; P<0.01), and medulla oblongata (0.55 +/- 0.18 nmol/g of wet tissue vs. 0.34 +/- 0.09 nmol/g of wet tissue; P<0.05), as well as with no changes in plasma histamine concentrations in comparison with the saline-treated group 20 min after injection. Pretreatment with (S)-alpha-fluoromethylhistidine (alpha-FMH, 0.5 mg intracerebroventricularly), an irreversible inhibitor of L-histidine decarboxylase, produced a decrease in central histamine concentrations and diminished volumes of blood required to achieve critical hypotension. Moreover, alpha-FMH inhibited L-histidine-induced increases in central histamine concentrations and its resuscitating effect. In conclusion, the increase in central histamine concentrations after loading with L-histidine in rats subjected to critical hemorrhagic hypovolemia leads to the reversal of hypotension and the improvement in the survival rate of 2 h. On the other hand, inhibition of L-histidine decarboxylase activity, and thus histamine synthesis, produces a decrease in hemodynamic stability in hypotension, which suggests the histaminergic system-induced activation of compensatory mechanisms in hemorrhagic shock.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006632:Histamine / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D006639:Histidine / Q000494:pharmacology*; D007022:Hypotension / Q000188:drug therapy* / Q000503:physiopathology*; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism; D008762:Methylhistidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012119:Respiration / Q000187:drug effects; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000503:physiopathology*
D008762:Methylhistidines; D006639:Histidine; C028309:alpha-fluoromethylhistidine; D006632:Histamine