Cardiac and regional haemodynamic effects of histamine N-methyltransferase inhibitor metoprine in haemorrhage-shocked rats.

Abstract

The increase in central histamine concentrations after inhibition of histamine N-methyltransferase (HNMT) activity is associated with the reversal of critical haemorrhagic hypotension, therefore the present study examines cardiac and regional haemodynamic effects of HNMT inhibitor metoprine in haemorrhage-shocked rats. Cardiovascular parameters were measured in 72 and central histamine concentrations in 12 male Wistar rats anaesthetised with ketamine/xylazine. Metoprine (5, 15 mg/kg) was administered intraperitoneally to normotensive and critically-hypotensive rats with mean arterial pressure (MAP) 20-25 mmHg. Haemorrhage-shocked rats were pre-treated intracerebroventricularly with histamine H(3) receptor agonist R(-)-alpha-methylhistamine (10 microg) or saline. MAP, heart rate (HR) and cardiac and regional haemodynamics were monitored within 2 h after treatment, or to death if it occurred earlier. Histamine concentrations were measured using enzyme immunoassay. ANOVA followed by Neuman-Keules test, and Fisher's exact test were used to compare the results. Bleeding resulted in an extreme decrease in cardiac index (CI), an increase in total peripheral resistance index (TPRI) and the death of control animals within 30 min. Metoprine induced increases in MAP and HR which were significantly higher in hypotensive than in normotensive animals. The resuscitating effect of metoprine (15 mg/kg) was associated with a rise in CI, a decrease in TPRI, and a 100% survival at 2 h. TPRI changes resulted from decreased renal, hindquarters and mesenteric vascular resistance. R(-)-alpha-methylhistamine inhibited metoprine-induced increases in endogenous histamine concentrations in the cerebral cortex (0.89 +/- 0.12 vs. 1.25 +/- 0.29 nmol/g of wet tissue; P < 0.05), hypothalamus (4.37 +/- 0.42 vs. 5.74 +/- 0.47 nmol/g of wet tissue; P < 0.01) and medulla oblongata (0.39 +/- 0.07 vs. 0.65 +/- 0.28 nmol/g of wet tissue; P < 0.05), diminished haemodynamic effects and decreased the survival rate at 2 h to 33% (P < 0.05 vs. the saline-pre-treated group). The results support the hypothesis that histaminergic system activation leads to mobilisation of compensatory mechanisms in haemorrhagic hypotension.