Reversal of Haemorrhagic Shock in Rats by Tetrahydroaminoacridine

Abstract

The cardiovascular effects of tetrahydroaminoacridine (tacrine; THA) were investigated in haemorrhaged rats. Intracerebroventricular (i.c.v.) injection of THA (10, 25 and 50 µg) restored blood pressure in a dose- and time-dependent manner. Atropine (10 µg, i.c.v.), a muscarinic receptor antagonist, attenuated the pressor response to THA (25 µg, i.c.v.), while mecamylamine (50 µg, i.c.v.), a nicotinic receptor antagonist, caused only a slight blockade in the pressor effect of THA. Simultaneous pretreatment with atropine and mecamylamine almost abolished the blood pressure effect of i.c.v. THA (25 µg). Haemorrhage increased plasma levels of adrenaline, noradrenaline, vasopressin and plasma renin activity. THA (25 µg, i.c.v.) administration caused additional increases in vasopressin and adrenaline levels but not of renin activity and noradrenaline levels. The reversal of hypotension by THA was greatly attenuated by administration of either prazosin, an α₁-adrenoceptor antagonist (0.5 mg/kg, i.v.) or by the vasopressin V₁ receptor antagonist [β-mercapto-β,β-cyclopenta-methylenepropionyl¹, O-Me-Tyr²-Arg⁸]-vasopressin (10 µg/kg, i.v.). Pretreatment of rats with both prazosin and the vasopressin antagonist simultaneously completely inhibited the pressor response. Intravenous administration of THA (1, 1.5 and 3 mg/kg) also reversed hypotension in rats. Atropine (10 µg, i.c.v.) greatly attenuated the pressor response to THA (1.5 mg/kg, i.v.), while mecamylamine (50 µg, i.c.v.) failed to change the pressor effect of THA. In anaesthetised haemorrhaged rats, THA (1.5 mg/kg, i.v.) increased blood pressure and survival time of the animals. These results show that centrally and peripherally injected THA reverses haemorrhagic hypotension and increases survival time in rats. Activation of central muscarinic and nicotinic receptors is involved in the pressor response to i.c.v. THA. The pressor effect of i.v. THA is solely mediated by central muscarinic receptors. Moreover, the increase in plasma adrenaline and vasopressin levels appears to be involved in the pressor effect of THA.