Evidence that hemorrhagic hypotension is mediated by the ventrolateral periaqueductal gray region.

Severe hemorrhage lowers arterial pressure by suppressing sympathetic activity. This study tested the hypothesis that the decompensatory phase of hemorrhage is mediated by the ventrolateral periaqueductal gray (vlPAG), a region importantly involved in the autonomic and behavioral responses to stress and trauma. Neuronal activity in the vlPAG was inhibited with either lidocaine or cobalt chloride 5 min before hemorrhage (2.5 ml/100 g body wt) was initiated in conscious, unrestrained rats. Bilateral injection of lidocaine (0.5 microl of a 2% or 1 microl of a 5% solution) into the caudal vlPAG delayed the onset and reduced the magnitude of the hypotension produced by hemorrhage significantly. In contrast, inactivation of the dorsolateral PAG with lidocaine was ineffective. Cobalt chloride (5 mM; 0.5 microl), which inhibits synaptic transmission but not axonal conductance, also attenuated hemorrhagic hypotension significantly. Microinjection of lidocaine or cobalt chloride into the vlPAG of normotensive, nonhemorrhaged rats did not influence cardiovascular function. These data indicate that the vlPAG plays an important role in the response to hemorrhage.

Blockade of delta opioid receptors in the ventrolateral periaqueductal gray region inhibits the fall in arterial pressure evoked by hemorrhage.

Severe hemorrhage lowers arterial pressure by suppressing sympathetic activity. The central mechanism that initially triggers the fall in arterial pressure evoked by hemorrhage is not well understood, although opioid neurons are thought to play a role. This study tested the hypothesis that hemorrhagic hypotension is mediated by delta opioid receptors in the ventrolateral periaqueductal gray (vlPAG), a region importantly involved in opioid analgesia. Depressor sites were first identified by microinjecting DL-homocysteic acid (20 nmol/0.1 microl) or beta-endorphin (0.5 nmol/0.1 microl) into the vlPAG of halothane-anesthetized rats. Consistent with earlier reports, DL-homocysteic acid injection into the caudal vlPAG lowered arterial pressure and heart rate; beta-endorphin evoked a comparable depressor response, but did not affect heart rate. Naloxone or selective opioid receptor antagonists were subsequently injected into the vlPAG 5 min before hemorrhage (1.9 or 2.5 ml/100 g of body weight over 20 min) was initiated using the same stereotaxic coordinates. Naloxone injection into the caudal vlPAG completely prevented the fall in arterial pressure evoked by hemorrhage. The response was dose-dependent and evident with both fixed volume and fixed pressure hemorrhage. The delta opioid receptor antagonist naltrindole inhibited hemorrhagic hypotension significantly in both conscious and anesthetized rats but mu and kappa receptor antagonists were ineffective. beta-Endorphin(1--27), an endogenous opioid receptor antagonist, was also significantly inhibitory. Naltrindole was ineffective when injected into the dorsolateral periaqueductal gray and did not influence cardiovascular function in nonhemorrhaged animals. These data support the hypothesis that hemorrhagic hypotension is mediated by delta opioid receptors in the vlPAG.

Reversal of Haemorrhagic Shock in Rats by Tetrahydroaminoacridine.

The cardiovascular effects of tetrahydroaminoacridine (tacrine; THA) were investigated in haemorrhaged rats. Intracerebroventricular (i.c.v.) injection of THA (10, 25 and 50 microg) restored blood pressure in a dose- and time-dependent manner. Atropine (10 microg, i.c.v.), a muscarinic receptor antagonist, attenuated the pressor response to THA (25 microg, i.c.v.), while mecamylamine (50 microg, 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 microg). Haemorrhage increased plasma levels of adrenaline, noradrenaline, vasopressin and plasma renin activity. THA (25 microg, 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 alpha(1)-adrenoceptor antagonist (0.5 mg/kg, i.v.) or by the vasopressin V(1) receptor antagonist [beta-mercapto-beta,beta-cyclopenta-methylenepropionyl(1), O-Me-Tyr(2)-Arg(8)]-vasopressin (10 microg/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 microg, i.c.v.) greatly attenuated the pressor response to THA (1.5 mg/kg, i.v.), while mecamylamine (50 microg, 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.

Cardiovascular effects of centrally injected tetrahydroaminoacridine in conscious normotensive rats.

In freely moving rats, intracerebroventricularly (i.c.v.) injected tetrahydroaminoacridine (10, 25, 50 microg) increased blood pressure and decreased heart rate in a dose- and time-dependent manner. Intravenous (i.v.) tetrahydroaminoacridine (1 and 3 mg/kg) also increased blood pressure. Atropine sulphate (10 microg; i.c.v.) pretreatment greatly attenuated the blood pressure response to i.c.v. tetrahydroaminoacridine while mecamylamine (50 microg; i.c.v.) failed to change the pressor effect. Neither atropine sulphate nor mecamylamine pretreatment affected the bradycardia induced by tetrahydroaminoacridine. However, the bradycardic response was completely blocked by atropine methylnitrate (2 mg/kg; i.p.) pretreatment. The pressor response to i.c.v. tetrahydroaminoacridine was associated with a several-fold increase in plasma levels of vasopressin, adrenaline and noradrenaline, but not of plasma renin. Pretreatment with prazosin (0.5 mg/kg; i.v.) attenuated the pressor effect without changing the bradycardia. Vasopressin V1 receptor antagonist [beta-mercapto-beta,beta-cyclopentamethylenepropionyl1,O-Me-Tyr2-A rg8]vasopressin (10 microg/kg; i.v.) pretreatment also partially inhibited the pressor response to i.c.v. tetrahydroaminoacridine and abolished the bradycardia. Tetrahydroaminoacridine's cardiovascular effects were completely blocked when rats were pretreated with prazosin plus vasopressin antagonist. The data show that tetrahydroaminoacridine increases blood pressure in normotensive freely moving rats by activating central muscarinic cholinergic transmission. Increases in plasma catecholamines and vasopressin are both involved in this response. The tetrahydroaminoacridine-induced reduction in heart rate appears to be due to the increase in vagal tone and plasma vasopressin.