dizocilpine-maleate and Hemorrhage

This study aimed to investigate the roles of glutamate (Glu) receptors in the anteroventral third ventricular region (AV3V), a pivotal area for water, cardiovascular and neuroendocrine regulations, in causing vasopressin (AVP) secretion and other phenomena in response to bleeding. The effects of intracerebral infusions of MK-801 [a N-methyl-D-aspartate (NMDA) receptor antagonist] or a metabotropic Glu receptor antagonist (MCPG) on plasma levels of AVP, electrolytes, osmolality and glucose, heart rate and arterial pressure following AV3V administration with NMDA or bleeding stimuli were analyzed in conscious rats. NMDA provoked prominent rises of plasma AVP, osmolality, glucose and arterial pressure, without changing plasma electrolytes or heart rate significantly. All the effects of NMDA were blocked by pre-administration of MK-801 into the same loci. Removal through a femoral arterial line of 10 ml blood per kg body weight did not affect arterial pressure or other variables significantly, although plasma AVP and angiotensin II (ANG II) tended to increase. When bleeding was repeated after 10 min (B2), arterial pressure dropped promptly, and plasma AVP, ANG II, osmolality and glucose augmented remarkably. MK-801 applied 35 min preceding B2, to loci such as the median preoptic nucleus, periventricular nucleus and medial preoptic area inhibited the response of plasma AVP significantly, without exerting any effects on other variables. When MK-801 was administered intracerebroventricularly, or when MCPG was infused into the AV3V, significant alterations did not occur in B2-evoked responses of plasma AVP nor in those of the other variables. In rats given sham bleeding after AV3V infusions of MK-801 or MCPG or intracerebroventricular applications of MK-801, all monitored variables roughly remained at stable levels throughout the experiments. We conclude that NMDA receptors in AV3V, but not metabotropic Glu receptors, may facilitate AVP secretion in hypotensive hypovolemia.

Topics: Analysis of Variance; Angiotensin II; Animals; Blood Glucose; Blood Pressure; Dizocilpine Maleate; Drug Interactions; Electrolytes; Excitatory Amino Acid Antagonists; Glycine; Heart Rate; Hemorrhage; Hypothalamus; Injections, Intraventricular; Male; N-Methylaspartate; Osmolar Concentration; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Third Ventricle; Time Factors; Vasopressins; Wakefulness

In our exsanguination cardiac arrest (CA) outcome model in dogs we are systematically exploring suspended animation (SA), i.e. preservation of brain and heart immediately after the onset of CA to enable transport and resuscitative surgery during CA, followed by delayed resuscitation. We have shown in dogs that inducing moderate cerebral hypothermia with an aortic arch flush of 500 ml normal saline solution at 4 degrees C, at start of CA 20 min no-flow, leads to normal functional outcome. We hypothesized that, using the same model, but with the saline flush at 24 degrees C inducing minimal cerebral hypothermia (which would be more readily available in the field), adding either fructose-1,6-bisphosphate (FBP, a more efficient energy substrate) or MK-801 (an N-methyl-D-aspartate (NMDA) receptor blocker) would also achieve normal functional outcome. Dogs (range 19-30 kg) were exsanguinated over 5 min to CA of 20 min no-flow, and resuscitated by closed-chest cardiopulmonary bypass (CPB). They received assisted circulation to 2 h, mild systemic hypothermia (34 degrees C) post-CA to 12 h, controlled ventilation to 20 h, and intensive care to 72 h. At CA 2 min, the dogs received an aortic arch flush of 500 ml saline at 24 degrees C by a balloon-tipped catheter, inserted through the femoral artery (control group, n=6). In the FBP group (n=5), FBP (total 1440 or 4090 mg/kg) was given by flush and with reperfusion. In the MK-801 group (n=5), MK-801 (2, 4, or 8 mg/kg) was given by flush and with reperfusion. Outcome was assessed in terms of overall performance categories (OPC 1, normal; 2, moderate disability; 3, severe disability; 4, coma; 5, brain death or death), neurologic deficit scores (NDS 0-10%, normal; 100%, brain death), and brain histologic damage scores (HDS, total HDS 0, no damage; >100, extensive damage; 1064, maximal damage). In the control group, one dog achieved OPC 2, one OPC 3, and four OPC 4; in the FBP group, two dogs achieved OPC 3, and three OPC 4; in the MK-801 group, two dogs achieved OPC 3, and three OPC 4 (P=1.0). Median NDS were 62% (range 8-67) in the control group; 55% (range 34-66) in the FBP group; and 50% (range 26-59) in the MK-801 group (P=0.2). Median total HDS were 130 (range 56-140) in the control group; 96 (range 64-104) in the FBP group; and 80 (range 34-122) in the MK-801 group (P=0.2). There was no difference in regional HDS between groups. We conclude that neither FBP nor MK-801 by aortic arch flush at the start of CA, plus

Topics: Animals; Aorta, Thoracic; Cardiopulmonary Bypass; Cardiopulmonary Resuscitation; Disease Models, Animal; Dizocilpine Maleate; Dogs; Fructose-Bisphosphatase; Heart Arrest; Hemorrhage; Hypothermia, Induced; Hypoxia, Brain; Neuroprotective Agents; Pulmonary Edema; Reperfusion; Treatment Outcome