Biomedical subjects

J R Kirsch

Publications and source records attributed to J R Kirsch.

At least 55 records · Page 3Linked to original sources

PubMed1994

Nitric oxide and prostanoids contribute to isoflurane-induced cerebral hyperemia in pigs.

BACKGROUND: The mechanism of isoflurane-induced cerebral hyperemia is poorly understood. Data from studies in vitro suggest that volatile anesthetics release a vasodilator prostanoid. We hypothesized that prostanoids and nitric oxide (NO) are mediators of this response in vivo. If true, inhibition of cyclooxygenase by indomethacin (5 mg/kg intravenously) or of nitric oxide synthase by N omega-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg intravenously) should attenuate isoflurane-induced hyperemia. Any response to L-NAME occurring via nitric oxide should be competitively reversed by L-arginine. METHODS: The cerebral blood flow (microsphere) response to 1 MAC isoflurane was tested at three time points (0, 90, and 180 min) in pentobarbital-anesthetized pigs. Isoflurane challenges were separated by 60-min periods of continuous intravenous pentobarbital alone. Control animals (n = 7) received no additional pharmacologic intervention. Experimental animals were randomized to receive L-NAME before the second and indomethacin before the third isoflurane challenge (n = 7); L-NAME before the second and L-arginine (400 mg/kg intravenously) before the third isoflurane challenge (n = 9); or indomethacin before the second and L-NAME before the third isoflurane challenge (n = 8). RESULTS: In control animals, isoflurane reproducibly increased cerebral blood flow (whole brain; 113 +/- 18%, 120 +/- 18%, and 103 +/- 19% increase above baseline at each time point, respectively). Both indomethacin and L-NAME attenuated (10 +/- 10% and 52 +/- 11% increase, respectively) the hyperemic response to isoflurane. The effect of L-NAME was reversed by L-arginine. CONCLUSIONS: We conclude that both prostanoids and nitric oxide contribute to isoflurane-induced hyperemia. We are unable to determine from our data what, if any, interaction exists between these two mechanisms.

Amino Acid Oxidoreductases↗

PubMed1994

Effects of pentoxifylline on cerebral blood flow, metabolism, and evoked response after total cerebral ischemia in dogs.

OBJECTIVE: To test the hypothesis that pentoxifylline improves recovery of cerebral electrical activity and metabolic function after a transient cerebral global ischemia by improving cerebral blood flow during the reperfusion period. DESIGN: Randomized, controlled, prospective study. SETTING: University research laboratory. SUBJECTS: Forty male beagle dogs. INTERVENTIONS: Six control dogs received pentoxifylline (40 mg/kg bolus followed by infusion at 0.2 mg/kg/hr) without ischemia. Thirteen dogs received Ringer's lactate solution with 12 mins of cerebral global ischemia (by aortic occlusion). Nine dogs received pentoxifylline before ischemic insult. Six dogs received pentoxifylline on reperfusion, and six dogs received pentoxifylline 30 mins after reperfusion. MEASUREMENTS AND MAIN RESULTS: Total and regional cerebral blood flow, cerebral oxygen consumption, and somatosensory evoked potentials were measured during 180 mins of reperfusion. Pentoxifylline did not affect cerebral blood flow, oxygen consumption, or somatosensory evoked potentials without ischemia. Pretreatment with pentoxifylline resulted in attenuated postischemic hyperemia at 10 mins of reperfusion (94 +/- 15 vs. 133 +/- 11 [SEM] mL/min/100 g; p < .05), but there was no difference in total cerebral blood flow or oxygen consumption during later points of reperfusion. Pentoxifylline treatment during reperfusion resulted in no recovery of cerebral blood flow or oxygen consumption. All ischemic groups demonstrated a rapid ablation of somatosensory evoked potential amplitude and there were no differences in the decrement of the amplitude on ischemia. At 180 mins of reperfusion, somatosensory evoked potentials recovered to the following percentages of the baseline control values: 28 +/- 4% in dogs treated with Ringer's lactate solution; 58 +/- 4% in the pentoxifylline pretreated group (p < .05); 40 +/- 5% in dogs receiving pentoxifylline at reperfusion (p > .05); and 53 +/- 8% in dogs receiving pentoxifylline at 30 mins of reperfusion (p < .05). CONCLUSIONS: Pentoxifylline treatment improves recovery of cerebral electrical function after complete transient cerebral global ischemia by a mechanism that does not involve improvement in cerebral blood flow or global oxygen consumption.

Animals↗

PubMed1994

Nitric oxide synthase inhibition with NG-mono-methyl-L-arginine reversibly decreases cerebral blood flow in piglets.

OBJECTIVE: We tested the hypothesis that, in piglets, the intravenous administration of the reversible inhibitor of nitric oxide synthase, NG-mono-methyl-L-arginine, decreases cerebral blood flow via a mechanism unrelated to cerebral oxygen consumption. DESIGN: Prospective, randomized, controlled animal study. SETTING: Animal laboratory at a university. SUBJECTS: Pentobarbital-anesthetized piglets (1 to 2 wks of age; 2.6 to 4.0 kg). INTERVENTIONS: Piglets were treated with either 50 mg of NG-mono-methyl-L-arginine, 100 mg of NG-mono-methyl-L-arginine, or an equal volume of saline by intravenous infusion over 10 mins. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure increased after NG-mono-methyl-L-arginine (50 mg dose: 84 +/- 6 to 100 +/- 7 mmHg; 100 mg dose: 82 +/- 4 to 107 +/- 4 mmHg; p < .001). Forebrain blood flow (microspheres) decreased (37 +/- 2 to 30 +/- 2 mL/min/100 g; p < .05) and cerebrovascular resistance increased (2.1 +/- 0.2 to 3.5 +/- 0.3 mmHg/mL/min/100 g; p < .05) only after 100 mg of NG-mono-methyl-L-arginine. Neurohypophysis blood flow decreased to 56 +/- 9% of the control value, while forebrain blood flow decreased only to 81 +/- 4% of the control value after 100 mg of NG-mono-methyl-L-arginine administration. Blood flow returned to control values by 30 mins after infusion. NG-mono-methyl-L-arginine administration had no effect on cerebral oxygen consumption at either dose. Intravenous administration of L-arginine (300 mg) immediately after the infusion of 100 mg of NG-mono-methyl-L-arginine was associated with prompt (by 3 mins) recovery of blood flow to all brain regions that were affected by NG-mono-methyl-L-arginine. CONCLUSIONS: These data suggest that nitric oxide and/or a nitric oxide-containing substance is an important mediator of cerebrovascular tone in piglets, acting via a mechanism unrelated to altering cerebral oxygen consumption.

Amino Acid Oxidoreductases↗

PubMed1994

Nitric oxide synthase inhibition attenuates hypoglycemic cerebral hyperemia in piglets.

We tested the hypothesis that nitric oxide (NO) mediates hypoglycemia-induced cerebral vasodilation in piglets. Piglets (1-2 wk old) were made hypoglycemic with insulin (200 U/kg i.v.) with and without an NO synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 40 mg/kg i.v.). Electroencephalogram (EEG), cerebral O2 consumption (CMRO2), and cerebral blood flow (CBF) were measured before L-NAME and insulin and for 180 min after insulin. Hypoglycemia led to isoelectric EEG earlier after L-NAME (87 +/- 8 min) than without L-NAME pretreatment (132 +/- 13 min). CBF increased in all brain regions during hypoglycemia at the onset of isoelectric EEG and was associated with increased CMRO2.L-NAME prevented the increase in CMRO2 and attenuated vasodilation in forebrain (154 +/- 37 vs. 400 +/- 60%), cerebellum (251 +/- 52 vs. 386 +/- 52%), and cortical gray matter (183 +/- 47 vs. 524 +/- 93%) but had no effect on CBF responses in brain stem, thalamus, caudate, or hippocampus. We conclude that NO or a NO-containing compound mediates cerebral vasodilation induced by profound insulin-hypoglycemia in piglets and that this vasodilation plays an important role in the adaptation of immature brain to hypoglycemia.

Amino Acid Oxidoreductases↗

PubMed1994

Cerebral blood flow is reduced by N omega-nitro-L-arginine methyl ester during delayed hypoperfusion in cats.

We tested the hypothesis that decreased tonic release of nitric oxide (NO) or a NO-containing compound, during postischemic delayed hypoperfusion, would result in an impaired response of cerebral blood flow (CBF) to NO synthase inhibition. We measured CBF (microspheres), cerebral oxygen consumption, and physiological variables in 30 halothane-anesthetized cats. In 12 animals, complete cerebral ischemia (verified by midischemic CBF measurement) was produced for 12 min by brachiocephalic and left subclavian artery occlusion with hemorrhagic hypotension (mean arterial blood pressure = 40 mmHg). Steady-state hypoperfusion was present by 120 min of reperfusion (30 +/- 4% of baseline). Nonischemic animals (n = 12) were submitted to the same surgical procedures and anesthetic duration. N omega-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg iv) or saline was administered 160 min after baseline measurements, equivalent to 140 min of reperfusion for animals treated with ischemia (n = 6 in each group). Blood pressure was controlled (aortic ligature) so that there was no change following L-NAME administration both in the ischemic and nonischemic groups. L-NAME reduced CBF during reperfusion in ischemic animals (from 37 +/- 2 to 24 +/- 2 ml.min-1 x 100 g-1) and in nonischemic animals (from 122 +/- 15 to 68 +/- 8 ml.min-1 x 100 g-1) with no change in cerebral oxygen consumption. In six additional cats, administration of L-arginine (250 mg/kg iv) reversed the effect of L-NAME. We conclude that tonic NO-mediated cerebral vasodilation occurs following transient global ischemia despite delayed hypoperfusion.

Animals↗

PubMed1994

Hypoxic reperfusion after ischemia in swine does not improve acute brain recovery.

We tested the hypothesis that transient hypoxic reperfusion after 15 min of global cerebral ischemia would improve acute recovery of electrical function. We also determined the changes in cerebral blood flow (CBF) and cerebral oxygen consumption (CMRO2) during transient hypoxic reperfusion. Pentobarbital-anesthetized pigs were exposed to cerebral ischemia by raising intracranial pressure to 100 mmHg above arterial pressure with rapid infusion of artificial cerebral spinal fluid into a lateral ventricle. During the reperfusion period, normoxia was maintained at an arterial oxygen partial pressure (PaO2) of 80-120 mmHg for 120 min of reperfusion and hypoxia at a PaO2 of 35-45 mmHg for the first 30 min of reperfusion in another group. The postischemic hypoxia group showed persistent elevation in microsphere-determined CBF at 30 min of reperfusion in all brain regions and lack of delayed hypoperfusion through 120 min of reperfusion. The normoxic group demonstrated transient postischemic hyperemia and hypoperfusion. CMRO2 was not significantly different between groups at any time point. In both groups, the somatosensory-evoked potential amplitude reached only 10% recovery by the end of 120 min of reperfusion. We conclude that hypoxemia during reperfusion after cerebral ischemia in this model does not improve acute brain electrical function and prolongs postischemic hyperemia.

Animals↗

PubMed1994

Effect of postischemic hypoperfusion on vasodilatory mechanisms in cats.

We addressed the mechanism for reduced pial vascular reactivity to muscarinic stimulation by evaluating pial vessel responses to receptor-dependent [10(-5) M acetylcholine (ACh)] and independent (10(-5) M A-23187) agonists and the endothelium-independent nitric oxide (NO) donor [10(-5) M nitroprusside (NP)]. Cerebral blood flow (CBF, microspheres) and pial arteriolar diameters (intravital microscopy) were measured in halothane-anesthetized cats. Cats (n = 13) were treated with 12 min of near-complete global cerebral ischemia, whereas control animals (n = 9) were identically instrumented but were not submitted to ischemia. Postischemic hypoperfusion was evident in most animals at 60 min of reperfusion, accompanied by attenuated pial arterial dilation to topical ACh (baseline dilation 23 +/- 4% vs. postischemia 11 +/- 3%) and A-23187 (16 +/- 4 vs. 0 +/- 3% dilation). Dilation to NP was unaffected. CBF response to intravenous administration of the muscarinic receptor agonist oxotremorine was also decreased throughout the forebrain (162 +/- 12 vs. 116 +/- 6% increase in flow) in these cats. These data suggest that endothelium-dependent vasodilation with topical muscarinic agonists is impaired during hypoperfusion, but vascular smooth muscle responsivity to NO remains intact. We conclude that the defect in the signal transduction pathway is not limited to the receptor and may involve an abnormality with NO synthesis or its destruction within endothelium.

Acetylcholine↗

PubMed1994

Dihydropyridine ligand binding decreases earlier in adolescent than in infant swine after global cerebral ischemia.

BACKGROUND AND PURPOSE: Voltage-dependent calcium channels (VDCCs) are thought to play a major role in the alteration of calcium homeostasis during ischemia. Tissue functional state as well as responsiveness to therapy with calcium channel blockers may be a function of regional changes in the density of VDCCs. This study determined whether VDCCs are altered by global ischemia in infant and adolescent swine. METHODS: We employed the radioligand 3HPN200-110 to quantify the binding characteristics of VDCCs in cerebral cortex, caudate, and hippocampus by equilibrium binding analysis. Adolescent and infant pigs underwent 3, 5, 10, and 20 minutes of global cerebral ischemia without reperfusion by ligation of the brachiocephalic and left subclavian arteries combined with hypotension to a mean arterial blood pressure of 50 mm Hg. Brain cortex, hippocampus, and caudate samples were taken during ischemia and frozen immediately in liquid nitrogen, and crude synaptosomal membranes were isolated by differential centrifugation/filtration. 3HPN200-110 equilibrium binding assays were performed in the presence or absence of 1.0 mumol/L unlabeled nitrendipine to determine total and nonspecific binding. RESULTS: Infant cortex maximal binding (Bmax) increased to 176% of control after 5 minutes of global cerebral ischemia and remained significantly elevated (172% of control) after 10 minutes before falling to near control levels by 20 minutes. Adolescent cortex Bmax increased to 157% of control levels after 5 minutes but did not remain elevated, falling to 131% of control by 10 minutes and near control by 20 minutes. Infant caudate and hippocampus binding were significantly elevated after 10 (124% and 149% of control, respectively) and 20 (115% and 120% of control, respectively) minutes of ischemia. Adolescent caudate and hippocampus binding was either not significantly different from control levels (hippocampus at 10 minutes) or less than control after 10 and 20 minutes of global cerebral ischemia. The decrease in binding following the initial upregulation, which appeared earlier in the adolescent than the infant pigs, may indicate decreased tolerance to ischemia in the adolescent. CONCLUSIONS: The binding of 3HPN200-110 in brain is altered during 20 minutes of global cerebral ischemia, and these changes are region- and age-dependent.

Aging↗

PubMed1994

Competitive N-methyl-D-aspartate receptor blockade reduces brain injury following transient focal ischemia in cats.

BACKGROUND AND PURPOSE: We tested the hypothesis that administration of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist NPC 17742 (2R,4R,5S-[2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid]) during transient focal ischemia affects early postischemic brain injury. METHODS: Halothane-anesthetized cats underwent 1 hour of left middle cerebral artery occlusion plus 4 hours of reperfusion. Control cats received saline (n = 7). Experimental cats were treated with NPC 17742 at a dose of 5 mg/kg IV from 45 minutes of ischemia to 15 minutes of reperfusion and 2.5 mg/kg per hour for 4 hours of reperfusion (NPC-5; n = 7) or 50 mg/kg from 45 minutes of ischemia to 15 minutes of reperfusion and 25 mg/kg per hour for 4 hours of reperfusion (NPC-50; n = 5). RESULTS: Microsphere-determined blood flow to the ipsilateral inferior temporal cortex and caudate nucleus decreased to the same extent during ischemia and recovered to the same extent during reperfusion in the three groups. Triphenyltetrazolium-determined injury volume of ipsilateral cerebral hemisphere (saline, 24 +/- 8%; NPC-5, 4 +/- 2%; NPC-50, 5 +/- 2% of hemisphere; mean +/- SE) and caudate nucleus (saline, 72 +/- 6%; NPC-5, 37 +/- 10%; NPC-50, 26 +/- 4%) was less in cats treated with both doses of drug compared with cats treated with saline. Recovery of somatosensory evoked potential amplitude was incomplete and similar in all groups (saline, 36 +/- 14%; NPC-5, 58 +/- 8%; NPC-50, 51 +/- 15% of baseline). CONCLUSIONS: These data indicate that activation of NMDA receptors plays an important role in the mechanism of acute injury in both cortex and caudate after 1 hour of transient focal ischemia in the cat. Because NPC 17742 afforded protection when administered at the end of ischemia and during reperfusion, NMDA receptor activation during reperfusion may contribute to the progression of injury in ischemic border regions.

Amino Acids↗

PubMed1994

Tirilazad treatment does not decrease early brain injury after transient focal ischemia in cats.

BACKGROUND AND PURPOSE: We tested the hypothesis that administration of the antioxidant tirilazad mesylate improves electrophysiological recovery and decreases infarct volume after transient focal cerebral ischemia in cats. METHODS: Halothane-anesthetized cats underwent 90 minutes of left middle cerebral artery and bilateral common carotid artery occlusion followed by 180 minutes of reperfusion. Cats were assigned to receive tirilazad (1.5 mg/kg plus 0.2 mg/kg per hour IV infusion) either at the beginning (n = 9) or conclusion (n = 9) of ischemia. Control cats received an equal volume of diluent (citrate buffer, pH 3.0; n = 7) at the beginning and conclusion of ischemia in a blinded fashion. Infarct volume was measured by 2,3,5-triphenyltetrazolium chloride staining. RESULTS: Blood flow to the left temporoparietal cortex decreased to less than 10 mL/min per 100 g with ischemia but was minimally affected on the right side. Blood flow distribution during ischemia or reperfusion was not different in the tirilazad-treated groups. No group demonstrated postischemic hyperemia or delayed hypoperfusion. Somatosensory evoked potential recorded over the left cortex was ablated during ischemia and recovered to less than 15% of baseline amplitude at 180 minutes of reperfusion in all groups. There were no differences among groups in infarct volume of left hemisphere (pretreatment, 25 +/- 6% [mean +/- SE]; posttreatment, 33 +/- 5%; control, 28 +/- 8% of hemisphere) or caudate nucleus (pretreatment, 46 +/- 7%; posttreatment, 41 +/- 10%; control, 55 +/- 13% of hemisphere). CONCLUSIONS: In an experimental model of focal ischemia involving severe reductions of blood flow followed by reperfusion in cats, administration of tirilazad at the onset of either ischemia or reperfusion does not ameliorate infarct volume assessed during early reperfusion. Our study does not address potential efficacy of tirilazad in the setting of a different dosing strategy or duration of reperfusion.

Analysis of Variance↗

PubMed1994

Nitric oxide synthase inhibition reduces caudate injury following transient focal ischemia in cats.

BACKGROUND AND PURPOSE: We tested the hypothesis that inhibiting nitric oxide production either before or during transient focal ischemia affects early postischemic brain injury. METHODS: Halothane-anesthetized cats underwent 1 hour of left middle cerebral artery occlusion plus 3 hours of reperfusion. Pretreatment groups received either intravenous N omega-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg, n = 10) or an equal volume of diluent (10 mL saline, n = 10) over 30 minutes before ischemia. Posttreatment groups received intravenous L-NAME (10 mg/kg) over 30 minutes from 45 minutes of ischemia to 15 minutes of reperfusion (n = 10) or intravenous L-NAME (10 mg/kg) plus L-arginine (200 mg/kg) over the same period followed by continuous L-arginine infusion (200 mg/kg per hour) for the remainder of reperfusion (n = 10). RESULTS: Microsphere-determined blood flow to ipsilateral caudate nucleus and inferior temporal cortex decreased to the same extent during ischemia and recovered to the same extent during reperfusion in the four groups. Triphenyltetrazolium-determined injury volume of ipsilateral caudate nucleus in cats treated with L-NAME before or during ischemia (42 +/- 7% and 42 +/- 3% of caudate nucleus, respectively; mean +/- SE) was less (P < .05) compared with that in cats pretreated with saline (72 +/- 5%) or cats treated with L-NAME plus L-arginine (68 +/- 5%). Ipsilateral cerebral hemispheric injury volume was similar among the four groups (23 +/- 5%, 13 +/- 3%, 18 +/- 5%, and 29 +/- 5% of hemisphere in groups treated with L-NAME before ischemia and during ischemia, the saline-treated group, and the group treated with L-NAME plus L-arginine, respectively). CONCLUSIONS: Inhibition of nitric oxide synthase decreases caudate injury volume from transient focal cerebral ischemia in cats. The beneficial effect is reversed by L-arginine and is not caused by favorable redistribution of blood flow during ischemia and reperfusion. Because L-NAME was efficacious when administered at reperfusion, nitric oxide generated during reperfusion appears to contribute to caudate injury.

Amino Acid Oxidoreductases↗

PubMed1994

Brain nitric oxide synthase activity in normal, hypertensive, and stroke-prone rats.

BACKGROUND AND PURPOSE: Nitric oxide-mediated cerebral vasodilation is altered in spontaneously hypertensive stroke-prone rats. Stroke predisposition in this strain could be related to a genetic defect of brain nitric oxide synthase, the enzyme responsible for nitric oxide production. We tested the hypothesis that brain nitric oxide synthase activity is altered in spontaneously hypertensive stroke-prone rats compared with spontaneously hypertensive or Wistar-Kyoto rats. METHODS: A colony of spontaneously hypertensive stroke-prone rats was bred, in which the rate of neurological events under salt load was assessed. In a separate cohort of animals brain nitric oxide synthase activity was measured in spontaneously hypertensive stroke-prone rats (n = 6) and in spontaneously hypertensive (n = 6) and genetically related Wistar-Kyoto rats (n = 6). Calcium dependency of nitric oxide synthase was also assessed in cortical brain samples from the three rat strains to determine if altered calcium-dependent activation of nitric oxide synthase was present. RESULTS: Brain nitric oxide synthase activity was highest in the cerebellum (eg, spontaneously hypertensive stroke-prone rats: cerebral cortex, 10.6 +/- 0.9; cerebellum, 50.1 +/- 12.0; brain stem, 14.7 +/- 10.3 pmol/mg protein per minute); however, there was no difference among the three rat strains in any region (eg, cerebral cortex: spontaneously hypertensive stroke-prone, 10.6 +/- 0.9; spontaneously hypertensive, 10.8 +/- 0.5; Wistar-Kyoto, 10.9 +/- 0.7 pmol/mg protein per minute) or at any calcium concentration tested. CONCLUSIONS: A genetic defect of brain nitric oxide synthase is unlikely to be the cause of stroke predisposition in spontaneously hypertensive stroke-prone rats.

Amino Acid Oxidoreductases↗

PubMed1994

Inhibition of nitric oxide synthase does not affect alpha 2-adrenergic-mediated cerebral vasoconstriction.

We assessed whether blocking nitric oxide (NO) synthase alters the cerebral blood flow (CBF) response to alpha 2-adrenergic stimulation during isoflurane anesthesia in dogs. In control animals (n = 6), CBF (microspheres), cerebral oxygen consumption (CMRO2), and electroencephalograph (EEG) were measured after 1 h of isoflurane (1.4% end-tidal) and before and 5, 10, and 20 min after injection of an alpha 2-adrenergic receptor agonist (dexmedetomidine 10 micrograms/kg, intravenous bolus). Dogs in a second group (n = 6) were treated similar to control animals except that an irreversible blocker of NO synthase, N omega-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg) was administered 1 h before induction of anesthesia. In control dogs, dexmedetomidine decreased CBF by 37% (P < 0.05). Blood flow remained decreased for the 20 min observation period in all brain regions except cerebellum and caudate. In the L-NAME group, control CBF was 45% less than baseline flow in the control group (P < 0.05) and dexmedetomidine further decreased CBF from 41 +/- 7 mL x 100 g-1 x min-1 to 24 +/- 2 mL.100 g-1 x min-1 (P < 0.05). There was no difference between groups in the percent of reduction of blood flow in any region after dexmedetomidine administration. Control CMRO2 was similar in the two groups and was unchanged by dexmedetomidine. These data demonstrate that L-NAME reduces CBF and that block of NO synthase does not affect alpha 2-adrenergic-mediated decreases in CBF during isoflurane anesthesia.

Amino Acid Oxidoreductases↗

PubMed1994

A cholinergic agonist induces cerebral hyperemia in isoflurane- but not pentobarbital-anesthetized dogs.

We tested whether the cerebral blood flow (CBF) response to the cholinergic agonist oxotremorine (OXO) is affected by the choice of anesthetics in dogs. We studied two anesthetics, pentobarbital and isoflurane, which produce similar levels of cerebral metabolic depression but have opposing effects on CBF. We also tested the contribution of nitric oxide (NO, or a NO-containing compound) in mediating the CBF response to OXO by determining whether NO synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME) would attenuate OXO-induced hyperemia in both anesthetic groups. CBF (microspheres) was measured before and after OXO administration (50 micrograms.kg-1.min-1 intravenously [i.v.] for 10 min). Animals were divided randomly to receive OXO alone (n = 10) or L-NAME (40 mg/kg i.v.) followed by OXO (n = 10). Within each group, half of the animals received pentobarbital anesthesia (30 mg/kg i.v.) and half received isoflurane (1.4% end-tidal). In pentobarbital-anesthetized animals OXO produced no change in blood flow to cerebrum, caudate, diencephalon, neurohypophysis, or cerebellum in the absence (e.g., cerebrum 37 +/- 2 vs 42 +/- 5 mL/min/100 g) or presence of L-NAME (e.g., cerebrum, 29 +/- 4 vs 30 +/- 3 mL.min-1 x 100 g-1). In isoflurane-anesthetized animals, however, blood flow to forebrain regions increased after OXO (e.g., cerebrum 108 +/- 10 vs 232 +/- 15 mL.min-1 x 100 g-1; P < 0.05) without alteration in oxygen consumption in cerebrum (CMRO2) or blood flow to hindbrain regions. In isoflurane-anesthetized animals, L-NAME decreased baseline blood flow to cerebrum, caudate, diencephalon, cerebellum, and neurohypophysis (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗

PubMed1994

Alpha 2-adrenergic agonist effects on normocapnic and hypercapnic cerebral blood flow in the dog are anesthetic dependent.

alpha 2-Adrenergic receptors are found on large and small cerebral vessels, but their role in control of cerebral blood flow (CBF) and cerebral vascular reactivity is unclear. We assessed the effects of dexmedetomidine (DEX), a highly selective alpha 2-adrenergic agonist, on the cerebrovascular response to hypercapnia in dogs anesthetized with either pentobarbital (PENTO) or isoflurane (ISO), drugs which produce different levels of CBF at a similar level of cerebral oxygen consumption (CMRO2). Dogs were anesthetized with either PENTO, 30 mg/kg, n = 6, or ISO 1.4% end-tidal, n = 7. CBF (radiolabeled microspheres) was determined during normocapnia and hypercapnia at baseline (pre-DEX), after DEX (10 micrograms/kg, intravenous bolus, plus an additional 5 micrograms/kg during hypercapnia), and after administration of a selective alpha 2-adrenergic receptor antagonist (atipamezole, 500 micrograms/kg, intravenous bolus). In the PENTO group, CBF increased from 31 +/- 3 to 137 +/- 24 mL.min-1.100 g-1 in response to hypercapnia (PCO2 approximately 90 mmHg) at pre-DEX and there was no change in normocapnic CBF or hypercapnic blood flow after DEX or atipamezole. In the ISO group, at pre-DEX, CBF increased from 86 +/- 8 to 166 +/- 19 mL.min-1.100 g-1 in response to hypercapnia (PCO2 approximately 90 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-2 Receptor Agonists↗

PubMed1993

MK-801 does not prevent impaired cerebrovascular reactivity to CO2 during hypoglycemia in piglets.

We tested the hypothesis that severe insulin-induced hypoglycemia would depress cerebrovascular reactivity to CO2 via a mechanism that could be prevented by administration of the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 in infant piglets. Cerebral blood flow (CBF) was measured (microspheres) in 2- to 3-wk-old pentobarbital-anesthetized piglets during hypocapnia, normocapnia, and hypercapnia. Repeat CBF measurements were made either 1 (n = 5) or 2 h (n = 6) after insulin (200 U/kg iv) to elicit the time course of altered reactivity to CO2. Repeat CBF measurements were made in a third group (n = 5) 2 h after treatment with insulin and MK-801 (1.5 mg/kg iv bolus, 0.15 mg.kg-1.h-1 iv infusion) to determine whether any alteration in reactivity to CO2 was due to a mechanism involving the NMDA receptor. Cerebrovascular resistance and cerebral O2 consumption (CMRO2) were calculated with each measurement of CBF. Cerebrovascular response to CO2 (change in cerebrovascular resistance/change in arterial CO2 tension) was ablated in the group of piglets exposed to 1 or 2 h of hypoglycemia (preinsulin 1-h group, 0.038 +/- 0.007; preinsulin 2-h group, 0.023 +/- 0.004 mmHg.ml-1.min.100 g.mmHg CO2(-1)). Treatment with MK-801 did not alter normoglycemic CO2 reactivity (preinsulin, 0.032 +/- 0.005 mmHg.ml-1.min.100 g.mmHg CO2(-1)) and did not prevent ablation of cerebrovascular CO2 reactivity during hypoglycemia. CMRO2 was not affected by hypoglycemia in any group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Effect of nitric oxide synthase inhibition on cerebral blood flow and injury volume during focal ischemia in cats.

BACKGROUND AND PURPOSE: We tested the hypothesis that inhibition of nitric oxide synthase activity in brain before ischemia alters cerebral blood flow and decreases brain injury after 4 hours of middle cerebral artery occlusion in cats. METHODS: Halothane-anesthetized cats underwent 4 hours of left middle cerebral artery occlusion after they were randomly assigned to receive either intravenous N omega-nitro-L-arginine methyl ester, at a dose that completely inhibited cortical nitric oxide synthase activity (10 mg/kg, n = 10), or an equal volume of diluent (10 mL saline, n = 10). Serial blood flow measurements were made with radiolabeled microspheres, and injury volume was measured by triphenyltetrazolium staining. RESULTS: Blood flow to caudate nucleus and inferior temporal cortex decreased to the same extent in both groups during middle cerebral artery occlusion. Somatosensory evoked potential amplitude was reduced to less than 10% of baseline values in both groups. Injury volume of ipsilateral caudate nucleus in cats pretreated with nitroarginine (52 +/- 5%, mean +/- SE) was less (P < .05) compared with the saline group (80 +/- 4%), whereas ipsilateral cerebral hemispheric injury volume was similar between the two groups (30 +/- 6% and 32 +/- 4% of hemisphere in saline and nitroarginine groups, respectively). CONCLUSIONS: These results suggest that inhibition of nitric oxide synthase decreases caudate injury volume at 4 hours of middle cerebral artery occlusion without an alteration in distribution of cerebral blood flow.

Amino Acid Oxidoreductases↗

PubMed1993

Effect of the 21-aminosteroid tirilazad on cerebral pH and somatosensory evoked potentials after incomplete ischemia.

BACKGROUND AND PURPOSE: Postischemic evoked potential recovery correlates with acidosis during ischemia and early reperfusion. Acidosis promotes lipid peroxidation in vitro. We tested the hypothesis that the 21-aminosteroid tirilazad mesylate (U74006F), an inhibitor of lipid peroxidation in vitro, ameliorates somatosensory evoked potential recovery and acidosis during reperfusion after severe incomplete cerebral ischemia. METHODS: Cerebral perfusion pressure was reduced to 11 +/- 1 mm Hg (+/- SEM) for 30 minutes by cerebral ventricular fluid infusion in anesthetized dogs. Cerebral intracellular pH and high-energy phosphates were measured by magnetic resonance spectroscopy. Dogs were randomized to receive vehicle (citrate buffer; n = 8) or tirilazad (1 mg/kg; n = 8) before ischemia in a blinded study. RESULTS: Cerebral blood flow was reduced to 6 +/- 1 mL/min per 100 g during ischemia, resulting in nearly complete loss of high-energy phosphates and an intracellular pH of 6.0-6.1 in both groups. Initial postischemic hyperemia was similar between groups but lasted longer in the vehicle group. Tirilazad accelerated mean recovery time of intracellular pH from 31 +/- 5 to 15 +/- 3 minutes and of inorganic phosphate from 13 +/- 2 to 6 +/- 1 minutes. Recovery of somatosensory evoked potential amplitude was greater with tirilazad (49 +/- 3%) than vehicle (33 +/- 6%). Fractional cortical water content was less with tirilazad (0.819 +/- 0.003) than vehicle (0.831 +/- 0.002). CONCLUSIONS: Tirilazad attenuates cerebral edema and improves somatosensory evoked potential recovery after incomplete ischemia associated with severe acidosis. Accelerated pH and inorganic phosphate recovery indicates that this antioxidant acts during the early minutes of reperfusion.

Acidosis↗