Biomedical subjects

J R Kirsch

Publications and source records attributed to J R Kirsch.

At least 37 records · Page 2Linked to original sources

PubMed1997

Intravenous basic fibroblast growth factor decreases brain injury resulting from focal ischemia in cats.

BACKGROUND AND PURPOSE: We tested the hypothesis that intravenous administration of basic fibroblast growth factor (bFGF) during 4 hours of permanent focal ischemia would affect acute brain injury. METHODS: Halothane-anesthetized cats underwent left middle cerebral artery (MCA) occlusion for 4 hours. Control cats received diluent (n = 14). Experimental cats were treated with bFGF at a rate of 5 (n = 13), 50 (n = 13), or 250 microg/kg per hour (n = 9) intravenously beginning 60 minutes after initiation of ischemia and continuing until the end of the protocol. RESULTS: As measured by the microsphere method, blood flow to ipsilateral caudate nucleus and ipsilateral inferior temporal cortex was decreased similarly during ischemia, before drug administration, in all groups. Likewise, there was no difference in blood flow to ipsilateral caudate nucleus or inferior temporal cortex as a result of bFGF administration during MCA occlusion. Triphenyltetrazolium-determined injury volume of the ipsilateral cerebral cortex (control, 40+/-7%; bFGF 5 microg/kg per hour, 22+/-5%; bFGF 50 microg/kg per hour, 26+/-7%; bFGF 255 microg/kg per hour, 23+/-6% of ipsilateral cerebral cortex; mean+/-SEM) was less in cats treated with bFGF. There was no difference among groups in injury volume to caudate nucleus (control, 29+/-8%; bFGF 5 microg/kg per hour, 29+/-8%; bFGF 50 microg/kg per hour, 21+/-7%; bFGF 250 microg/kg per hour, 32+/-7% of ipsilateral caudate nucleus). Somatosensory evoked potential amplitude decreased similarly (to <20% of baseline amplitude in all groups) during MCA occlusion and was not altered by bFGF administration. CONCLUSIONS; These data indicate that systemic administration of bFGF ameliorates acute injury in the cerebral cortex without increasing blood flow during focal ischemia in cats. Because bFGF afforded protection when administered after the onset of ischemia, bFGF may provide its beneficial effect by limiting progression of injury in ischemic border regions.

Animals↗

PubMed1996

Intensity of halothane- and hypercapnia-induced cerebral hyperemia is strain-dependent in rats.

Cerebrovascular responses to physiologic and pharmacologic stimuli vary between laboratories using different strains of the same species. We tested whether the cerebral blood flow (CBF) response to 1% halothane or hypercapnia is strain-dependent in rats. Age-matched adult male (n = 14 of each strain) Wistar, Wistar-Kyoto (WKY), and spontaneously hypertensive rats (SHR) were anesthetized with pentobarbital and mechanically ventilated. Under baseline conditions blood flow to cerebrum (microspheres) in WKY (66 +/- 5 mL.min-1.100 g-1) was less than (P < 0.05) in Wistar (88 +/- 5 mL.min-1.100g-1) and SHR (83 +/- 5 mL.min-1.100 g-1). Blood flow to brainstem was greater (P < 0.05) in Wistar (106 +/- 8 mL. min-1.100 g-1) than in WKY (71 +/- 5 mL.min-1. 100 g-1) and SHR (84 +/- 4 mL.min-1.100 g-1). In the halothane protocol (n = 8 each strain), administration of 1% halothane, during normocapnia, increased blood flow to the cerebrum in WKY (64 +/- 6 to 120 +/- 12 mL.min-1.100 g-1, P < 0.05) and SHR (78 +/- 6 to 115 +/- 8 mL.min-1.100 g-1, P < 0.05) but not Wistar rats (88 +/- 8 to 102 +/- 5 mL.min-1.100 g-1, not significant). Discontinuing halothane caused blood flow to return to baseline values. In the hypercapnia protocol (n = 6 each strain), exposure to 3% CO2 (to achieve a PaCO2 of 50-55 mm Hg) and 6% CO2 (to achieve a PaCO2 of 60-70 mm Hg) caused blood flow to the cerebrum to increase in Wistar (87 +/- 11 to 112 +/- 15 to 162 +/- 23) to similar amount as observed in WKY (69 +/- 7 to 115 +/- 13 to 162 +/- 23 mL.min-1. 100 g-1) but less than that observed in SHR (89 +/- 7 to 174 +/- 24 to 237 +/- 28 mL.min-1.100 g-1). These data demonstrate that the cerebral hyperemic response to vasodilator stimuli is strain-dependent in rats.

Anesthetics, Inhalation↗

PubMed1996

Enhanced recovery of brain electrical activity by adenosine 3',5'-cyclic monophosphate following complete global cerebral ischemia in dogs.

OBJECTIVE: To test the hypothesis that adenosine 3',5'-cyclic monophosphate (cAMP) or dibutyl-cAMP (a more lipid-soluble, less rapidly metabolized analog of cAMP) would improve recovery of cerebral electrical activity and metabolic function after transient global cerebral ischemia by improving cerebral blood flow during the reperfusion period. DESIGN: Randomized, controlled, prospective study. SETTING: University research laboratory. SUBJECTS: Twenty-five male beagle dogs. INTERVENTIONS: Nine control dogs received saline (20-mL/kg bolus and 0.01 mL/kg/min) intravenously, beginning 25 mins before 12 mins of cerebral global ischemia (by aortic occlusion). The dogs in the experimental groups received either cAMP (40 mg/kg 25 mins before ischemia and 0.2 mg/kg/min throughout reperfusion, n = 7), or dibutyl-cAMP (6 mg/kg 25 mins before ischemia and 3 mg/kg at 60, 90, and 120 mins of reperfusion, n = 9). MEASUREMENTS AND MAIN RESULTS: Total and regional cerebral blood flow, cerebral oxygen consumption, and somatosensory evoked potentials were measured during 180 mins of reperfusion. Pretreatment with dibutyl-cAMP resulted in increased postischemic hyperemia at 30 mins of reperfusion (e.g., whole brain: control 40 +/- 6; cAMP 56 +/- 9; dibutyl-cAMP 67 +/- 10 mL/min/100 g [mean +/- SEM, p < .05 control vs. dibutyl-cAMP group]) but no difference in total cerebral blood flow or oxygen consumption during later points of reperfusion. All groups demonstrated rapid ablation of the amplitude of somatosensory evoked potentials during ischemia, with no difference between the groups. At 180 mins of reperfusion, somatosensory evoked potentials recovered to 28 +/- 4% of the preischemic baseline value in dogs treated with saline, whereas the somatosensory evoked potentials recovered to 58 +/- 4% of preischemic baseline value in the cAMP-pretreated group (p < .05), and to 70 +/- 6% of preischemic baseline value in dogs treated with dibutyl-cAMP (p < .05). CONCLUSIONS: cAMP and dibutyl-cAMP improve recovery of cerebral electrical function after complete transient global cerebral ischemia. Although hyperemia was more prolonged in cAMP- and dibutyl-cAMP-treated dogs, there was no difference between groups in degree of postischemic delayed hypoperfusion. Therefore, we believe that the mechanism for cerebral protection afforded by cAMP and dibutyl-cAMP is not related to cerebral circulatory effects.

Animals↗

PubMed1996

Treatment modalities for hypertensive patients with intracranial pathology: options and risks.

OBJECTIVES: To review the cerebrovascular pathophysiology of hypertension, and the risks and benefits of antihypertensive therapies in the patient with intracranial ischemic or space-occupying pathology. DATA SOURCES: Review of English language scientific and clinical literature, using MEDLINE search. STUDY SELECTION: Pertinent literature is referenced, including clinical and laboratory investigations, to demonstrate principles of pathophysiology and controversies regarding the treatment of hypertension in patients with intracranial ischemic or space-occupying pathology. DATA EXTRACTION: The literature was reviewed to summarize the pathophysiology, risks, and benefits of antihypertensive therapies in the patient with intracranial ischemic or space-occupying pathology. Treatment strategies were outlined with a particular emphasis on how antihypertensive agents may affect the brain. DATA SYNTHESIS: Cerebral autoregulation typically occurs over a range of cerebral perfusion pressures between 50 and 150 mm Hg. Chronic hypertension results in adaptive changes that allow cerebral autoregulation to occur over a high range of pressures. Acute hypertension (rapid increase in perfusion pressure above the autoregulatory limit) may result in cerebral edema, persistent vasodilation, and brain injury. Treatment of a hypertensive emergency must be undertaken conservatively since the chronically hypertensive patient is at risk for ischemic brain injury when perfusion pressure is rapidly decreased beyond autoregulatory limits. In the patient with head injury or primary neurologic injury, acute antihypertensive intervention can result in further brain injury. Selection of appropriate antihypertensive therapy necessitates the careful consideration of agent-specific effects on cerebral blood flow, autoregulation, and intracranial pressure. For example, some vasodilators treat hypertension but also dilate the cerebral vasculature, and increase cerebral blood volume and intracranial pressure while decreasing cerebral perfusion pressure. Pharmacologic blockade of alpha 1- or beta 1-adrenergic receptors can reduce arterial blood pressure with little or no effect on intracranial pressure within the autoregulatory range. Like the direct peripheral vasodilators, calcium-channel antagonists are limited by cerebral vasodilation and increased intracranial pressure. Angiotensin converting enzyme inhibitors can also be used for mild to moderate hypertension but have the potential to further increase intracranial pressure in patients with intracranial hypertension. Barbiturates offer an alternative antihypertensive therapy since they decrease blood pressure as well as cerebral blood flow and oxygen metabolism. CONCLUSIONS: The treatment of acute hypertension in the patient with intracranial ischemic or space-occupying pathology requires an understanding of the pathophysiology of hypertension and determinants of cerebral perfusion pressure. Individual agents should be selected based on their ability to promptly and reliably decrease blood pressure, while considering effects on cerebral blood flow and intracranial pressure.

Acute Disease↗

PubMed1996

Capnography facilitates tight control of ventilation during transport.

OBJECTIVE: We tested the hypothesis that Paco2 would be more tightly controlled if end-tidal CO2 monitoring was used during hand ventilation for transport of intubated patients. DESIGN: Randomized, prospective analysis of the no-monitor and monitor-blind groups (the monitor was on the bed during transport but only the investigator was aware of the end-tidal CO2 values). Nonrandomized, prospective analysis of the monitor group (ventilation controlled using end-tidal CO2 value from monitor). SETTING: University hospital operating room and intensive care unit (ICU). PATIENTS: Fifty intubated patients who were transported from the operating room to the ICU or from the ICU to the neuroradiology suite were assigned randomly to one of two groups: a) no-monitor group (n = 25); and b) monitor-blind group (n = 25). An additional group (monitor group, n = 10) was subsequently added to the study. INTERVENTIONS: Capnography was instituted in all patients in a blocked fashion. MEASUREMENTS AND MAIN RESULTS: Arterial blood gases and end-tidal CO2 values were measured before and after transport. When comparing overall group data, pre- and post-Paco2 values were similar: monitor 39 +/- 2 vs. 41 +/- 2 torr (5.2 +/- 0.3 vs. 5.5 +/- 0.3 no-monitor 39 +/- 1 vs. 37 +/- torr (5.2 +/- 0.1 vs. 5.0 +/- 0.1 kPa). However, when comparing Paco2 values for individual patients, we found that there was significantly greater variability for Paco2 after transport when end-tidal CO2 was not used for control of ventilation during transport. CONCLUSIONS: These data do not support routine monitoring of end-tidal CO2 during short transport times in adult patients requiring mechanical ventilation. However, the monitor may prevent morbidity in patients requiring tight control of Paco2.

Adolescent↗

PubMed1996

Anesthetics and cerebroprotection: experimental aspects.

A number of anesthetic agents have significant cerebroprotective potential and alter ischemic tolerance in vivo, at least within specific experimental conditions such as focal or incomplete, global cerebral ischemia. As compared to the unanesthetized state, each of these agents has some influence on CBF and metabolism, and many have significant effects on vascular responses to dilator stimuli. Relevant studies that provide clues to the mechanisms of anesthetic action in brain injury have been reviewed, and it is likely that these mechanisms are multifactorial and may overlap from one class of agents to another. Lastly, there is a clear need for further studies that specifically evaluate the neuroprotective mechanism of each agent, determine the effect on outcomes when the anesthetic is administered only as a posttreatment at clinically relevant concentrations, and compare anesthetics with the unanesthetized state when possible.

Anesthesia, General↗

PubMed1996

Correlation of the average water diffusion constant with cerebral blood flow and ischemic damage after transient middle cerebral artery occlusion in cats.

Magnetic resonance water diffusion imaging can detect early ischemic changes in stroke. Using a middle cerebral artery occlusion model, we examined which range of values of the orientation-independent diffusion quantity Dav = 1/3Trace(D) = 1/3(Dxx + Dyy + Dzz) is an early noninvasive indicator of reduced cerebral perfusion and focal brain injury. Cats underwent either a 30-min occlusion followed by 3.5 h reperfusion (n = 7) or a 60-min occlusion followed by 4-h reperfusion (n = 6). Repeated measurements of CBF were made with radiolabeled microspheres, and acute focal injury was measured with triphenyltetrazolium chloride (TTC) staining. During occlusion, the decrease in Dav correlated with CBF for caudate [30-min occlusion (n = 13): p < 0.0001: 60-min occlusion (n = 6): p < 0.02] and for cortex [30-min occlusion (n = 12): p < 0.0001: 60-min occlusion (n = 5): p < 0.04]. Variable caudate and hemispheric injury levels were found among cats in both groups. The area of tissue injury demarcated by TTC began to correlate with the area of reduced Dav by 30 min of occlusion (p < 0.02), and this correlation improved (p < 0.0001) at 1, 1.5, and 2.0 h after the onset of occlusion. The time necessary to reach a one-to-one correspondence between the percent of hemisphere injured and the percent of hemispheric area with Dav < 0.65 x 10(-9) m2/s was 2 h after occlusion. Thus, the absolute value of Dav is a good indicator of the risk of tissue injury, whereas the combination of Dav and the length of time of Dav reduction is an excellent predictor of acute focal tissue injury demarcated by TTC staining.

Animals↗

PubMed1996

PPBP [4-phenyl-1-(4-phenylbutyl) piperidine] decreases brain injury after transient focal ischemia in rats.

BACKGROUND AND PURPOSE: We tested the hypothesis that intravenous administration of the potent sigma-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) during transient focal ischemia would decrease postischemic brain infarction volume in rats. METHODS: Rats underwent intravascular focal ischemia for 2 hours followed by 22 hours of reperfusion. Halothane anesthesia was used only during initiation and cessation of ischemia. Rats received saline (n = 10) or 1 mumol/kg per hour PPBP (n = 10) by continuous intravenous infusion starting 1 hour after the initiation of ischemia and continuing through 22 hours of reperfusion. RESULTS: There was no difference between groups in blood pressure, arterial blood gas values, and body temperature. Triphenyltetrazolium-determined infarction volume of ipsilateral cerebral cortex (saline, 39 +/- 6%; PPBP, 21 +/- 7% of ipsilateral hemisphere; mean +/- SEM) and striatum (saline, 68 +/- 6%; PPBP, 33 +/- 8% of ipsilateral striatum) was smaller in rats treated with PPBP than in rats treated with saline. CONCLUSIONS: These data indicate that sigma-receptors may play an important role in the mechanism of injury both in cortex and striatum after 2 hours of transient focal ischemia in rats. Because PPBP afforded protection when administered at the end of ischemia and during reperfusion, sigma-receptors may influence the progression of injury in ischemic border regions.

Animals↗

PubMed1995

Cerebral blood flow during cardiopulmonary bypass: influence of temperature and pH management strategy.

Because disordered autoregulation of cerebral blood flow may underlie neurologic injury associated with cardiopulmonary bypass (CPB), we studied the effects of normothermic (37 degrees C) and hypothermic (18 degrees C) CPB on cerebral vascular reactivity in 6 to 8-week-old piglets. Hypothermic CPB animals were subdivided into alpha-stat and pH-stat groups (n = 6 animals each group) according to acid-base management protocol. Cerebral blood flow (CBF), cerebral oxygen consumption (CMRO2), cerebral vascular resistance (CVR), and CBF response to hypercapnia were examined before, during, and 1 hour after CPB and used to calculate CVR per millimeter of mercury change in arterial partial pressure of CO2: (CVRnormocapnia - CVRhypercapnia)/(PaCO2 hypercapnia - PaCO2 normocapnia). Before CPB, CBF, CMRO2, and vascular reactivity to elevated CO2 were similar in the three groups; these parameters remained unchanged by normothermic CPB. However, during hypothermic CPB, CBF and CMRO2 decreased in both alpha-stat and pH-stat groups; in the alpha-stat group, CBF decreased from 27 +/- 5 mL.min-1.100 g-1 (normothermic CPB) to 5 +/- 1 mL.min-1.100 g-1 (hypothermic CPB) (p < 0.05) and CMRO2 decreased from 1.8 +/- 0.21 to 0.24 +/- 0.04 mL.min-1.100 g-1 (p < 0.05), whereas in the pH-stat group CBF decreased from 28 +/- 2 to 9 +/- 1 mL.min-1. 100 g-1 (p < 0.05) and CMRO2 decreased from 1.63 +/- 0.07 to 0.31 +/- 0.09 mL.min-1.100 g-1 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Tirilazad pretreatment improves early cerebral metabolic and blood flow recovery from hyperglycemic ischemia.

Acidosis may augment cerebral ischemic injury by promoting lipid peroxidation. We tested the hypothesis that when acidosis is augmented by hyperglycemia, pretreatment with the 21-aminosteroid tirilazad mesylate (U74006F), a potent inhibitor of lipid peroxidation in vitro, improves early cerebral metabolic recovery. In a randomized, blinded study, anesthetized dogs received either tirilazad mesylate (1 mg/kg plus 0.2 mg/kg/h; n = 8) or vehicle (n = 8). Hyperglycemia (400-500 mg/dl) was produced prior to 30 min of global incomplete cerebral ischemia. Intracellular pH and high energy phosphates were measured by phosphorus magnetic resonance spectroscopy. During ischemia, microsphere-determined CBF decreased to 8 +/- 4 ml min-1 100 g-1 and intracellular pH decreased to 5.6 +/- 0.2 in both groups. During the first 20 min of reperfusion, ATP partially recovered in the vehicle group to 57 +/- 21% of baseline, but then declined progressively in association with elevated intracranial pressure. By 30 min, ATP recovery was greater in the tirilazad group (77 +/- 35 vs. 36 +/- 19%), although postischemic hyperemia was similar. By 45 min, the tirilazad group had a higher intracellular pH (6.5 +/- 0.5 vs. 5.9 +/- 0.6) and a lower intracranial pressure (18 +/- 6 vs. 52 +/- 24 mm Hg). By 180 min, blood flow and ATP were undetectable in seven of eight vehicle-treated dogs, whereas ATP was > 67% and pH was > 6.7 in six of eight tirilazad-treated dogs. Thus, tirilazad acts during early reperfusion to prevent secondary metabolic decay associated with severe acidotic ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗

PubMed1995

Postischemic cerebral blood flow recovery in the female: effect of 17 beta-estradiol.

Female reproductive hormones are considered to be protective agents in atherosclerotic vascular disease and stroke. The present study determined if there are unique cerebrovascular responses in female animals to global cerebral ischemia and if 17 beta-estradiol is important to postischemic outcome in brain. Three groups of anesthetized, sexually mature rabbits were treated with normotensive four-vessel occlusion (6 min) and 3 h of reperfusion: females chronically instrumented with 17 beta-estradiol implants (EFEM; n = 8, plasma estradiol level = 365 +/- 48 pg/ml), untreated females (FEM; n = 8, estradiol = 13 +/- 3 pg/ml), and untreated males (M; n = 8, estradiol < limit of radioimmunoassay). CBF (microspheres) and somatosensory evoked potential (SEP) amplitude were measured during ischemia/reperfusion. Baseline hemispheric blood flow and regional flow distribution were not altered by chronic estradiol treatment. Hemispheric blood flow was equivalently reduced during ischemia in FEM and M (6 +/- 1 and 9 +/- 2 ml min-1 100 g-1, respectively); however postischemic hyperemia was greater in FEM than M (CBF = 257 +/- 27 and 183 +/- 27 ml min-1 100 g-1. However, EFEM experienced higher CBF during ischemia (e.g., 13 +/- 2 ml min-1 100 g-1) and less hyperemia (134 +/- 4 ml min-1 100 g-1 in hemispheres) in numerous brain regions than FEM. CBF at 3 h reperfusion was not different among the groups. Recovery of SEPs was incomplete and similar in all groups. We conclude that chronic exogenous 17 beta-estradiol treatment increases CBF during global incomplete ischemia and ameliorates postischemic hyperemia in the female animal.

Animals↗

PubMed1995

Effect of nitric oxide synthase inhibition on postischemic cerebral hyperemia.

We tested the hypothesis that inhibition of nitric oxide synthase (NOS) activity in brain before ischemia decreases postischemic hyperemia. Pentobarbital-anesthetized piglets underwent 15 min of complete global cerebral ischemia induced by elevation of intracranial pressure followed by 20 min of reperfusion. Before ischemia the animals were randomly assigned to receive either intravenous N omega-nitro-L-arginine methyl ester (L-NAME 10 mg/kg, n = 6, or 50 mg/kg, n = 6) or an equal volume of saline (10 ml, n = 8). Serial cerebral blood flow (radiolabeled microspheres) was measured at baseline and during ischemia and reperfusion. Forebrain postischemic hyperemia was documented after administration of saline (42 +/- 4 to 88 +/- 10 ml.min-1.100 g-1) and 10 mg/kg L-NAME (36 +/- 4 to 59 +/- 9 ml.min-1.100 g-1) but not after 50 mg/kg L-NAME (29 +/- 3 to 34 +/- 7 ml.min-1.100 g-1). However, the percent reduction in cerebral vascular resistance (CVR) fell during reperfusion to a similar extent in all three groups because of differences between groups in cerebral perfusion pressure changes during the protocol. CVR fell to the lowest level at 8 min of reperfusion in the saline-treated animals (2.0 +/- 0.16 to 0.68 +/- 0.05 mmHg.ml-1.min.100 g) compared with the L-NAME-treated animals (50 mg/kg: 4.0 +/- 0.3 to 1.8 +/- 0.2 mmHg.ml-1.min.100 g).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗

PubMed1995

Time-dependent inhibition of oxotremorine-induced cerebral hyperemia by N omega-nitro-L-arginine in cats.

BACKGROUND AND PURPOSE: Oxotremorine (OXO) is a cholinergic agonist that increases cerebral blood flow (CBF) when administered intravenously. We tested the hypothesis that OXO causes a dose-related increase in CBF in cats via a muscarinic mechanism that involves stimulation of nitric oxide synthase. METHODS: Halothane-anesthetized male cats were studied under controlled ventilation. In three groups we measured cerebral blood flow (CBF; microspheres) during 30 minutes of intravenous OXO infusion at doses of 0.5 (n = 3), 5 (n = 6), or 50 micrograms.kg-1.min-1 (n = 6). The role of muscarinic receptor activation in the CBF response to OXO (50 micrograms.kg-1.min-1) was assessed by determining the effect of atropine sulfate (2 mg.kg-1, n = 6) pretreatment in a separate group of cats. The role of nitric oxide synthase was assessed by determining the CBF response to OXO (50 micrograms.kg-1.min-1) either 30 (n = 6) or 60 minutes (n = 5) after administration of 50 mg/kg N omega-nitro-L-arginine (LNA). RESULTS: CBF to forebrain (pre-OXO, 144 +/- 12 mL.min-1.100 g-1) was unchanged with OXO 0.5 or 5 micrograms.kg-1.min-1 but increased at 10 (209 +/- 26 mL.min-1 x 100 g-1) and 30 minutes (243 +/- 35 mL.min-1 x 100 g-1) of OXO infusion at 50 micrograms.kg-1.min-1 (P < .05). Atropine sulfate prevented OXO-induced hyperemia at 10 minutes of infusion but not at 30 minutes of infusion (135 +/- 12% of pre-OXO). LNA decreased baseline CBF by approximately 50%. Treatment with LNA 30 minutes before OXO did not affect the extent of OXO-induced hyperemia (CBF, 142 +/- 15% of pre-OXO at 10 minutes and 153 +/- 18% of pre-OXO at 30 minutes of OXO infusion). Treatment with LNA 60 minutes before OXO ablated OXO-induced hyperemia. CONCLUSIONS: In halothane-anesthetized cats, OXO (50 micrograms.kg-1.min-1) increases forebrain CBF by a muscarinic mechanism that involves stimulation of nitric oxide synthase. The ability of nitric oxide synthase inhibitors to block agonist-induced nitric oxide-mediated vasodilation (response to OXO) is time dependent and may not be predicted by ability of the inhibitor to significantly decrease basal CBF.

Animals↗

PubMed1995

Effect of nitric oxide synthase inhibition on the cerebral vascular response to hypercapnia in primates.

BACKGROUND AND PURPOSE: The role of nitric oxide in cerebrovascular response to changes in PCO2 is unclear. In the present study, we assessed responses at two levels of hypercapnia in a primate model before and after blockade of nitric oxide synthesis. METHODS: We compared the effects of two levels of hypercapnia, defined as PCO2 of approximately 70 mm Hg (high-CO2 group, n = 5) and PCO2 of approximately 50 mm Hg (moderate-CO2 group, n = 6), on increases in regional cerebral blood flow (microspheres) before and after inhibition of nitric oxide synthase with N omega-nitro-L-arginine methyl ester (L-NAME; 60 mg.kg-1) in isoflurane-anesthetized cynomolgus monkeys (1.0% end-tidal concentration). RESULTS: Before L-NAME administration, hypercapnia increased flow in all regions (eg, forebrain, high-CO2 group 69 +/- 10 to 166 +/- 15 mL.min-1.100 g-1; moderate-CO2 group, 49 +/- 7 to 93 +/- 15 mL.min-1.100 g-1) and decreased cerebral vascular resistance (high-CO2, 1.1 +/- 0.1 to 0.4 +/- 0.1 mm Hg.mL-1.min.100 g; moderate-CO2, 1.4 +/- 0.1 to 0.7 +/- 0.1 mm Hg.mL-1.min.100 g). During normocapnia, L-NAME decreased cerebral blood flow (high-CO2, 37 +/- 9%; moderate-CO2, 40 +/- 6%) and increased cerebral vascular resistance (high-CO2, 93 +/- 33%; moderate-CO2, 88 +/- 20%). After L-NAME, hypercapnia still increased blood flow in all regions (eg, forebrain: high-CO2, 56 +/- 7 to 128 +/- 3 mL.min-1.100 g-1, moderate-CO2, 36 +/- 5 to 57 +/- 8 mL.min-1.100 g-1) and decreased vascular resistance (high-CO2, 1.5 +/- 0.1 to 0.6 +/- 0.1 mm Hg.mL-1.min.100 g; moderate-CO2, 2.0 +/- 0.3 to 1.2 +/- 0.1 mm Hg.mL-1.min.100 g). In both groups L-NAME attenuated hypercapnia hyperemia by approximately 30% in cortex but not in other regions. CONCLUSIONS: Nitric oxide contributes to basal vascular tone but is not a major contributor to the mechanism of hypercapnia-induced cerebral vasodilation, except in cortex, in primates.

Amino Acid Oxidoreductases↗

PubMed1995

Cerebral blood flow during inhibition of brain nitric oxide synthase activity in normal, hypertensive, and stroke-prone rats.

BACKGROUND AND PURPOSE: Because tonic production of nitric oxide (NO) is important in regulating cerebrovascular tone and NO may be important in the mechanism of brain injury from focal ischemia, we speculated that stroke predisposition in spontaneously hypertensive stroke-prone rats (SHR-SP) may be related to impaired tonic production of NO. This study was designed to test the hypothesis that the cerebral blood flow (CBF) response to inhibition of NO synthase in SHR-SP would be different than that observed in normal Wistar-Kyoto (WKY) rats and non-stroke-prone spontaneously hypertensive rats (SHR). METHODS: Pentobarbital-anesthetized, mechanically ventilated rats were tested for CBF response to saline, 5 or 20 mg/kg IV of NG-monomethyl-L-arginine (L-NMMA), or 20 mg/kg IV of N omega-nitro-L-arginine (L-NA). In addition, specificity for an NO-dependent mechanism was assessed by determining the ability to reverse any alteration in CBF with L-arginine. Hemorrhage was used to minimize any increase in mean arterial blood pressure (MABP) from NO synthase inhibition. In a separate cohort of rats, differential sensitivity of NO synthase for inhibition by nitro-arginine analogues was determined. RESULTS: Baseline MABP was greater in SHR-SP (185 +/- 3, n = 38) and SHR (169 +/- 3, n = 38) compared with WKY rats (101 +/- 2 mm Hg, n = 38, P < .05). Baseline CBF was similar between strains; however, cerebrovascular resistance was higher in SHR-SP (2.16 +/- 0.09, n = 27) and SHR (1.94 +/- 0.07, n = 27) compared with WKY rats (1.23 +/- 0.06 mm Hg/mL per minute per 100 g, n = 27, P < .05). CBF was unchanged with 5 mg/kg L-NMMA or with L-arginine in the absence of L-NMMA in each strain. CBF decreased similarly in SHR and SHR-SP (n = 9 each) in response to 20 mg/kg L-NMMA (SHR, 85 +/- 6 to 67 +/- 6; SHR-SP, 87 +/- 7 to 69 +/- 5 mL/min per 100 g) and was completely reversed by L-arginine. CBF did not decrease with 20 mg/kg L-NMMA in WKY rats. Administration of L-NA (n = 5 each) produced similar reduction of CBF (WKY rats, 67 +/- 6%; SHR, 49 +/- 9%; SHR-SP, 61 +/- 6% of baseline) and inhibition of NO synthase in each strain (approximately 80% inhibition). CONCLUSIONS: There was no difference in the cerebrovascular response to NO synthase inhibition in SHR-SP and non-stroke-prone SHR. Therefore, it is unlikely that an altered sensitivity of NO synthase to inhibition can explain predisposition to stroke in SHR-SP.

Amino Acid Oxidoreductases↗

PubMed1995

PPBP [4-phenyl-1-(4-phenylbutyl) piperidine], a potent sigma-receptor ligand, decreases brain injury after transient focal ischemia in cats.

BACKGROUND AND PURPOSE: We tested the hypothesis that administration of 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP), a potent sigma-receptor ligand, during transient focal ischemia would affect early postischemic brain injury. METHODS: Halothane-anesthetized cats underwent left middle cerebral artery occlusion for 90 minutes followed by 4 hours of reperfusion. Control cats received saline (n = 10). Experimental cats (2 groups, n = 10 per group) were treated with PPBP at a rate of 0.1 mumol/kg per hour (PPBP-0.1) or administered 1 mumol/kg per hour (PPBP-1) intravenously from 75 minutes after initiation of ischemia and continuing during the 4 hours of reperfusion. RESULTS: As measured by the microsphere method, blood flow to the ipsilateral caudate nucleus was decreased similarly in all groups during ischemia. Blood flow to the ipsilateral inferior temporal cortex was decreased during ischemia in all groups but was higher in cats subsequently treated with PPBP at the highest dose, even before drug administration. There was no difference in blood flow to the ipsilateral caudate nucleus or inferior temporal cortex (area of greatest cortical injury) during reperfusion. Triphenyltetrazolium-determined injury volume of the ipsilateral cerebral hemisphere (control, 29 +/- 5%; PPBP-0.1, 17 +/- 3%; PPBP-1, 6 +/- 1% of ipsilateral hemisphere; mean +/- SEM) and caudate nucleus (control, 49 +/- 5%; PPBP-0.1, 39 +/- 6%; PPBP-1, 25 +/- 5% of ipsilateral caudate nucleus) was less in cats treated with 1 mumol/kg per hour of PPBP compared with cats treated with saline. Cats treated with 0.1 mumol/kg per hour had a 45% smaller hemispheric injury volume than the control group without differences in intraischemic blood flow. Recovery of somatosensory evoked potential amplitude was greater in cats treated with PPBP-1 compared with control (control, 18 +/- 11%; PPBP-0.1, 30 +/- 14%; PPBP-1, 54 +/- 14% of baseline). CONCLUSIONS: These data indicate that sigma-receptors may play an important role in the mechanism of acute injury in both the cortex and the caudate nucleus after 90 minutes of transient focal ischemia in the cat. Because PPBP afforded protection when administered at the end of ischemia and during reperfusion, sigma-receptors may contribute to the progression of injury in ischemic border regions.

Animals↗

PubMed1994

Reduced cerebral blood flow but intact reactivity to hypercarbia and hypoxia following subarachnoid hemorrhage in rabbits.

Subarachnoid hemorrhage (SAH) was produced in rabbits by four subarachnoid injections of blood (n = 7) or saline (n = 6); a control group (n = 6) had no injections. Basilar artery vasospasm was assessed by serial angiograms. Resting CBF (microspheres) and CBF reactivity to hypercapnia (65 and 85 mm Hg) and hypoxia (fractions of inspired oxygen of 0.15 and 0.10) were determined. Basilar artery vasospasm was seen with SAH. Resting CBF was reduced by 31% (SAH 43 +/- 12, saline 65 +/- 17, control 60 +/- 21 ml 100 g-1 min-1), and resting cerebrovascular resistance was increased (SAH 1.84 +/- 0.30, saline 1.31 +/- 0.49, control 1.39 +/- 0.25 mm Hg ml-1 100 g-1 min-1) after SAH. CBF rose to a similar degree in all three groups in response to hypercarbia and hypoxia. We conclude that resting CBF is reduced in this model of SAH, but vascular reactivity remains intact.

Animals↗

PubMed1994

Cerebral blood flow in primates is increased by isoflurane over time and is decreased by nitric oxide synthase inhibition.

BACKGROUND: Cerebral blood flow (CBF) decreases over time in dogs and goats during volatile anesthesia. In the current study, we determined CBF during administration of isoflurane for 4 h in cynomolgus monkeys. In addition, we determined if nitric oxide (NO) contributes to cerebrovascular tone during isoflurane anesthesia by determining the CBF (microsphere) response to inhibition of NO synthase with N omega-nitro-L-arginine methyl ester (L-NAME). METHODS: CBF was measured in five monkeys anesthetized with isoflurane (1.0% end-tidal). After 4 h of isoflurane (1.0% = 1 MAC), the effects of intravenous L-NAME (60 mg/kg over 10 min) followed by intravenous L-arginine (600 mg/kg over 10 min) on CBF were measured at constant cerebral perfusion pressure and arterial carbon dioxide tension. RESULTS: CBF was unchanged over time (4 h) in cerebellum but increased by 50 +/- 18% in both forebrain and hindbrain (P < 0.05). CBF decreased by 41-48% (P < 0.05) 20 min after L-NAME in forebrain, cerebellum, and hindbrain, at which time brain NO synthase activity was less than 10% of baseline. Twenty minutes after L-arginine, CBF was increased in cerebellum by 32 +/- 8% and in forebrain by 41 +/- 9% (P < 0.05). The cerebral metabolic rate of oxygen consumption was unaffected by time or by L-NAME or L-arginine. CONCLUSIONS: These data demonstrate that CBF increases over time during isoflurane anesthesia in primates. Tonic production of NO contributes to control of CBF in primates during isoflurane anesthesia. Increased CBF by L-arginine after L-NAME supports the hypothesis that L-NAME decreases CBF via a mechanism requiring NO synthesis.

Amino Acid Oxidoreductases↗