Preservation of autoregulatory cerebral vasodilator responses to hypotension after inhibition of nitric oxide synthesis

Effects of inhibition of nitric oxide (NO) synthesis on the cerebrovascular autoregulatory vasodilator response to hypotension were studied in conscious rats. Cerebral blood flow (CBF) was determined with [¹⁴C]iodoantipyrine in a saline-treated control group and in three groups following inhibition of NO synthase activity by twice daily intraperitoneal injections of 50 mg/kg ofN^G-nitro-l-arginine methyl ester (l-NAME) for four days. In the saline-control group (n = 8) and in thel-NAME-treated Group (a) (n = 8) CBF was determined while systemic mean arterial blood pressure (MABP) remained at its resting level (means ± S.D., 128±6 and 151±11 mmHg, respectively). In the other groups CBF was determined after MABP was reduced by blood withdrawal to 118±9 and 88±8 mmHg in Groups (b) (n = 8) and (c) (n = 8), respectively. Despite the elevated MABP, global CBF was significantly lower inl-NAME-treated Group (a) than in the saline-controls (P < 0.005), indicating cerebral vasoconstriction striction resulting from inhibition of NO synthesis. Global CBF was not significantly reduced further in the two groups with hypotension. Local CBF in the hypotensive rats showed no significant reductions below values inl-NAME-treated control rats (Group (a)) in 31 of 32 brain structures; the only exception was in the auditory cortex of the severely hypotensive rats (Group (c)). The autoregulatory mechanism for cerebral vasodilatation to compensate for reduced arterial blood pressure is maintained following inhibition of NO synthesis.     

Transient cerebral vasodilatory effect of neuropeptide y mediated by nitric oxide

The effects of intracarotidly injected neuropeptide Y (NPY; 0.1 μg/kg) on the local cerebral blood volume (CBV) and blood flow (CBF) in the parieto-temporal cortex were examined by the photoelectric method in 17 anesthetized cats. CBV reflects the cumulative crosssectional area of the cerebral microvascular beds. NPY immediately caused transient but significant increases in CBV and CBF, which lasted for less than 5 min. Thereafter, CBV returned to and remained at the control level, although CBF was decreased by 30–40% for 60 min during the monitoring period. The CBV increases after NPY were prevented by a 15-min preinjection of 0.35 mg/kg/min of N^g-monomethyl-L-arginine (L-NMMA), which is a competitive blocker of nitric oxide synthesis. The CBV increases after NPY reappeared following a 15-min administration of 0.25 mg/kg/min of L-arginine, which is a precursor of nitric oxide. We conclude that NPY administered in vivo exerts a previously unreported effect of transient vasodilatation on the cerebral microvessels. This action appears to be mediated by nitric oxide, which is a major candidate as an endothelium-derived relaxing factor (EDRF).     

The role of nitric oxide in the regulation of cerebral blood flow

The role of nitric oxide in the cerebral circulation under basal conditions and when exposed to hypoxic, hypercapnic and hypotensive stimuli, was studied in mechanically ventilated rats using a venous outflow technique, by examining the effects of inhibition of nitric oxide synthase with N-nitro-l-arginine methyl ester (l-NAME).l-NAME (10 or 30 mg/kg injected intravenously) raised mean arterial blood pressure by 14% and 24%, and increased cerebrovascular resistance (CVR) by 20% and 24%, respectively. Cerebral blood flow (CBF) was unaltered, as were blood gases and pH. The increases in MABP and CVR were attenuated byl-arginine (300 mg/kg). Following the administration ofl-NAME, the increases in CBF elicited by ventilation with 8% oxygen for 25 s were unaltered, in comparison to control responses.l-NAME attenuated the increases in CBF and reduced the time for recovery to basal flow rates evoked by ventilation with 10% carbon dioxide. These effects were reversed byl-, but not byd-, arginine. Autoregulation by CBF during hypotensive episodes, as measured by comparisons of CVR values, was unaffected byl-NAME. The results suggest that endogenous nitric oxide is involved in the responses of the cerebral vasculature to elevated levels of CO₂ in the arterial blood. Nitric oxide does not appear to play a major role in autoregulation to increases or decreases in MABP, or in hypoxia-evoked vasodilation.     

Effect of nimodipine on the autoregulation of cerebral blood flow studied by laser-Doppler flowmetry

The present work examines whether nimodipine impairs autoregulation of CBF during hypotension. The CBF of 16 anesthetized rabbits was measured with a laser-Doppler flowmetry probe placed on the external surface of a plexiglas window, chronically inserted in the skull. Autoregulation was triggered by aortic bleeding. First, the effects of three doses of nimodipine (1, 3 and 10 μg/kg) and the solvent were studied in 10 rabbits in which MABP was maintained at 50 mmHg for one minute. Second, 10 μg/kg i.v. nimodipine was administered to 6 rabbits in which MABP was kept at 30 mmHg for one minute. Before bleeding, the 10 μg/kg dose significantly decreased MABP (from 96 ± 11mmHg to 81 ± 11mmHg, P < 0.01) and increased CBF (from 104 ± 20%to147 ± 25%, P < 0.01) as compared to the solvent. In the first set of experiments, only the 10 μg/kg dose suppressed the autoregulatory vasodilation, but CBF was not different from control (84 ± 17%versus87 ± 12%), probably because of the previous induced vasodilation. In the second set of experiments, active vasodilation occurred and the CBF during hypotension was not different from control (72 ± 26%versus65 ± 11%). We conclude that under nimodipine the triggering of the active autoregulatory vasodilation is dependent on both the severity of hypotension and the previous nimodipine-induced vasodilation.     

Endorphinergic mechanisms in cerebral blood flow autoregulation

The influence of naturally occurring opioid peptides (Met-enkephalin (Met-Enk), dynorphin (DYN), β-endorphin (β-EP)) as well as morphine and the opiate antagonist naloxone and specific antisera on cerebral blood flow autoregulation was studied in anesthetized, artificially ventillated rats. Local hypothalamic blood flow (CBF, H₂-gas clearance technique) and total cerebral blood volume (CBV, photoelectric method) were simultaneously recorded. Autoregulation was tested by determining CBF and CBV during consecutive stepwise lowering of the systemic mean arterial pressure to 80, 60 and 40 mm Hg, by hemorrhage. Resting CBF decreased following Met-Enk, DYN, β-EP or morphine administration without simultaneous changes in CBV. Naloxone administration, on the contrary, increased CBV without affecting local CBF. Autoregulation of cerebral blood flow was maintained until 80 mm Hg, but not completely at 60 and 40 mm Hg arterial pressure in the control group. General opiate receptor blockade by 1 mg/kg s.c. naloxone abolished autoregulation at all levels, since CBF and CBV passively followed the arterial pressure changes. Intracerebroventricularly injected naloxone (1 μg/kg) as well as a specific antiserum against β-EP, but not against Met-Enk or DYN, resulted in the very same effect as peripherally injected naloxone. The present findings suggest that central, periventricular β-endorphinergic mechanisms might play a major role in CBF autoregulation.     

Prognostic value of cerebral blood flow autoregulation in the long-term prognosis of ischemic cerebrovascular disease

The correlation between long-term prognosis, cerebral blood flow (CBF) and CBF autoregulation was studied in 34 patients with cerebral infarction (mean age, 64 years). CBF was measured by the nitrous oxide method 1–6 months (mean 87 days) after disease onset. CBF autoregulation was evaluated quantitatively from the Dysautoregulation Index (DI) (ΔCBF/Δeffective MABP). Reductions in effective MABP were induced with a tilt table. No significant correlation was noted among CBF, DI and activities of daily living at the time of measurement. The patients' physical condition was reevaluated by questionnaire 2 years or more (mean 32 months) later. Better functional state at follow-up was related to higher CBF and lower DI values although the differences were not significant. The relationships among CBF, DI and changes in physical condition during the period were evaluated. The mean CBF values in patients with a better prognosis exceeded those of poor prognosis patients. The CBF values in the group who became independent significantly exceeded those in the group that deteriorated (P < 0.05). The CBF values in the latter showed small but significant decreases during head-up tilting (P < 0.05). The DI in this group was significantly higher than in the groups with a less severe outcome (P < 0.01, P < 0.05, respectively).In conclusion, determinations of CBF autoregulation, together with flow values, in the chronic state may have some value in predicting the long-term prognosis in cerebral infarction.     

Adrenergic reactivity after inhibition of nitric oxide synthesis in the cerebral circulation of awake goats

The interaction between nitric oxide (NO) and adrenergic reactivity in the cerebral circulation was studied using in vivo and in vitro preparations. Blood flow to one brain hemisphere (cerebral blood flow) was electromagnetically measured in conscious goats, and the effects of norepinephrine, tyramine and cervical sympathetic nerve stimulation were recorded before (control) and after inhibition of NO formation with N^w-nitro- -arginine methyl ester ( -NAME). The responses to norepinephrine, tyramine and electrical field stimulation were also recorded in segments, 4 mm in length, from the goat's middle cerebral artery under control conditions and after -NAME. In vivo, -NAME (10 goats, 47 mg kg⁻¹ administered i.v.) reduced resting cerebral blood flow by 37±2%, increased mean systemic arterial pressure by 24±3%, reduced heart rate by 35±2%, and decreased cerebrovascular conductance by 52±2% (all P<0.01). Norepinephrine (0.3–9 μg), tyramine (50–500 μg), and supramaximal electrical sympathetic cervical nerve stimulation (1.5–6 Hz) decreased cerebrovascular conductance, and these decreases were significantly higher after -NAME than under control conditions, remaining higher for about 48 h after this treatment. Norepinephrine (10⁻⁸–10⁻³ M), tyramine (10⁻⁶–10⁻³ M) and electrical field stimulation (1.5–6 Hz) contracted isolated cerebral arteries, and the maximal contraction, but not the sensitivity, was significantly higher in the arteries treated than in non-treated with -NAME (10⁻⁴ M). Therefore, the reactivity of cerebral vasculature to exogenous and endogenous norepinephrine may be increased after inhibition of NO synthesis. This increase might be related, at least in part, to changes at postjunctional level in the adrenergic innervation of the vessel wall, and it might contribute to the observed decreases in resting cerebral blood flow after inhibition of NO synthesis.     

Cerebral extracellular lactate concentration and blood flow during chemical stimulation of the nucleus tractus solitarii in anesthetized rats

The extracellular lactate concentration and blood flow in the cerebral cortex of urethane-anesthetized, paralyzed and artificially ventilated rats were monitored continuously and simultaneously using an enzyme electrode and a laser Doppler flowmeter (LDF), respectively, during chemical stimulation of the nucleus tractus solitarii (NTS) by microinjection of -glutamate (1.7 nmol 50 nl). Chemical stimulation of the NTS significantly decreased the arterial blood pressure (ABP) from 85 ± 17 to 68 ± 14 mmHg, heart rate from 418 ± 13 to 402 ± 19 beats · min⁻¹ and cerebral blood flow (CBF) by 17.9 ± 6.2% (P < 0.001). However, chemical stimulation of the NTS significantly increased the lactate concentration by 58.9 ± 17.3 μM (P < 0.001). Barostat maneuver, which held systemic ABP constant during chemical stimulation of the NTS attenuated the responses in CBF and lactate concentration by 30 and 27%, respectively. The onset of the increase in lactate concentration was delayed about 19 s after that of the CBF decrease. Circulatory lactate produced no significant change in the cerebral extracellular lactate concentration. These results indicate that chemical stimulation of the NTS induces an increase in extracellular lactate concentration in the cerebral cortex through a decrease in CBF via cerebral vasoconstriction.     

Cyclical fluctuations in blood pressure, heart rate and cerebral blood volume in preterm infants

Many recently published papers describe cyclical changes of cerebral circulatory variables, mainly in cerebral blood flow velocity (CBFV) performed with Doppler sonography. In this paper we focus on another important variable of cerebral circulation: on cerebral blood volume (CBV) measured by near infrared spectrophotometry (NIRS). In a retrospective analysis of NIRS measurements in 20 preterm infants (median 27 3/7 weeks of gestation), the dominating frequencies and prevalence of cyclical changes of CBV and its possible correlation with peripheral circulatory variables (mean arterial pressure and heart rate) was examined. In 19 out of the 20 infants cyclical changes of CBV were found within a frequency range of 2–4.7 cycles/min which is comparable to the results of the Doppler studies describing fluctuations in CBFV. A dominating frequency of heart rate (HR), was found only in 12 out of 20 infants, and it was with 2.1–3.8 cycles/min in a similar range compared to CBV. In mean arterial blood pressure (MABP), however we detected cycles with longer periods every 1–2.5 min in 14 out of 20 infants. There was a significant coherence between MABP/CBV and HR/CBV. The area under the coherence curve, however, was significantly larger between MABP and CBV as compared to HR and CBV (P=0.0007, Wilcoxon signed-rank test).     

Regional cerebral blood flow in man at rest and during exercise

Summary Regional cerebral blood flow (rCBF) of the left hemisphere was measured in 12 healthy young men at rest and during physical work on a bicycle ergometer in the supine position at work-load levels of 25 W or 100 W using the intravenous ¹³³Xe method. Regional mean cerebral blood flow, regional gray-matter flow, and relative gray-matter weight was determined for six regions of interest. Arterial blood pressure, pulse frequency and expiratory CO₂ concentration were recorded. Cerebral blood flow in all regions was significantly (P<0.001) higher during exercise than at rest. The increase in the 100 W group (24.7%) was significantly (P<0.05) greater than in the 25 W group (13.5%), but resting blood flow levels and alveolar CO₂ concentrations were also different in both groups. Mean arterial blood pressure, pulse frequency and alveolar CO₂ concentrations, but not arterial pCO₂, were significantly higher during exercise and there was a faster washout of whole-body xenon. The CBF increase was interpreted as a combined effect of elevated systemic blood pressure and functionally activated brain metabolism. There was no evidence of impaired cerebral autoregulation.     

Cerebral blood flow regulation in neonatal rabbits is altered by chronic cocaine administration

Maternal cocaine abuse has several deleterious effects in the newborn, including perinatal asphyxia, hypoxia, and hypercapnia. We hypothesized that chronic cocaine exposure during development may alter cerebral blood flow (CBF) regulation. We studied 16 neonatal rabbits that had received cocaine (20 mg/kg, i.p. b.i.d.) or saline since birth. Changes in CBF were measured by laser doppler flowmetry before (baseline), and during hypercapnia (FiCO₂=7.5%), hypoxia (FiO₂=12%), and asphyxia (apnea for 1 min). During hypercapnia, CBF increased less in cocaine than in control animals (28±3% vs. 69±10%, P<0.05). During hypoxia, CBF increased similarly in both groups. During reventilation after asphyxia, CBF increased more in cocaine than in control animals (391±52% vs. 225±43%, P<0.05). Chronic cocaine exposure during brain development appears to alter CBF regulation to hypercapnia and asphyxia, which may put the drug exposed newborn at risk for neurologic injury around birth.     

脑血流自动调节范围内维持脑血流恒定的因素

目的探讨脑血流自动调节范围内稳定脑血流速度的血流动力学因素。方法利用经颅多普勒检测SD大鼠大脑中动脉的血流速度(cerebral blood flow velocity,CBFV),并同步记录有创动脉血压,绘制自动调节曲线,判断脑血流自动调节上、下限。计算临界关闭压(critical closing pressure,CCP)和血管面积阻力指数(resistance area product,RAP)。分析CCP、RAP与平均动脉压(mean artery blood pressure,MABP)之间的关系。结果动脉血压升高或降低过程中,正常大鼠脑血流自动调节上、下限分别为148.12±7.49 mm Hg、62.96±3.34 mm Hg。脑血流自动调节范围内,CBFV随动脉血压改变轻微(每10 mm Hg MABP,升压:0.65±0.27 cm/s;降压:0.43±0.23 cm/s),而CCP和RAP则随动脉血压明显改变(每10 mm Hg MABP,升压:4.60±1.06 mm Hg、0.11±0.04mm Hg;降压:6.74±0.59 mm Hg、0.09±0.02 mm Hg)。虽然CBFV、CCP、RAP的变化都与MABP相关,但控制CBFV的变动后,CCP和RAP随MABP改变相关性更加明显,其中CCP的变化幅度以及与MABP的相关性明显大于RAP(升压:Beta=0.561、0.418;降压:Beta=0.694、0.266,P均=0.000)。结论大鼠脑血流自动调节有效范围内,脑血流的稳定主要通过CCP和RAP改变对抗动脉血压的变动而实现,尤其是CCP相应升高或降低。     

Brain blood flow during hypercapnia in fish: no role of nitric oxide

Very little is known about the regulation of cerebral blood flow (CBF) in lower vertebrates, especially fish. In mammals, hypercapnia causes cerebral vasodilation and increased CBF through mechanisms that involve the production of nitric oxide (NO). We have used epi-illumination microscopy in vivo to observe effects of hypercapnia on venular erythrocyte velocity, used as an index of CBF velocity, in rainbow trout (Oncorhynchus mykiss) and crucian carp (Carassius carassius). Rainbow trout exposed to a pCO₂ of 7.5 mmHg displayed a small increase of CBF velocity in two out of five fishes, while dorsal aortic blood pressure (P_DA) did not change. Exposing trout to a pCO₂ of 22.5 mmHg, resulted in an 80% increase in CBF velocity and a 21% increase in P_DA. Trout exposed to a pCO₂ of 75 mmHg showed an additional increase in blood pressure, while no further increase was seen in CBF velocity compared to a pCO₂ of 22.5 mmHg. By contrast, no change in CBF velocity was seen in crucian carp, even at a pCO₂ of 75 mmHg. None of the circulatory changes seen in the trout could be blocked by superfusing the brain surface with the NO synthase blocker N^G-nitro- -arginine. The results point at striking species differences in the responses of CBF and P_DA to hypercapnia in fish, and that the hypercapnia induced increase in CBF velocity seen in rainbow trout is independent of NO production.     

Local hemodynamic changes during transient middle cerebral artery occlusion and recirculation in the rat: a [C]iodoantipyrine autoradiographic study

We evaluated acute alterations of local cerebral perfusion following 30 min of transient right proximal middle cerebral artery (MCA) clip-occlusion in the rat and following two intervals of postischemic reperfusion. Local cerebral blood flow (1CBF) was assessed by [¹⁴C]iodoantipyrine autoradiography. Brain temperature was controlled at 35.5–36.5°C throughout the experiment. We measured ICBF in four groups of rats: (a) sham-operated controls (n = 5), (b), following 30 min MCA occlusion (n = 5), (c) following 30 min of MCA occlusion with 15-min reperfusion (n = 6) and (d) following 30 min of MCA with 120-min reperfusion (n = 6). 1CBF was measured in seven regions of the ischemic and non-ischemic hemispheres. MCA occlusion induced an ipsilateral reduction of 1CBF, which was most severe in the parietal cortex (8.4 ± 4.0% of control, mean ± S.D.), and dorsolateral caudoputamen (20.0 ± 13.4% of control). 1CBF in the non-ischemic hemisphere and in ipsilateral regions lying outside the MCA territory also decreased significantly. 1CBF recovery was incomplete when assessed following only 15 min of reperfusion. Reperfusion of 120 min led to return of cortical CBF to control levels, but 1CBF in the caudoputamen remained depressed (50–55% of control values). Caudoputaminal CBF and cortical CBF values were highly correlated with one another under normal and ischemic conditions, but this correlation was disrupted following reperfusion. On the basis of these results, we speculate that, if a means were found to enhance the early recovery of 1CBF following transient ischemia, this might expand the therapeutic window of opportunity for the institution of other neuroprotective strategies.     

Longitudinal relation between blood pressure,antihypertensive use and cerebral blood flow,using arterial spin labelling MRI

Consistent cerebral blood flow (CBF) is fundamental to brain function. Cerebral autoregulation ensures CBF stability. Chronic hypertension can lead to disrupted cerebral autoregulation in older people, potentially leading to blood pressure levels interfering with CBF. This study tested whether low BP and AHD use are associated with contemporaneous low CBF, and whether longitudinal change in BP is associated with change in CBF, using arterial spin labelling (ASL) MRI, in a prospective longitudinal cohort of 186 community-dwelling older individuals with hypertension (77 ± 3 years, 53% female), 125 (67%) of whom with 3-year follow-up. Diastolic blood pressure, systolic blood pressure, mean arterial pressure, and pulse pressure were assessed as blood pressure parameters. As additional cerebrovascular marker, we evaluated the ASL signal spatial coefficient of variation (ASL SCoV), a measure of ASL signal heterogeneity that may reflect cerebrovascular health. We found no associations between any of the blood pressure measures and concurrent CBF nor between changes in blood pressure measures and CBF over three-year follow-up. Antihypertensive use was associated with lower grey matter CBF (−5.49 ml/100 g/min, 95%CI = −10.7|−0.27, p = 0.04) and higher ASL SCoV (0.32 SD, 95%CI = 0.12|0.52, p = 0.002). These results warrant future research on the potential relations between antihypertensive use and cerebral perfusion.     

Blockade of K(ATP) channels with glibenclamide does not alter functional activation of cerebral blood flow in the unanesthetized rat

Possible involvement of ATP-sensitive K⁺ (K_ATP) channels in the cerebral blood flow (CBF) response to neuronal functional activation was investigated in unanesthetized rats. Glibenclamide (1, 2, or 10 μmol/l), a specific inhibitor of K_ATP channels, was infused intracisternally continuously for 30 min prior to and during the 1-min period of measurement of CBF. Unilateral functional activation was maintained throughout the measurement of CBF by continuous stroking of the vibrissae on the left side of the face. Local CBF was determined bilaterally by the quantitative autoradiographic [¹⁴C]iodoantipyrine method in four structures of the whisker-to-barrel cortex pathway and in 18 structures unrelated to the pathway. Glibenclamide tended to lower baseline CBF in almost all regions examined, statistically significantly (P<0.05) in the cerebellar lobules with all doses, in the cerebellar cortex with 10 μmol/l, in the pontine nuclei with 2 and 10 μmol/l, and in the spinal trigeminal nucleus of the unstimulated side with all doses. Vibrissal stimulation increased CBF unilaterally in all the stations of the pathway, but the percent increases were not statistically significantly affected by the glibenclamide treatment, except in the spinal trigeminal nucleus where it was reduced statistically significantly (P<0.05) only by 2 μmol/l glibenclamide. These results indicate that K_ATP channels may play a role in the tonic regulation of baseline CBF in some regions but provide no support for their role in the increases in CBF evoked by functional activation.     

Acute increases in forebrain blood flow during alerting responses in conscious rabbits

We have previously shown that alerting responses (documented by appearance of theta rhythm in the hippocampal EEG) are associated with a characteristically timed acute vasoconstriction in the ear artery bed of the conscious rabbit. We have now determined what happens to forebrain blood flow (Doppler probe chronically implanted around the internal carotid artery) during similar alerting responses in conscious rabbits, comparing forebrain flow to simultaneously measured ear flow. During an alerting response, forebrain flow increased by 31±8% of baseline (n=6, P<0.01), with the increase commencing within 1 s of the stimulus, at approximately the same time as the decrease in ear flow. Arterial pressure increased from 77±3 to 81±3 mmHg (P<0.01), so that internal carotid conductance increased from 0.17±0.02 to 0.20±0.02 kHz/mmHg (P<0.01). During a 1 h continuous recording period in the laboratory there was a negative correlation between forebrain and skin flow, with the Pearson coefficient in individual rabbits ranging from −0.18 to −0.62 (n=6, all correlations P<0.01). During this period, forebrain blood flow was just as variable, from second to second, as distal aortic flow, but not as variable as ear blood flow. Our study thus demonstrates that alerting responses in rabbits are associated with rapid increases in cerebral vascular conductance. We believe that this is the first demonstration of this phenomenon in the conscious experimental animal.     

Persistence of Impaired Autoregulation of Cerebral Blood Flow in the Postictal Period in Piglets

Cerebral blood flow (CBF) autoregulation was evaluated in the postictal period in unanesthetized term newborn piglets with a mean age of 5.7 +/- 3 days. Seven animals (group 1) received 1 mg/kg bicuculline to induce brief generalized seizures, and six control animals (group II) received saline. Twenty to 90 min after the end of seizure activity in group I or saline injection in group II, CBF was measured by the radioactive labeled microspheres method at three levels of mean arterial blood pressure (MABP) obtained by controlled blood withdrawal within the normal range for autoregulation. In the postictal period, baseline CBF was higher in group I than in group II (85 +/- 21 vs. 48 +/- 7 ml/min/100 g, p less than 0.001). During hypotension, total CBF was positively correlated with variations of MABP in group I (r = 0.739, p less than 0.01) but not in group II. Regional CBF showed the same correlation with MABP. These data show that after seizures in piglets, the rise in CBF is associated with a persistent impairment of CBF autoregulation. These hemodynamic alterations may be relevant in the pathogenesis of hemorrhagic or ischemic brain lesions.     

The antioxidative potential of cerebral microvessels in experimental diabetes mellitus

To determine if experimental diabetes is associated with decreased antioxidative potential along with increased peroxidation of lipids in cerebral microvessels, streptozotocin-induced diabetic rats were compared with control rats and to diabetic rats treated with insulin. Isolated cerebral microvessels from diabetic rats had significantly higher concentrations of malondialdehyde (MDA; μg/mg protein) (0.0283 ± 0.0017) compared with control (0.0201 ± 0.0016) or insulin-treated diabetic rats (0.196 ± 0.0022) P < 0.01. The antioxidative potential was measured in the presence of a peroxy radical generator 2,2′-azobis(2-amidinopropane) (AAPH) and hydroxyl radical generator CuSO₄ with monitoring of the fluorescence of phycoerythrin at 37°C. The free radical quenching activity of cerebral microvessels expressed as % inhibition of phycoerythrin oxidation by AAPH was significantly reduced in diabetic rats (38.7 ± 4.5%) compared with control (54.3 ± 4.9%) or insulin-treated diabetic rats (57.6 ± 2.9%) (P < 0.01). The % inhibition of oxidation by cerebral microvessels in the presence of CuSO₄ was only 15.7 ± 3.1% and did not differ significantly in diabetic rats (13.1 ± 2.1%). The results indicate that antioxidative potential of cerebral microvessels, especially in the presence of peroxy radical generator, is reduced in diabetes along with increased accumulation of lipid peroxidation byproducts. Increased oxidative stress may be one of the many mechanisms underlying the diabetes-related changes in the blood-brain barrier.     

The effects of ketamine–xylazine anesthesia on cerebral blood flow and oxygenation observed using nuclear magnetic resonance perfusion imaging and electron paramagnetic resonance oximetry

Ketamine–xylazine is a commonly used anesthetic for laboratory rats. Previous results showed that rats anesthetized with ketamine–xylazine can have a much lower cerebral partial pressure of oxygen (P_tO₂), compared to unanesthetized and isoflurane anesthetized rats. The underlying mechanisms for the P_tO₂ reduction need to be elucidated. In this study, we measured regional cerebral blood flow (CBF) using nuclear magnetic resonance (NMR) perfusion imaging and cortical P_tO₂ using electron paramagnetic resonance (EPR) oximetry in the forebrain of rats under isoflurane, ketamine, ketamine–xylazine and isoflurane–xylazine anesthesia. The results show that in ventilated rats ketamine at a dose of 50 mg/kg does not induce significant changes in CBF, compared to isoflurane. Ketamine–xylazine in combination causes 25–65% reductions in forebrain CBF in a region-dependent manner. Adding xylazine to isoflurane anesthesia results in similar regional reductions in CBF. EPR oximetry measurements show ketamine increases cortical P_tO₂ while xylazine decreases cortical P_tO₂. The xylazine induced reduction in CBF could explain the reduced brain oxygenation observed in ketamine–xylazine anesthetized rats.