Role of nitric oxide in regulation of cerebral microvascular tone and autoregulation of cerebral blood flow in cats

The role of nitric oxide in the regulation of cerebrocortical microvascular tone and autoregulation of cerebral blood flow (CBF) was examined in 24 anesthetized cats. The local cerebral blood volume (CBV), mean transit time of blood (MTT), and CBF in the cortex were measured by our photoelectric method. CBV represents the cumulative dimensions of the cerebral microvessels. Intravenous injection of 0.35–0.7 mg/kg/minN^G-monomethyl-l-arginine (l-NMMA), an inhibitor of nitric oxide synthesis, significantly increased mean arterial blood pressure (MABP; 8.4–14.1%,P < 0.01), decreased CBV (15.2–28.7%,P < 0.01), and decreased CBF (20.0–29.8%,P < 0.01) in a dose-related manner. The changes in MABP, CBV, and CBF elicited byl-NMMA were inhibited (P < 0.05) by simultaneous infusion of 35 mg/kg/minl-arginine. Autoregulation of CBF was examined during controlled hypotension of −30 to −40 mmHg (artificial bleeding) and recovery of blood pressure (reinfusion of blood). Although CBF remained constant with blood pressure changes in the control state (ΔCBF/ΔMABP of 0.037±0.155 with hypotension), CBF became dependent on blood pressure changes (ΔCBF/ΔMABP of 0.478±0.135, P < 0.05) during infusion of 0.35 mg/kg/minl-NMMA. It is concluded that nitric oxide participates in both the regulation of basal tone of cerebral microvessels and the autoregulation of CBF.     

Hemodynamic sequelae of ventricular tachyarrhythmias on cerebral blood flow

Abstract

The present experiments were designed to compare the behavior of cerebral blood flow (CBF) during acute moderate and severe hypotensive episodes induced by either ventricular tachycardias (VT) or by hemorrhage. Using the microsphere method CBF was determined in 20 Sprague-Dawley rats during sinus rhythm (Group A), in 28 animals during high-rate VT (Group B) and in 10 animals after hemorrhage (Group C). According to the decrease in blood pressure and with respect to the lower threshold of cerebral autoregulation Group B was divided into subgroups (B₁: 80-130 mmHg; B₂: 50-80 mmHg) retrospectively. While CBF remaIned constant In Group B₁ (0.98 ± 0.3 ml g^-1 min_-1 vs. 1.01 ± 0.32 In controls, NS), CBF decreased markedly during severely hypotensive VT in Group B₂ (0.52 ± 0.2 ml g_-1 min_-1, p < 0.001 vs. A; p < 0.05 vs. C) and during hypovolemic hypotension in Group C (0.77 ± 0.22 ml g_-1 min_-1 vs. A; NS). Cerebrovascular resistance and autoregulation indices indicated a maintenance of CBF regulation during hypovolemic hypotension and a failure during normovolemic hypotension. These findings indicate that the autoregulatory ability of the brain is substantially more stable during hypovolemic hypotension than during normovolemic hypotension. Therefore, the hemodynamic sequelae of acute hypotensive episodes on CBF depend on the underlying cause of hypotension. [Neural Res 1998; 20: 549-554]     

Consecutive in vivo measurement of nitric oxide in transient forebrain ischemic rat under normothermia and hypothermia

The effects of hypothermia on production of nitric oxide (NO) in ischemic brain were investigated by using in vivo microdialysis. Male Wistar rats were randomly divided into three groups; saline-treated normothermic group (37°C, n=6), 30 mg/kg N-nitro- -arginine methyl ester( -NAME)-treated normothermic group (n=6), and saline-treated hypothermic group (30°C, n=6). Transient forebrain ischemia was produced by bilateral common carotid artery occlusion combined with hypotension (MABP=50 mmHg). Saline-treated normothermic animals resulted in a reduction of LCBF to 9% of baseline. Saline-treated hypothermic rats revealed the similar changes of LCBF. In contrast, -NAME administration reduced the basal CBF to 85% of saline-treated group and to 8% after ischemia. NO products were decreased during ischemia and transiently increased after reperfusion in saline-treated groups. However, the increase of NO products after reperfusion was less significant in the hypothermia. -NAME-treated group showed a constant reduction of NO production during ischemia and after reperfusion.     

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.     

Nitric oxide synthase inhibition depresses the height of the cerebral blood flow-pressure autoregulation curve during moderate hypotension.

Variations in the height of the CBF response to hypotension have been described recently in normal animals. The authors evaluated the effects of nitric oxide synthase (NOS) inhibition on these variations in height using laser Doppler flowmetry in 42 anesthetized (halothane and N2O) male Sprague-Dawley rats prepared with a superfused closed cranial window. In four groups (time control, enantiomer control, NOS inhibition, and reinfusion control) exsanguination to MABPs from 100 to 40 mm Hg was used to produce autoregulatory curves. For each curve the lower limit of autoregulation (the MABP at the first decrease in CBF) was identified; the pattern of autoregulation was classified as "peak" (15% increase in %CBF), "classic" (plateau with a decrease at the lower limit of autoregulation), or "none" (15% decrease in %CBF); and the autoregulatory height as the %CBF at 70 mm Hg (%CBF(70)) was determined. NOS inhibition decreased %CBF(70) in the NOS inhibition group (P = 0.014), in the control (combined time and enantiomer control) group (P = 0.015), and in the reinfusion control group (P = 0.025). NOS inhibition via superfusion depressed the autoregulatory pattern (P = 0.02, McNemar test on changes in autoregulatory pattern) compared with control (P = 0.375). Analysis of covariance showed that changes induced by NOS inhibition in the parameters of autoregulatory height are not related to changes in the lower limit, but are strongly (P < 0.001) related to each other. NOS inhibition depressed the autoregulatory pattern, decreasing the seemingly paradoxical increase in CBF as blood pressure decreases. These results suggest that nitric oxide increases CBF near the lower limit and augments the hypotensive portion of the autoregulatory curve.     

Impaired cerebral autoregulation 24 h after induction of transient unilateral focal ischaemia in the rat

Cerebral blood flow (CBF) and cerebral autoregulation have been investigated 24 h after transient focal ischaemia in the rat. Cerebral blood flow was measured autoradiographically before and during a moderate hypotensive challenge, to test autoregulatory responses, using two CBF tracers, (99m)Tc-d,l-hexamethylproyleneamine oxide and 14C-iodoantipyrine. Prior to induced hypotension, CBF was significantly reduced within areas of infarction; cortex (28 +/- 20 compared with 109 +/- 23 mL/100 g/min contralateral to ischaemic focus, P = 0.001) and caudate (57 +/- 31 compared with 141 +/- 32 mL/100 g/min contralaterally, P = 0.005). The hypotensive challenge (mean arterial pressure reduced to 60 mmHg by increasing halothane concentration) did not compromise grey matter autoregulation in the contralateral hemisphere; CBF data were not significantly different at normotension and during hypotension. However, in the ipsilateral hemisphere, a significant volume of cortex adjacent to the infarct, which exhibited normal flow at normotension, became oligaemic during the hypotensive challenge (e.g. frontal parietal cortex 109 +/- 15% to 65 +/- 15% of cerebellar flow, P < 0.01). This resulted in a 2.5-fold increase in the volume of cortex which fell below 50% cerebellar flow (39 +/- 34 to 97 +/- 46 mm3, P = 0.003). Moderate hypotension induced a significant reduction in CBF in both ipsilateral and contralateral subcortical white matter (P < 0.01). In peri-infarct caudate tissue, CBF was not significantly affected by hypotension. In conclusion, a significant volume of histologically normal cortex within the middle cerebral artery territory was found to have essentially normal levels of CBF but impaired autoregulatory function at 24 h post-ischaemia.     

Local cerebral blood flow response to locally infused 2-chloroadenosine during hypotension in piglets

Brain interstitial adenosine increases during hypotension in piglets. If adenosine is to participate in the regulation of neonatal cerebral blood flow (CBF) during hypotension, it must retain its vasodilatory action under that condition. To examine this issue, we studied the effects of locally infused 2-chloroadenosine (2-CADO), a stable adenosine analog, on local CBF in the piglet frontal cortex during normotension and graded hemorrhagic hypotension. We used the modified brain microdialysis/hydrogen clearance technique to simultaneously infuse 2-CADO into the frontal cortex and measure local CBF from the same area. When 2-CADO from 10(-8) M to 10(-3) M was infused under control conditions (n = 7), CBF increased 61% at 10(-5) M, 167% at 10(-4) M, and 210% at 10(-3) M. In hypotension experiments, local infusion of 10(-5) M 2-CADO (n = 8) caused significant increases in CBF (P less than 0.05) under control conditions (MABP = 65 mmHg) and at hypotensive blood pressures of 55 mmHg and 44 mmHg, respectively. At a blood pressure of 33 mmHg, however, infusion of the analog failed to increase CBF. Local infusion of 10(-3) M 2-CADO also produced a similar change in CBF during graded hypotension. These results indicate that 2-CADO dilates intracerebral vessels during normotension, and mild and moderate hypotension, and support the hypothesis that endogenous adenosine mediates autoregulatory adjustments of CBF during hypotension in newborn piglets.     

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.     

Effects of NMDA receptor glycine recognition site antagonism on cerebral metabolic rate for glucose and cerebral blood flow in the conscious rat

Glycine is a requisite cofactor for glutamatergic activation of the N-methyl-

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-aspartate (NMDA) receptor. Antagonism of glutamate at the NMDA receptor has been shown to cause substantial changes in regional cerebral metabolic rate for glucose utilization (CMRglu) and blood flow (CBF). This study examined CMRglu and CBF changes caused by antagonism of glycine at the NMDA receptor recognition site. Rats were anesthetized with halothane and vascular access was obtained. The animals were then awakened. One hour later, either vehicle (control) or ACEA 1021 (5 mg/kg followed by 3.5 mg·kg⁻¹·h⁻¹ or 10 mg/kg followed by 7 mg·kg⁻¹·h⁻¹) was infused intravenously. CMRglu and CBF were then determined. Autoradiographic analysis of 25 regions revealed effects of ACEA 1021 on CMRglu in the frontal, sensory, parietal and auditory cortices and the anteroventral and subthalamic nuclei. These changes deviated less than 15% from control. Effects on CBF were also small. The CMRglu and CBF effects of ACEA 1021 are substantially less than those previously observed for either competitive or non-competitive glutamate NMDA antagonists. We conclude that inhibition of the NMDA glycine recognition site has little or no effect on CMRglu or CBF at the doses examined. This is consistent with the absence of psychotomimetic effects observed for this class of drugs.     

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.     

Effect of up-regulation of NMDA receptors on cerebral O2 consumption and blood flow in rat

We tested the hypothesis that cerebrocortical blood flow and O₂ consumption would be proportional to an up-regulated number of functional N-methyl- -aspartate (NMDA) receptors. Previous work had shown a relationship between cerebral metabolism and NMDA receptor activity. We increased the specific binding to NMDA receptors in the cerebral cortex, from 2.2 ± 0.9 to 4.5 ± 0.8 (density units) in male Long-Evans rats by daily giving two intraperitoneal injections (30 mg/kg) of CGS-19755, an NMDA receptor inhibitor, for 7 consecutive days (discontinued for 20 h before experiment). Twelve up-regulated (CGS treated) and 12 control rats were used in this study. Under isoflurane anesthesia and after topical stimulation of the right cerebral cortex with 10⁻² M NMDA, the blood flow (¹⁴C-iodoantipyrine method) increased from 98 ± 11 ml/min/100 g in the unstimulated cortex of the control rats to 161 ± 37 ml/min/100 g in the stimulated cortex. The unstimulated value for blood flow (95 ± 7 ml/min/100 g) did not change in the upregulated group but it doubled (194 ± 69 ml/min/100 g) in the stimulated, upregulated cortex. Similarly, O₂ consumption (cryomicrospectrophotometrically determined) in normal rats increased 46%, from 9.3 ± 1 ml/min/100 g to 13.6 ± 4 after NMDA stimulation. While in the upregulated animals, O₂ consumption increased 103% from 7.9 ± 0.6 to 16 ± 6.5 after NMDA stimulation. In conclusion, NMDA receptor upregulation does not alter basal cerebrocortical blood flow or O₂ consumption but in the NMDA-stimulated cortex, the blood flow and O₂ consumption increase is dependent on the number of NMDA receptors present.     

Mild hypothermia disturbs regional cerebrovascular autoregulation in awake rats

The effects of mild hypothermia on regional CBF (rCBF) and autoregulation were investigated in 60 awake and spontaneously breathing Wistar rats. They were divided into normothermic (rectal and brain temperatures: 37.0±0.5°C) and mildly hypothermic (33.0±0.5°C) groups the temperature of the latter group was controlled by cooling a lead cast around each rat with ice-cold water. rCBF was measured by means of an autoradiographic technique with ¹⁴C-iodoantipyrine. In normothermia, rCBF in most of the supratentorial cortical regions was maintained down to a mean arterial blood pressure (MABP) of 50 mmHg, produced by exsanguination, while rCBF in most of the brain stem regions showed a tendency to increase despite this reduction of MABP (predysautoregulatory overshoot of CBF). In the mildly hypothermic group, pre-exsanguination rCBF values were lower than those in normothermia, and rCBF in all brain regions declined significantly in proportion to decreasing MABP, produced by exsanguination. It is, therefore, concluded that mild hypothermia disturbs cerebrovascular autoregulation in awake rats.     

l-Arginine ameliorates recirculation and metabolic derangement in brain ischemia in hypertensive rats

The effects of

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-arginine (a precursor of nitric oxide, NO) on cerebral blood flow (CBF), cerebrovascular resistance (CVR) and metabolites in the ischemic brain were examined in spontaneously hypertensive rats with bilateral carotid artery occlusion for 30 min followed by 60 min-recirculation. The administration of

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-arginine (300 mg/kg, i.v.) increased the CBF by an average of 11 ml·100 g⁻¹·min⁻¹ (P<0.05 vs. at rest), and N^ω-nitro-

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-arginine (

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-NNA, an inhibitor of NO synthase, 5 mg/kg, i.v.) reduced the CBF by 5–6 ml·100 g⁻¹·min⁻¹ with increase in the mean arterial pressure by 26 mmHg. During ischemia the CBF significantly decreased to below 8% of the resting values in all rats. The largest blood flow in postischemic hyperemia was 171±9% of the resting CBF in the rats with

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-arginine (P<0.05 vs.

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-NNA and saline), followed by 126±5 with saline and 109±3 with

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-NNA. The CVR at 60 min of recirculation was 3.291±0.144 mmHg·ml⁻¹·100 g⁻¹·min⁻¹ in the rats with saline, remained low level of 2.711±0.124 with

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-arginine (P<0.01 vs.

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-NNA and P<0.05 vs. saline) and in contrast, significantly increased to 5.732±0.184 with

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-NNA (P<0.01 vs.

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-arginine and saline, respectively). Tissue lactate with saline increased 2.3-fold at 60 min of recirculation, whereas the increase was inhibited to 1.4-fold after

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-arginine treatment (P<0.01 vs.

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-NNA) and in contrast, significantly increased 5.7-fold with

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-NNA. The ATP and glucose levels were better preserved in the rats with

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-arginine than in those with

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-NNA or saline. These findings support that the enhanced postischemic hyperemia is beneficial to the ischemic brain and the administration of

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-arginine may be potentially useful for the treatment of acute stroke.     

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.     

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.     

Alpha-Stat Versus pH-Stat Guided Ventilation in Patients with Large Ischemic Stroke Treated by Hypothermia

Background  Moderate hypothermia (MH) is a therapeutic approach for ischemic stroke as well as cardiac arrest. Two different technical strategies of ventilation during MH called alpha- and pH-stat dramatically influence cerebral blood flow (CBF). In turn this might influence neuronal damage and intracranial pressure (ICP). Therefore, effects of ventilation on CBF and ICP were measured in patients undergoing MH because of large ischemic stroke to address optimal ventilation management. Methods  Eight patients (n = 8) with large ischemic stroke in the territory of the middle cerebral artery (MCA) were treated by MH of 33°C within 24 h after symptom onset. MH was applied at least for 72 h. Each day, patients were ventilated repetitively with either alpha-stat or pH-stat for 60 min periods. Alpha-stat was applied between the measurements. ICP, CBF, and mean arterial blood pressure (MABP) were measured. The xenon clearance method was used to assess CBF at the bedside. Results  There were no significant differences between ICP values for alpha-stat or pH-stat during days 1 and 2 after induction of hypothermia. However, ICP was higher in the pH- as compared to the alpha-stat group (P < 0.05) and exceeded a mean of 20 mmHg on day 3. pH-stat led to a significant increase of CBF in all measures (P < 0.05), while MABP was unaffected. Conclusions  pH-stat implies a better CBF to the injured brain, while it might be dangerous by elevating ICP in more subacute stages.     

Acute sympathetic denervation does not eliminate the effect of angiotensin converting enzyme inhibition on CBF autoregulation in spontaneously hypertensive rats

The effect of angiotensin converting enzyme inhibition with captopril (10 mg/kg i.v.) on CBF autoregulation was studied in 16 spontaneously hypertensive rats (8 control and 8 treated with captopril) subjected to acute cervical sympathectomy. CBF was measured repetitively by the intra-arterial 133Xe injection method, during the manipulation of MABP by norepinephrine or hemorrhagic hypotension. Prior to the administration of drugs, baseline MABP was 112 +/- 10 mm Hg in the control group and 119 +/- 11 mm Hg in the captopril group. Baseline CBF was 99 +/- 19 ml/100 g/min, with no difference in the two groups. In agreement with previous findings in rats with intact sympathetic nerves, the lower limit of CBF autoregulation was reduced from the MABP interval of 70-89 to 50-69 mm Hg by captopril.     

Effects of ginsenosides on Ca channels and membrane capacitance in rat adrenal chromaffin cells

We investigated the effects of ginseng total saponins (GTS) and five ginsenosides on voltage-dependent Ca²⁺ channels and membrane capacitance using rat adrenal chromaffin cells. In this study, cells were voltage-clamped in a whole-cell recording mode and a perforated patch-clamp technique was used. The inward Ca²⁺ currents (I_Ca) was elicited by depolarization and the change in cell membrane capacitance (ΔC_m) was monitored. The application of GTS (100 μg/ml) induced rapid and reversible inhibition of the Ca²⁺ current by 38.8 ± 3.6% (n = 16). To identify the particular single component that seems to be responsible for Ca²⁺ current inhibition, the effects of five ginsenosides (ginsenoside Rb₁, Rc, Re, Rf, and Rg₁) on the Ca²⁺ current were examined. The inhibitions to the Ca²⁺ current by Rb₁, Rc, Re, Rf, and Rg₁ were 15.3 ± 2.2% (n = 5); 36.9 ± 2.4% (n = 7); 28.1 ± 1.9% (n = 12); 19.0 ± 2.5% (n = 10); and 16.3 ± 1.6% (n = 15), respectively. The order of inhibitory potency (100 μM) was Rc > Re > Rf > Rg₁ > Rb₁. A software based phase detector technique was used to monitor membrane capacitance change (ΔC_m). The application of GTS (100 μg/ml) induced inhibitory effects on ΔC_m by 60.8 ± 9.7% (n = 10). The inhibitions of membrane capacitance by Rb₁, Rc, Re, Rf, and Rg₁ were 35.3 ± 5.5% (n = 7); 41.8 ± 7.0% (n = 8); 40.5 ± 5.9% (n = 9); 51.2 ± 7.6% (n = 9); and 35.9 ± 5.1% (n = 10), respectively. The inhibitory potencies of the ginsenosides on ΔC_m were Rf > Rc > Re > Rg₁ > Rb₁. Therefore, we found that GTS and ginsenosides exerted inhibitory effects on both Ca²⁺ currents and ΔC_m in rat adrenal chromaffin cells. These results suggest that ginseng saponins regulate catecholamine secretion from adrenal chromaffin cells and this regulation could be the cellular basis of antistress effects induced by ginseng.