Sympathetic nerves protect the blood-brain barrier in stroke-prone spontaneously hypertensive rats.

Disruption of the blood-brain barrier may play a major role in the pathogenesis of hypertensive encephalopathy. In this study we determined whether sympathetic nerves to cerebral vessels protect the blood-brain barrier during chronic hypertension. We removed the cervical sympathetic ganglion on one side in 24 stroke-prone hypertensive rats when they were 1 month old. After signs of cerebral dysfunction developed at the mean age of 160 +/- 5 days (SE), we injected 125I-albumin and Evans blue dye intravenously to evaluate the permeability of the 125I-albumin was 3.53 +/- 0.83 (brain albumin x 100/blood albumin) in areas of the cerebrum stained with blue dye and 0.24 +/- 0.02 in unstained areas (p less than 0.05). We conclude that sympathetic nerves protect the blood-brain barrier against disruption during chronic hypertension and thereby may protect against hypertensive encephalopathy.

Increased susceptibility to osmotic disruption of the blood-brain barrier in chronic hypertension.

We examined the effects of chronic hypertension and acute reduction of arterial pressure on the susceptibility of the blood-brain barrier (BBB) to disruption. The BBB was disrupted with an intracarotid injection of 1.6 M arabinose in spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP), and normotensive Wistar-Kyoto (WKY) rats. Permeability of the BBB was determined from the ratio of 125I-albumin in brain to 125I-albumin in blood. When the BBB was intact, permeability was less than 0.4%. After hypertonic arabinose, permeability of the BBB was greater (mean +/- SE) in SHRSP (17.6% +/- 1.6%) and in SHR (21.1% +/- 3.1%) than in WKY (10.3% +/- 2.4%) (p less than 0.05). When arterial pressure of SHRSP was reduced acutely with nitroprusside before arabinose, the BBB permeability to albumin was not reduced (21.5% +/- 1.5%). In other rats, we examined survival after osmotic disruption. In SHRSP, 14 of 15 rats died within 1 day after osmotic disruption with marked cerebral edema. In WKY, four of 15 rats died (p less than 0.05 vs SHRSP). When arterial pressure of SHRSP was reduced before arabinose, mortality was reduced to six of 15 (p less than 0.05 vs untreated SHRSP). We conclude that the BBB in SHRSP has enhanced vulnerability that is detrimental to survival. Reduction of arterial pressure improves survival in SHRSP without affecting BBB permeability to albumin.(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathetic nerves protect against stroke in stroke-prone hypertensive rats. A preliminary report.

Studies were performed to determine whether sympathetic nerves protect against stroke in hypertensive rats. The superior cervical ganglion was removed on one side in 28 stroke-prone spontaneously hypertensive rats (SHRSP) when the rats were 4 weeks old. The rats were fed Japanese rat chow and 1% saline drinking water. When the rats were 19 weeks old, systolic pressure was 206 +/- 4 mm Hg (mean +/- SE). All rats died between 19 and 23 weeks of age. Microscopic and histological examination demonstrated cerebral hemorrhage in seven rats. All the hemorrhages occurred in the denervated hemispheres. Ischemic cerebral infarctions were found in 13 rats; in 10 rats, the infarcts were only in the denervated hemisphere. Pathological changes of cerebral arteries (hyalinosis, fibrinoid changes, and thrombus formation) were observed primarily in denervated hemispheres. Wall-to-lumen ratio was less in arteries of the denervated hemisphere than in arteries of the innervated hemisphere. These preliminary observations suggest that denervation of cerebral vessels increases susceptibility to stroke and inhibits development of cerebral vascular hypertrophy in SHRSP.

Inhibition of angiotensin-converting enzyme modulates the autoregulation of regional cerebral blood flow in hypertensive rats.

The inhibition of angiotensin-converting enzyme activities is considered to favorably modulate the hemodynamics of the brain. We designed the present study to examine the effects of angiotensin-converting enzyme inhibitors on regional differences in the lower limits of cerebral blood flow autoregulation in spontaneously hypertensive rats. Angiotensin-converting enzyme inhibitors (either 10 mg/kg captopril or SQ 29,852 in saline) were intravenously injected 15 minutes before hemorrhagic hypotension was induced. Cerebral blood flows to the parietal cortex and thalamus were simultaneously measured by hydrogen clearance. Both captopril and SQ 29,852 significantly decreased mean arterial pressure by 14 to 18 mm Hg and also reduced calculated cerebral vascular resistance by 11% to 15% of resting values, which resulted in a well-maintained cerebral blood flow. The lower limits of autoregulation were 76 +/- 2% (mean +/- SEM) and 77 +/- 2% of resting values in the cortex and thalamus, respectively, in control rats. Administration of either captopril or SQ 29,852 significantly reduced the lower limits to 65 +/- 3% (P < .01 versus control) and 67 +/- 2% (P < .05), respectively, in the cortex, which were slightly but always larger than the 71 +/- 3% and 71 +/- 2% reduction, respectively, in the thalamus. The inhibition of angiotensin-converting enzyme activities thus may be more protective against acute hypotension for cerebral microcirculation in the cortex than in the thalamus.

Evidence that disruption of the blood-brain barrier precedes reduction in cerebral blood flow in hypertensive encephalopathy.

Alternative hypotheses concerning the pathogenesis of hypertensive encephalopathy are that vasospasm produces cerebral ischemia and cerebral edema, or that passive dilation of cerebral vessels during severe hypertension produces disruption of the blood-brain barrier and cerebral edema. Stroke-prone spontaneously hypertensive rats (SHRSP) were studied when they developed signs of neurological dysfunction. We measured regional cerebral blood flow (rCBF) with 14C-iodoantipyrine, and permeability of the blood-brain barrier with Evans blue dye. Twelve rats had focal disruption of the barrier without histological evidence of ischemic infarction or cerebral hemorrhage: areas with disruption of the barrier had severe focal edema in seven rats and minimal edema in five rats. In areas with disruption of the barrier and marked focal edema, rCBF was decreased to 38 +/- 8 (mean +/- SE) ml/min/100 g vs 102 +/- 13 (p less than 0.05) in other areas of the ipsilateral hemisphere, and 86 +/- 16 in the homologous area of the contralateral hemisphere (p less than 0.05). In contrast, in areas with disruption of the blood-brain barrier with only minimal edema, rCBF was normal or increased: rCBF was 100 +/- 11 ml/min/100 g vs 85 +/- 12 in other areas of the ipsilateral hemisphere (p greater than 0.05) and 64 +/- 8 in the homologous area contralaterally (p less than 0.05). The findings indicate that edema precedes reduction in rCBF in SHRSP and suggest that the initiating event in hypertensive encephalopathy is disruption of the blood-brain barrier, and not vasospasm.

Cerebral autoregulation in young spontaneously hypertensive rats. Effect of sympathetic denervation.

Autoregulation of cerebral blood flow was studied with the hydrogen clearance method during development of hypertension in young spontaneously hypertensive rats. To examine the influence of sympathetic nerves on autoregulatory range, the unilateral superior cervical ganglion was removed 2 hours or 2 or 5 weeks before the study. Wall-to-lumen ratio of cerebral arteries was determined with freeze substitution technique. Basal blood pressures were 87 +/- 1 mm Hg (mean +/- SEM) at 4 weeks of age, 105 +/- 2 at 6 weeks, and 126 +/- 3 at 9 weeks, although resting cerebral blood flow was unchanged. Initially, cerebral blood flow remained relatively constant when the blood pressure was raised by intravenous infusion of phenylephrine. The upper limits of cerebral blood flow autoregulation in these groups were 110 +/- 4 mm Hg, 126 +/- 7, and 159 +/- 6 respectively. Acute ganglionectomy significantly lowered the upper limits (p less than 0.05), but chronic denervation did not affect the autoregulatory range. The wall-to-lumen ratios of cerebral arteries were 0.136 +/- 0.007 at 4 weeks and 0.130 +/- 0.005 at 9 weeks. These differences were not significant, nor did sympathetic denervation alter the ratio. These results indicate that (1) the upward shift of the autoregulation is closely related to a rise in the basal blood pressure, (2) acute interruption of sympathetic nerves modulates the autoregulatory range, and (3) adaptation of cerebral blood flow autoregulation to early developmental hypertension may be attributed to factors other than vascular smooth muscle hypertrophy.

Inhibition of acetylcholinesterase modulates the autoregulation of cerebral blood flow and attenuates ischemic brain metabolism in hypertensive rats.

We designed the present study to examine whether or not the inhibition of acetylcholinesterase modulates cerebral microcirculation in hypotension and improves brain metabolism in ischemia induced by bilateral carotid artery occlusion in hypertensive rats. Blood flow to the parietal cortex was determined by the H2 clearance method. Lactate, pyruvate, and ATP were estimated by enzymatic methods. Acetylcholinesterase inhibitor (AChEI, ENA-713), at 0.05, 0.1, or 0.5 mg/kg, was intravenously injected 10 min before either hemorrhagic hypotension or cerebral ischemia. The levels of acetylcholine in the control were 29.3 +/- 8.1 (mean +/- SD) and 39.5 +/- 8.1 pmol/mg in the cortex and hippocampus, respectively, and they were significantly decreased by 15-19% after 60 min of ischemia in the vehicle-treated rats. AChEI preserved the levels to 93-98% of the control (p < 0.05 versus vehicle). The lower limit of autoregulation was 74 +/- 9% of the resting values. The administration of AChEI helped preserve blood flow and lowered the limit to 64 +/- 6% (p < 0.05 versus control). After 60 min of ischemia, lactate increased 6.5-fold and ATP decreased to 64% of the control value. The administration of AChEI dose-dependently reduced the lactate level 1.9- to 3.9-fold and well preserved the ATP level to 94-97% of the control. The inhibition of acetylcholinesterase activity may preserve cerebral autoregulation during hypotension and protect cerebral metabolism against ischemic insult.

Ischemia-induced release of amino acids in the hippocampus of aged hypertensive rats.

We have recently demonstrated the age-related vulnerability of hippocampal neurons to 20-min forebrain ischemia in spontaneously hypertensive rats (SHR). In the present study, we investigated the effect of aging on the release of amino acids in the hippocampus during transient cerebral ischemia for 20 min. Concentrations of extracellular amino acids and cerebral blood flow in the CA1 subfield were examined by an in vivo brain dialysis technique and a hydrogen clearance method, respectively, in adult (5-7 month) and aged (19-23 month) female SHR. During cerebral ischemia by bilateral carotid artery occlusion, cerebral blood flow to the hippocampus decreased to 20% of the resting values in both groups. After recirculation, both groups showed delayed hypoperfusion which was more prominent in the aged SHR. In the adult rats, concentrations of both aspartate and glutamate increased to approximately 8-fold of the resting values during ischemia. The elevation of these excitatory amino acids in the adult SHR was not significantly different from that in the aged rats. In contrast, the concentration of taurine increased 26-fold in the adult SHR but only 16-fold in the aged rats. Changes in other amino acids were not different between the two groups. These results indicate that an imbalance of excitatory and inhibitory amino acids, e.g., smaller release of taurine, during ischemia may, at least in part, contribute to the age-related vulnerability of hippocampal neurons to transient cerebral ischemia in SHR.

Fibrinogen and low density lipoprotein in the development of cerebral atherosclerosis.

Cerebral arteries from 65 human subjects were examined by immunofluorescence, using antisera against human fibrinogen and low density lipoprotein (LDL). Deposition of fibrinogen and LDL was most frequent at the bifurcation of the middle cerebral arteries and least in the basilar arteries in all age groups. In general, deposition of LDL was associated with deposition of fibrinogen, and lone deposition of LDL in the absence of fibrinogen was only rarely seen. Fibrinogen was scattered in the intercellular spaces, and located in the inner layer or edges of the thickened intima of the bifurcation with increasing plaque formation. Fibrinogen was observed even in the subendothelial region of the uninvolved intima at the bifurcations. LDL was present in the cytoplasm of the endothelial cells in the earliest stage, and it increased in the extracellular stroma with increase in intimal thickening, corresponding closely to the distribution of perifibous oil-red-O-stained lipids. No LDL was detected in the uninvolved intima. The observations suggest that deposition of fibrinogen in the intima might precede LDL deposition and possibly play a more important role than LDL in the development of atherosclerotic lesions in the cerebral arteries, especially in their early stage. Severe atherosclerosis at the bifurcations may be in part due to increased permeation of these plasma proteins, possibly as a result of hemodynamic stress.

Cerebral and aortic atherosclerosis in Hisayama, Japan.

This study of autopsy cases in the general population of the town, Hisayama, describes the incidence and severity of aortic and cerebral atherosclerosis in Japan. Atherosclerosis was more severe in the aorta than in the cerebral arteries of all age groups and its disparity became more conspicuous with age. In hypertensive cases, atherosclerosis was more severe in both the aorta and the cerebral arteries from and beyond the 6th decade of age. The severity of atherosclerosis in the aorta in those with systolic hypertension was lower under the age of 79 and higher after the age of 80 than in diastolic hypertension; the cerebral arteries were afflicted similarly by the two forms of hypertension. The serum cholesterol level correlated better with the severity of aortic than cerebral atherosclerosis.

Hypercoagulable state under low-intensity warfarin anticoagulation assessed with hemostatic markers in cardiac disorders.

The hemostatic condition under low-intensity anticoagulation in cardiac disorders is not fully elucidated. The aim of this study was to ascertain whether hemostatic molecular markers are a useful assessment for anticoagulation to detect the hypercoagulable state. A hematologic study was performed in 75 outpatients, without thromboembolic episodes, treated with low-intensity anticoagulation (average international normalized ratio [INR] 1.72) because of potential cardiac sources of arterial emboli, and in 40 age-matched control subjects. The average level of thrombin-antithrombin III complex (TAT) was significantly lower in patients than in control subjects (p = 0.005), and the mean value of D-dimer was not statistically different between patients and control subjects. Although TAT correlated moderately with D-dimer (r = 0.45, p = 0.0001), INR did not correlate with TAT or D-dimer. Elevated TAT > 3.0 ng/ml and/or D-dimer S 150 ng/ml were observed in 15 patients (20.0%), whereas the remaining 60 patients (80.0%) had no obvious increase in the level of TAT or D-dimer at overall INR. Antithrombin III activity did not correlate significantly with INR, but protein C activity and free protein S antigen showed a significant negative relation to INR (r = 0.82, r = 0.62, respectively, p = 0.0001). Low-intensity anticoagulation was sufficient to reduce coagulation and subsequent fibrinolytic activation in cardiac disorders, but may not be sufficient in some patients with elevated TAT or D-dimer concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Spontaneous recovery from non-insulin-dependent diabetes mellitus induced by neonatal streptozotocin treatment in spontaneously hypertensive rats.

We studied the long-term change in glycemic level in a model of non-insulin-dependent diabetes mellitus (NIDDM) induced by neonatal streptozotocin (STZ) treatment in spontaneously hypertensive rats (SHR). Two-day-old male SHR were intraperitoneally injected with 37.5 to 75.0 mg/kg of STZ or vehicle alone as control. According to nonfasting plasma glucose levels at 12 weeks of age, rats were divided into mild (less than 16.8 mmol/L) and severe (greater than or equal to 16.8 mmol/L) diabetes groups. In the mild diabetes group (n = 5), plasma glucose decreased significantly from 14.2 +/- 1.8 mmol/L (mean +/- SEM) at 20 weeks to 7.3 +/- 0.3 mmol/L at 52 weeks (P less than .05) with progressing age. At 52 weeks, overnight fasting plasma glucose levels were significantly lower and serum immunoreactive insulin (IRI) was higher than in controls, respectively (4.1 +/- 0.3 v 5.7 +/- 0.3 mmol/L, P less than 0.01; 625 +/- 50 v 409 +/- 50 pmol/L, P less than .05), and insulinoma was found in 60% of rats. Therefore, the recovery from hyperglycemia may be attributed to the development of insulinoma. In the severe diabetes group (n = 6), plasma glucose remained high until 28 weeks (27.2 +/- 1.5 mmol/L), but thereafter decreased with age, as it did in the mild diabetes group (13.7 +/- 3.5 mmol/L at 52 weeks, P less than .005). However, no insulinoma was found, and the mechanism for the recovery was unclear. The present study demonstrates that hyperglycemia spontaneously ameliorates in a neonatal STZ diabetes model of SHR, although this phenomenon may be strain-related.

Diabetes induced by neonatal streptozotocin treatment in spontaneously hypertensive and normotensive rats.

The development of non-insulin-dependent diabetes mellitus (NIDDM) induced by neonatal streptozotocin (STZ) treatment was compared between male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). The animals were intraperitoneally given 37.5, 50.0, 62.5, or 75.0 mg/kg of STZ at two days of age. At two days after STZ injection, plasma glucose was elevated in both groups of rats according to the dose of STZ, but the level was higher in SHR than in corresponding WKY. At ten days of age, plasma glucose in WKY returned to the similar level to that in vehicle-treated control irrespective of the doses of STZ, while in SHR it remained above control and its level was significantly higher than that in WKY. At 12 weeks of age, plasma glucose was within the control range in WKY, while in SHR it was markedly and dose-dependently elevated. The present study indicates that SHR are susceptible to NIDDM induced by neonatal STZ treatment. The difference in response to STZ between SHR and WKY was discussed.

Glucose tolerance and insulin secretion in conscious and unrestrained normotensive and spontaneously hypertensive rats.

We compared the glucose tolerance and insulin responses to intravenous (IV) glucose administration of a dose of 1 g/kg body weight in a conscious and unrestrained state of spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) with catheters chronically indwelled into artery and vein. Both plasma glucose levels at two minutes and ten minutes following IV glucose load as well as the incremental and total areas of plasma glucose were slightly but significantly lower in SHR than in WKY. Glucose disappearance rate (K value) was 7.7 +/- 0.3%/min in SHR, being slightly but significantly higher than that of 6.8 +/- 0.3%/min in WKY. On the other hand, insulin responses to the glucose load at ten minutes and 30 minutes as well as incremental and total insulin areas were significantly lower in SHR than in WKY. There was no significant difference in insulinogenic index between SHR and WKY. Our observations suggest that in a conscious and unrestrained state, SHR have the greater glucose tolerance associated with reduced insulin secretion than do WKY.

Carbon dioxide reactivity of cerebral cortical and pial arteries in spontaneously hypertensive and normotensive rats--a morphometric study.

The responsiveness of cerebral arteries to the changes in arterial carbon dioxide tension (paCO2) was studied in spontaneously hypertensive rats (SHRs) and normotensive rats (NTRs). A freeze substitution method was applied for the preparation of pial and cortical arteries for morphometrical study. Hypercapnia was induced by giving 8% CO2, and hypocapnia was provided by hyperventilation. The ratios of internal (d) to external diameter (D) (d/D ratio) of both pial and cortical arteries in SHR were not different from those in NTRs during normocapnia. In hypercapnia, the ratios of pial and larger cortical arteries (D greater than or equal to 20 micron) in SHRs were 80.9 +/- 0.8% and 78.6 +/- 0.6%, respectively, being significantly smaller than 86.2 +/- 0.7% and 82.2 +/- 0.5% in NTR. In contrast, the d/D ratio of pial arteries in hypocapnia was 72.5 +/- 1.4% in SHRs, which was significantly larger than 67.5 +/- 1.4% in NTRs. The responsiveness of smaller cortical arteries (D less than 20 micron) to paCO2 was not different between SHRs and NTRs. The present results suggest that in SHRs cerebrovascular CO2 reactivity is decreased as compared to NTRs, especially in pial and larger cortical arteries.

Freeze substitution as a means of preserving meningeal vessel morphology.

This study compares freeze substitution with formaldehyde fixation as a means of preserving meningeal vessel morphometry. The diameters of vessels fixed by freeze substitution correlated very well with the in vivo diameters of the same vessels (correlation coefficient 0.9766). On the other hand, diameters of vessels perfusion fixed with 10% buffered formalin displayed poor correlation with in vivo diameters of the same vessels (correlation coefficient 0.1594).

Effect of chronic sympathetic denervation on cerebrovascular hypertrophy during the development of hypertension in rats.

The present study was designed to examine the trophic effect of sympathetic nerves on cerebrovascular hypertrophy in developmental hypertension. Unilateral superior cervical ganglionectomy was performed in spontaneously hypertensive rats at 4 weeks of age, and wall-to-lumen ratios of cerebral arteries were determined at 5 weeks, 2 months or 5 months after denervation. To estimate the thickness of the vessel wall, a freeze substitution technique was used for the preparation of cerebral arteries. Basal mean arterial blood pressure measured through cannulated femoral artery was 127 +/- 2, 146 +/- 7 and 168 +/- 6 mm Hg (mean +/- S.E.M.) at 9 weeks, 3 months and 6 months of age, respectively. The wall-to-lumen ratios in the denervated and innervated hemispheres were 0.124 +/- 0.004 and 0.129 +/- 0.005 at 9 weeks, 0.127 +/- 0.003 and 0.169 +/- 0.004 (P less than 0.02 vs denervated) at 3 months, and 0.194 +/- 0.007 and 0.222 +/- 0.006 (P less than 0.05 vs denervated) at 6 months. The effect of denervation was more significant in downstream vessels (diameter less than or equal to 100 microns) than larger ones. We conclude that wall-to-lumen ratio is correlated well with a rise in basal blood pressure, and chronic interruption of the sympathetic nerves attenuates normal occurrence of vascular hypertrophy during the development of hypertension.

Importance of bilateral sympathetic innervation on cerebral blood flow autoregulation in the thalamus.

Effects of bilateral sympathetic innervation on the regulation of cerebral blood flow to the thalamus were examined in spontaneously hypertensive rats (SHR). The superior cervical ganglion was removed on one side or bilaterally, and blood flow in the thalamus was repeatedly measured with a hydrogen clearance technique during a stepwise increase in arterial pressure. Regional blood flow in the thalamus was unchanged following acute ganglionectomy: 55 +/- 6 ml/100 g/min in the intact rats and 56 +/- 4 in the denervated rats. Sympathectomy on one side neither had effects on the pressure-flow relationship nor on the blood pressure levels of upper limits of autoregulation in the ipsilateral thalamus. In contrast, bilateral sympathetic denervation impaired the autoregulatory function in the thalamus and the upper limits were significantly lower than those in intact rats: 206 +/- 8 vs 226 +/- 10 mm Hg, respectively (P less than 0.02). It is concluded that overlapping innervation of sympathetic nerves has an important role in regulation of blood flow to the thalamus during an acute rise in arterial pressure in SHR.

Mortality and histological findings of the brain during and after cerebral ischemia in male and female spontaneously hypertensive rats.

Mortality and pathological changes of the brain during and after cerebral ischemia induced by bilateral carotid artery occlusion (BCO) were studied in male and female spontaneously hypertensive rats (SHR). Systolic arterial blood pressure at rest was significantly higher in male SHR (228 +/- 13 mm Hg, mean +/- S.E.M.) than female (192 +/- 12) (P less than 0.05). The average survival time during permanent occlusion was 11 +/- 6 h (mean +/- S.D.) in male SHR and 17 +/- 7 in female (P less than 0.005), though the cumulative mortality during 24-h ischemia was not different between male (88%) and female SHR (84%). Severe ischemic changes of nerve cells in the brain, especially in the cortex and hippocampus, were observed in 50% of male SHR at 3-h ischemia, while only 15% was observed in female SHR even after 7-h ischemia. After the temporary ischemia followed by reperfusion for 24 h, the mortality was varied between male and female SHR; 0, 31 and 100% after 1-, 3- and 5-h ischemia, respectively, in male SHR and 0% after 1- to 3-h ischemia and 33% after 5- to 7-h ischemia, respectively, in female. Ischemic changes of the brain tissue, such as acidophilic cytoplasm, nuclear degeneration and intercellular edema, were more frequent and severe in male SHR than female after recirculation following 3- or 5-h ischemia. It is concluded that the mortality and post-ischemic viability seem to be determined by the duration of ischemia and also by the degree of the neuronal damage, and female SHR is more tolerated for ischemic insult in comparison to male SHR.

L-arginine ameliorates recirculation and metabolic derangement in brain ischemia in hypertensive rats.

The effects of L-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 L-arginine (300 mg/kg, i.v.) increased the CBF by an average of 11 ml x 100 g-1 x min-1 (P < 0.05 vs. at rest), and N(omega)-nitro-L-arginine (L-NNA, an inhibitor of NO synthase, 5 mg/kg, i.v.) reduced the CBF by 5-6 ml x 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 L-arginine (P < 0.05 vs. L-NNA and saline), followed by 126 +/- 5 with saline and 109 +/- 3 with L-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 L-arginine (P < 0.01 vs. L-NNA and P < 0.05 vs. saline) and in contrast, significantly increased to 5.732 +/- 0.184 with L-NNA (P < 0.01 vs. L-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 L-arginine treatment (P < 0.01 vs. L-NNA) and in contrast, significantly increased 5.7-fold with L-NNA. The ATP and glucose levels were better preserved in the rats with L-arginine than in those with L-NNA or saline. These findings support that the enhanced postischemic hyperemia is beneficial to the ischemic brain and the administration of L-arginine may be potentially useful for the treatment of acute stroke.