Cerebral blood flow and tissue metabolism in experimental cerebral ischemia of spontaneously hypertensive rats with hyper-, normo-, and hypoglycemia

The present study was designed to clarify the effect of blood glucose level on cerebral blood flow and metabolism during and after acute cerebral ischemia induced by bilateral carotid ligation (BCL) in spontaneously hypertensive rats (SHR). Blood glucose levels were varied by intraperitoneal infusion of 50% of glucose (hyperglycemia), insulin with hypertonic saline (hypoglycemia) or hypertonic saline (normoglycemia). Cerebral blood flow (CBF) in the parietal cortex and thalamus was measured by hydrogen clearance technique, and the supratentorial metabolites of the brain frozen in situ were determined by the enzymatic method. In non-ischemic animals, blood glucose levels had no influence on the supratentorial lactate, pyruvate or adenosine triphosphate (ATP) concentrations. In ischemic animals, however, cortical CBF was reduced to less than 1% of the resting value at 3 hours after BCL. However, there were no substantial differences of CBF during and after ischemia among 3 glycemic groups. Cerebral lactate in the ischemic brain greatly increased in hyperglycemia (34.97 +/- 1.29 mmol/kg), moderately in normoglycemia (23.43 +/- 3.13 mmol/kg) and less in hypoglycemia (7.20 +/- 1.54 mmol/kg). In contrast, cerebral ATP decreased in hyperglycemia (0.93 +/- 0.19 mmol/kg) as much as it did in normoglycemia (1.04 +/- 0.25 mmol/kg), while ATP reduction was much greater in hypoglycemia (0.45 +/- 0.05 mmol/kg). At 1-hour recirculation after 3-hour ischemia, ATP tended to increase in all groups of animals, indicating the recovery of energy metabolism. Such metabolic recovery after recirculation was good in hypo- and normoglycemia, and was also evident in hyperglycemia. Our results suggest that hyperglycemia is not necessarily an unfavorable condition in acute incomplete cerebral ischemia.     

Regional cerebral blood flow in conscious stroke-prone spontaneously hypertensive rats

Regional cerebral blood flow (rCBF) was measured autoradiographically with [14C]iodoantipyrine as a diffusible tracer in two strains of conscious normotensive rats (Wistar Kyoto and local Wistar) and in two groups of spontaneously hypertensive stroke-prone rats (SHRSP) with a mean arterial pressure (MAP) below or above 200 mm Hg. In spite of the large differences in arterial pressure, rCBF did not differ significantly between the hypertensive and the normotensive groups in any of the 14 specified brain structures measured. However, rCBF increased asymmetrically within part of the caudate-putamen in two of nine SHRSP with a MAP above 200 mm Hg, indicating a regional drop in the elevated cerebrovascular resistance.     

Renal blood flow in acute cerebral ischemia in spontaneously hypertensive rats: effects of alpha- and beta-adrenergic blockade

The influences of acute cerebral ischemia on renal hemodynamics were examined in spontaneously hypertensive rats in which cerebral ischemia was induced by bilateral carotid artery occlusion. Renal and cerebral blood flow were measured with a hydrogen clearance technique. Either phenoxybenzamine (0.5 mg/kg body wt) or propranolol (2 mg/kg) was given i.v. immediately after ischemia was induced to examine the drugs' effects on cerebral and renal hemodynamics. One hour after ischemia, cerebral blood flow was markedly reduced to 5, 3, and almost 0% of the preischemic value in the untreated, phenoxybenzamine-treated, and propranolol-treated rats, respectively. In contrast, renal blood flow at that time was decreased to 65, 88, and 67%, respectively. The calculated renal vascular resistance was similarly increased to 151% in the untreated and 136% in the propranolol-treated rats, but decreased to 82% in the phenoxybenzamine-treated rats. The present results indicate that in acute cerebral ischemia renal blood flow was considerably decreased with concomitant increased renal vascular resistance, and that such reduction in renal blood flow was minimized by alpha-adrenergic blockade but not by beta-blockade. It is concluded that activation of the alpha-adrenergic system in acute cerebral ischemia causes renal vasoconstriction.     

Effects of long-term antihypertensive treatment on cerebral, thalamic and cerebellar blood flow in spontaneously hypertensive rats (SHR)

Cerebral blood flows (CBF) were measured in the parietal cortex, the thalamus and the cerebellum by the hydrogen clearance technique in anesthetized spontaneously hypertensive rats, of which hypertension was treated for 16 weeks (long-term) or 8 weeks (short-term) with antihypertensive agents of hydralazine and guanethidine. As compared to non-treated control animals, CBF in the three regions were significantly increased while the calculated cerebrovascular resistances (CVR) were decreased in hypertension-treated animals. Such CBF and CVR changes were greater in SHR with long-term than short-term therapy. Both an increase in CBF and a decrease in CVR were closely related to a fall in the blood pressure. From the present results, it was concluded that earlier and longer treatment of hypertension could lessen or even prevent the increased CVR due to the hypertensive vascular changes, and increase CBF as a result.     

Pentoxifylline: cerebral blood flow and glucose utilization in conscious spontaneously hypertensive rats

Pentoxifylline, 0.30 mg/kg/min, significantly reduced cerebral blood flow by 10-44% in 19 of 23 regions studied in conscious spontaneously hypertensive rats. Bilateral ligation of the common carotid arteries reduced cerebral blood flow to 24-46% of resting values in 20 structures; a further reduction to 10-27% of resting values was seen after pentoxifylline in 10 cortical or subcortical structures. Thus, in conscious hypertensive rats, there is no evidence that pentoxifylline redistributes blood flow from normal to low flow brain regions. Pentoxifylline did not reduce the metabolic rate of glucose.     

Cerebral blood flow and neuronal damage during progressive cerebral ischemia in gerbils

A combined autoradiographic and immunohistochemical method was used to correlate the extent of focal cerebral ischemia and morphologic ischemic damage following unilateral carotid occlusion in 16 gerbils for 5-30 minutes. Immunohistochemical lesions detectable by the reaction for microtubule-associated proteins 1 and 2 were visible in the subiculum-CA1 and CA2 regions of the hippocampus and layer III/IV of the cerebral cortex after 5 minutes of ischemia (n = 4). Local blood flow was promptly reduced but still heterogeneous after 10 minutes of ischemia (n = 4); local blood flow in immunohistochemical lesions was less than 5 ml/100 g/min except in highly vulnerable regions, where flow values of 5-15 ml/100 g/min were observed. After 15 minutes of ischemia (n = 4) local blood flow in less vulnerable regions including the thalamus and caudoputamen also declined to less than 5 ml/100 g/min, and immunohistochemical lesions became visible in those regions after 30 minutes of ischemia (n = 4). On the other hand, many brain regions tolerated local blood flow of less than 5 ml/100 g/min without ischemic damage. The present study demonstrates that selective tissue vulnerability during progressive cerebral ischemia depends on the degree of hypoperfusion and on factors inherent to neurons in various brain regions.     

Regional cerebral blood flow during hypotension in normotensive and stroke-prone spontaneously hypertensive rats: effect of sympathetic denervation

This study was performed to determine whether, in hypertensive and normotensive rats, chronic sympathetic denervation impairs cerebral vasodilator responses during hypotension, and to determine whether there are regional differences in the autoregulatory response of brain vessels during hypotension. The superior cervical ganglion was removed on one side in stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive (WKY) rats. Cerebral blood flow (CBF) was measured with microspheres when the rats were 5-6 months old. Chronic sympathetic denervation had little or no effect on cerebral vasodilator responses during acute hypotension in SHRSP and WKY. We suggest that the increase in incidence of ischemic infarction that we have observed previously after chronic sympathetic denervation in SHRSP probably is not the result of ischemia during episodes of hypotension. We also observed major regional differences in the response of cerebral vessels during acute hypotension in SHRSP: blood flow to brainstem was preserved better than flow to cerebrum and cerebellum. Thus the "lower limit" of the autoregulatory plateau differs in various regions of the brain in SHRSP.     

Regional cerebral blood flow autoregulation in normotensive and spontaneously hypertensive rats--effects of sympathetic denervation

The present study was designed to investigate the effect of acute sympathetic denervation on the regional cerebral blood flow (CBF) autoregulation during acute elevation of blood pressure in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). CBF to the parietal cortex and thalamus was measured by the hydrogen clearance method and, to test autoregulation, systemic arterial blood pressure was elevated by intravenous infusion of phenylephrine. Superior cervical ganglia were removed on both sides to interrupt sympathetic innervation in the deeper structures of the brain. Acute bilateral sympathetic denervation did not alter the resting blood pressure or CBF in either SHR or WKY. In innervated SHR, resting mean arterial pressure (MAP) was 165 +/- 5 mm Hg (mean +/- SEM) and the upper limit of autoregulation in the cortex was 210 +/- 3 mm Hg, which was significantly lower than that in the thalamus (229 +/- 3 mm Hg, p less than 0.02). In bilaterally denervated SHR, the upper limits were lowered to 193 +/- 4 mm Hg in the cortex (p less than 0.02 vs. innervated SHR) and to 207 +/- 5 mm Hg in the thalamus (p less than 0.02 vs. innervated). In WKY, resting MAP was approximately 55 mm Hg lower than that in SHR. Acute denervation reduced the upper limits from 142 +/- 3 mm Hg to 130 +/- 4 in the cortex (p less than 0.05) and from 158 +/- 4 to 145 +/- 4 in the thalamus (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Age-related vulnerability to cerebral ischemia in spontaneously hypertensive rats.

BACKGROUND AND PURPOSE: We sought to determine the effects of aging on regional cerebral blood flow and ischemic brain damage in transient cerebral ischemia in rats. METHODS: Five adult (5-6 months) and five aged (18-22 months) female spontaneously hypertensive rats were subjected to 20 minutes of bilateral carotid occlusion and 60 minutes of recirculation under amobarbital anesthesia (100 mg/kg i.p.). Regional cerebral blood flow in the hippocampus and striatum was measured using the hydrogen clearance method. Nine adult and 14 aged rats were subjected to 20 minutes of bilateral carotid occlusion or were sham-operated under ether anesthesia. Seven days after 20 minutes of cerebral ischemia, the rats' brains were perfusion fixed. Ischemic damage in the hippocampus and striatum was graded (0 [normal] to 3 [majority of neurons damaged]). RESULTS: After 20 minutes of bilateral carotid occlusion, striatal cerebral blood flow decreased to 9.1 +/- 1.5 and 3.9 +/- 2.0 ml/100 g/min in aged and adult rats, respectively, and hippocampal cerebral blood flow decreased to 8.6 +/- 2.4 and 5.7 +/- 2.4 in aged and adult rats, respectively. Although these ischemic cerebral blood flow values were not significantly different between the two age groups, scores for ischemic damage in the hippocampus CA-1 subfield and striatum were significantly higher in aged than in adult rats (p less than 0.05, Kruskal-Wallis' h test with Bonferroni correction). CONCLUSIONS: We conclude that aging may be a primary factor in the development of greater ischemic neuronal damage observed in aged hypertensive rats.     

Neuroprotective effects of candesartan against cerebral ischemia in spontaneously hypertensive rats

The cerebral protective effects of 4-week treatment with candesartan (0.3, 1, 3 mg/kg/day) and ramipril (0.5, 1.5, 5 mg/kg/day) were examined in spontaneous hypertensive rats 24 h after middle cerebral artery occlusion. We found that both candesartan and ramipril could reduce the infarct volume and neurological deficit scores compared with control. Importantly, the neuroprotective effects of candesartan (1 mg/kg/day) were abolished by PD123319 (an AT2 receptor antagonist, 10 mg/kg/day). AT1 receptor gene expression was downregulated while AT2 receptor gene expression was upregulated by candesartan. It is concluded that candesartan appears to provide beneficial effects against stroke in spontaneous hypertensive rats in three ways: AT1 receptor antagonism, downregulation of AT1 receptor expression and upregulation of AT2 receptor expression.     

Cerebral blood flow and cerebral hematocrit in patients with cerebral ischemia measured by single-photon emission computed tomography

Abstract– Single-photon emission computed tomography (SPECT) was used for the measurement of regional cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral hematocrit (Hct). CBF was measured using N-isopropyl-p-I-123-Iodoamphetamine. CBV was measured by both RBC tracer (Tc-99m RBC) and plasma tracer (Tc-99m human serum albumin) and cerebral hematocrit (Hct) was calculated. In normals, the cerebral-to-large vessel Hct ratio was 75.9%. Isovolemic hemodilution in patients with high Hct tended to increase the cerebral-to-large vessel Hct ratio. Low CBF, high CBV and slow cerebral blood mean transit time (MTT by dynamic CT scanning) was seen during the acute stage of completed infarction and during the symptom-free interval of TIA. Cerebral Hct was increased in the ischemic region of poor prognosis.     

Effects of hyperventilation on cerebral blood flow and brain tissue metabolism in normotensive and spontaneously hypertensive rats

Cerebral vascular carbon dioxide (CO2) reactivities were compared in normotensive (NTR) and hypertensive (SHR) rats. Cerebral blood flow (CBF) in cortex and thalamus were evaluated before and during one hour of hyperventilation. After one hour of hyperventilation brain lactate, pyruvate, and ATP concentrations were also determined. Significant and similar reductions of CBF due to hyperventilation induce hypocapnia were found in both NTR and SHR groups. In contrast the percent increase in cerebrovascular resistance (CVR) per unit decrease in paCO2 was significant, indicating that hypocapnia induced vasoconstriction is greater in NTR than in SHR groups. During hyperventilation the average value for lactate in the NTR group was 3.98 mM/kg. In contrast it was 3.15 mM/kg in the SHR group, a significant difference (p less than 0.05). When paCO2 fell below 15 mm Hg the cerebral lactate increased strikingly in the NTR group and cortical CVR was reduced suggesting that an accumulation of the ischemic metabolites caused dilatation of the constricted cerebral vessels. In contrast the SHR group disclosed no such changes. The increase CVR characteristic of SHR appeared to diminish the cerebral vasoconstrictive response to hypocapnia. As a result ischemic metabolites in the brain do not increase in this group to the degree that they do in NTR.     

Effect of allopurinol on ischemia and reperfusion-induced cerebral injury in spontaneously hypertensive rats

In spontaneously hypertensive rats, we studied the participation of xanthine oxidase-linked free radical in ischemia and reperfusion-induced cerebral injury, using allopurinol, a xanthine oxidase inhibitor. The loss of righting reflex was noted in some animals after a 4 hour occlusion of bilateral common carotid arteries and 19 of 25 animals died within 72 hours after reperfusion. One hour after reperfusion, the cerebral water content increased significantly, with an increase in sodium content and a decrease in potassium content. In 7 animals treated with oral administrations of allopurinol (200 mg/kg) 24 hours and 1 hour before occlusion, no death was found either during occlusion or after reperfusion, and the loss of righting reflex was noted in only one animal 24-72 hours following reperfusion. The increase in cerebral water content and accompanied changes in electrolyte contents were clearly prevented by allopurinol. These results suggest the possibility that the production of xanthine oxidase-linked free radical participates in cerebral injury due to ischemia and reperfusion in spontaneously hypertensive rats.     

Protective effects of 4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride (bifemelane) on acutely induced cerebral ischemia in Mongolian gerbils and spontaneously hypertensive rats (SHR)

Effects of new antihypoxic agent (bifemelane) on survival and brain metabolism were studied in acute cerebral ischemia induced by bilateral carotid artery ligation in mongolian gerbils and SHR. Either 10 mg/kg or 30 mg/kg body weight of bifemelane solved in distilled water was intraperitoneally administered 1 hr in gerbils and 1.5 hrs in SHR prior to carotid ligation, and same amount of vehicle was also given in similar manner for control animals. Brain tissue metabolites such as lactate, pyruvate and ATP were determined by using the enzymatic technique in the ischemic brain frozen in situ 1 hr after carotid ligations in SHR. Mean survival times following carotid ligations were 186 +/- 255 min (+/- SD) in control gerbils, 429 +/- 455 min in those with 10 mg/kg of bifemelane, and 310 +/- 429 min in those with 30 mg/kg respectively, its difference between control and 10 mg/kg group being significant (P less than 0.05). Supratentorial lactate concentrations in the ischemic brains of SHR were substantially the same among the groups, whereas ATP levels were 0.62 +/- 0.24 mM/kg in control animals, 1.10 +/- 0.67 mM/kg in rats with 10 mg/kg of the drug, and 1.13 +/- 0.42 mM/kg in those with 30 mg/kg, respectively. In animals with a high dose pretreatment, the reduction of ATP was significantly smaller than that in control (P less than 0.02), indicating that this agent prevents a decline of high energy phosphate in the ischemic brain although anaerobic metabolites increase similarly in animals of all experiment groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of antihypertensive treatment with budralazine on autoregulation of cerebral blood flow in spontaneously hypertensive rats

We studied the effect of chronic antihypertensive treatment with budralazine on the lower blood pressure limit of cerebral blood flow autoregulation using spontaneously hypertensive rats. Cerebral blood flow in the parietal cortex and caudate nucleus was measured to determine the lower limit using the hydrogen clearance method. The lower limit in both cerebral regions was significantly higher in 10 untreated spontaneously hypertensive rats than in 10 Wistar-Kyoto rats. The upward-shifted lower limit was restored to close to normal in the caudate nucleus and was partially restored in the parietal cortex of nine rats by 9 weeks of treatment with the high dose (50-68 mg/kg/day) of budralazine, which kept blood pressure constant at approximately normotension during the treatment period; the lower limit was slightly restored in both cerebral regions of seven rats by 4 weeks of treatment with the high dose. However, 9 weeks of treatment with the low dose (19-27 mg/kg/day) of budralazine, which produced moderate continuous hypotension in nine rats, did not apparently influence the lower limit. Our results suggest that long-term antihypertensive therapy with budralazine reduces the upward-shifted lower blood pressure limit of cerebral blood flow autoregulation toward normal and that the restoration induced by budralazine depends on the degree of blood pressure reduction as well as on the duration of the therapeutic period.     

Cerebral blood flow during dihydralazine-induced hypotension in hypertensive rats

The cerebrovascular effects of graded, controlled dihydralazine-induced hypotension were studied in rats with renal hypertension (RHR) and spontaneous hypertension (SHR). Repeated measurements of cerebral blood flow (CBF) were made using the intraarterial 133Xenon injection technique in anaesthetised normocapnic animals. Dihydralazine was administered in single increasing i.v. doses (0.1 to 2 mg/kg), and CBF measured after each dose when a stable blood pressure had been reached. From a resting level of 145 +/- 7 mm Hg in RHR and 138 +/- 11 mm Hg in SHR, mean arterial pressure (MAP) fell stepwise to a minimum of around 50 mm Hg. CBF was preserved during dihydralazine induced hypotension, and remained at the resting level of 79 +/- 13 ml/100 g . min in RHR and 88 +/- 16 ml/100 g . min in SHR. Following 2 hours hypotension at the lowest pressure reached, the rats were sacrificed by perfusion fixation and the brains processed for light microscopy. Evidence of regional ischaemic brain damage was found in 4 of 11 animals: in 2 cases the damage appeared to be accentuated in the arterial boundary zones. Although the lower limit of CBF autoregulation in these rats is around 100 mm Hg during haemorrhagic hypotension, dihydralazine brought MAP to around 50 mm Hg without any concomitant fall in CBF. This was interpreted as being due to direct dilatation of cerebral resistance vessels. The combination of low pressure and direct dilatation may have resulted in uneven perfusion, thus accounting for the regional ischaemic lesions.     

Effects of carbon dioxide inhalation on cerebral blood flow and oxygen tissue level in spontaneously hypertensive rabbits.

BACKGROUND AND PURPOSE: Because previous studies have yielded conflicting results, this study was designed to investigate the efficiency of cerebrovascular reactivity to carbon dioxide in hypertension associated with moderate diffuse cerebral ischemic lesions. METHODS: The effects of carbon dioxide inhalation on mean arterial blood pressure, heart and respiration rates, cerebral cortical blood flow, polarographically detected oxygen currents (oxygen availability), and cerebral electrical activity were compared in 14 spontaneously hypertensive and 16 normotensive rabbits anesthetized with urethane and alpha-chloralose. Blood flow was measured with the hydrogen clearance and thermal clearance methods. RESULTS: In the resting state the frequency of electrical activity shifted to slower components, the levels of oxygen availability and cerebral blood flow were lower (p less than 0.01), and the ratio of the two latter parameters was greater (p less than 0.01) in hypertensive rabbits than in normotensive animals. Carbon dioxide inhalation induced more marked increases in cerebral blood flow, respiration rate, and oxygen availability in hypertensive (p less than 0.01) than in normotensive (p less than 0.05) rabbits. The ratio of oxygen availability to cerebral blood flow decreased (p less than 0.01) in the former and did not change significantly in the latter group. The carbon dioxide-induced rise in blood flow was also slower and more protracted in hypertensive rabbits (p less than 0.01). Histological investigation revealed groups of neurons with ischemic changes in the cortex of the hypertensive rabbits. CONCLUSIONS: We suggest that in hypertensive rabbits the mild multiple ischemic lesions are the basis of functional disturbances, including reduced resting cerebral blood flow, greater oxygen tissue level, slower response to carbon dioxide, and greater vasodilatory capacity.