Lower Limit Of Cerebral Blood Flow Autoregulation Research Articles

No effect of the angiotensin receptor blocker candesartan on cerebrovascular autoregulation in rats during very high and low sodium intake.

Autoregulation of cerebral blood flow (CBF) denotes that CBF is constant despite fluctuation of blood pressure within wide limits. Inhibition of the renin–angiotensin system (RAS) is known to decrease the lower and upper limits of CBF autoregulation. We have previously shown that this includes inhibition by the angiotensin receptor blocker (ARB) candesartan. In the present study we investigated the influence of the ARB candesartan on the lower limit of CBF autoregulation in two groups of Sprague-Dawley rats, on high (4.0% Na+) and low (0.004% Na+) sodium diet, respectively. Control animals were given the same diet, but no ARB. CBF was studied with the laser Doppler method. Blood pressure was lowered by controlled bleeding. Results revealed that both high and low sodium diet with low and high renin levels respectively block the influence of candesartan on CBF autoregulation. This was expected in rats on a high salt diet with a low renin level, but unexpected in rats with a low salt intake with a high renin level.

Cerebral Blood Flow Autoregulation in Sepsis for the Intensivist: Why Its Monitoring May Be the Future of Individualized Care.

Cerebral blood flow (CBF) autoregulation maintains consistent blood flow across a range of blood pressures (BPs). Sepsis is a common cause of systemic hypotension and cerebral dysfunction. Guidelines for BP management in sepsis are based on historical concepts of CBF autoregulation that have now evolved with the availability of more precise technology for its measurement. In this article, we provide a narrative review of methods of monitoring CBF autoregulation, the cerebral effects of sepsis, and the current knowledge of CBF autoregulation in sepsis. Current guidelines for BP management in sepsis are based on a goal of maintaining mean arterial pressure (MAP) above the lower limit of CBF autoregulation. Bedside tools are now available to monitor CBF autoregulation continuously. These data reveal that individual BP goals determined from CBF autoregulation monitoring are more variable than previously expected. In patients undergoing cardiac surgery with cardiopulmonary bypass, for example, the lower limit of autoregulation varied between a MAP of 40 to 90 mm Hg. Studies of CBF autoregulation in sepsis suggest patients frequently manifest impaired CBF autoregulation, possibly a result of BP below the lower limit of autoregulation, particularly in early sepsis or with sepsis-associated encephalopathy. This suggests that the present consensus guidelines for BP management in sepsis may expose some patients to both cerebral hypoperfusion and cerebral hyperperfusion, potentially resulting in damage to brain parenchyma. The future use of novel techniques to study and clinically monitor CBF autoregulation could provide insight into the cerebral pathophysiology of sepsis and offer more precise treatments that may improve functional and cognitive outcomes for survivors of sepsis.

Cigarette smoke extract inhibits fluid and HCO3− secretion and CFTR activity in guinea pig pancreatic ductal cells

Spontaneous depolarizations around the core are a consistent feature of focal cerebral ischemia, but the associated regional hemodynamic changes are heterogeneous. We determined how the features of depolarizations relate to subsequent cerebral blood flow (CBF) changes in global forebrain ischemia.Forebrain ischemia was produced in halothane-anesthetized rats (n = 13) by common carotid artery occlusion and hypovolemic hypotension. Mean arterial blood pressure (MABP) was monitored via a femoral catheter. Specific illuminations allowed the capture of image sequences through a cranial window to visualize: changes in membrane potential (voltage-sensitive dye method); CBF (laser speckle contrast imaging); cerebral blood volume (intrinsic optical signal, IOS at 540–550 nm); and hemoglobin deoxygenation (IOS at 620–640 nm).A depolarization occurred (n = 9) when CBF fell below 43.4 ± 5% of control (41 ± 4 mmHg MABP), and propagated with a distinct wave front at a rate of 2.8 mm/min. Depolarizations were either persistent (n = 4), intermediate (n = 3) or short, transient depolarization (n = 2). Persistent and intermediate depolarizations were associated with sustained hypoperfusion (−11.7 ± 5.1%) and transient hypoperfusion (−17.4 ± 5.2, relative to CBF before depolarization). Short, transient depolarizations did not generate clear CBF responses.Depolarizations during incomplete global ischemia occurred at the lower limit of CBF autoregulation, propagated similar to spreading depolarization (SD), and the hemodynamic responses indicated inverse neurovascular coupling. Similar to SDs associated with focal stroke, the propagating event can be persistent or transient.

An Observational Study of Cerebral Blood Flow Velocity During Hypotensive Epidural Anesthesia.

Hypotensive epidural anesthesia (HEA), as practiced at our institution, uses sympathetic blockade to achieve mean arterial blood pressure (MAP) of ≤50 mm Hg while administering epinephrine by infusion to support the circulation. HEA has not been associated with gross adverse effects on neurologic outcome or cognitive function in the postoperative period, suggesting adequate cerebral blood flow (CBF). However, the use of MAPs well below the commonly accepted lower limit of CBF autoregulation suggests that CBF should be significantly reduced below normal levels. To examine these conflicting hypotheses, we performed a prospective investigation of the effects of HEA on CBF velocity (CBFV), an accepted index of cerebral perfusion. Fifty-two hip replacement patients were studied. HEA was induced by lumbar epidural injection of local anesthetic and infusion of epinephrine to achieve an MAP of ≤50 mm Hg. Propofol/midazolam sedation was administered. Baseline CBFV was recorded pre-HEA (after sedation and before local anesthetic injection) and continuously thereafter. During HEA, MAP decreased by 40% and was stable throughout. The CBFVmean at baseline and at 3 HEA intervals during surgery was 46 ± 12 (SD), 45 ± 12, 47 ± 14, and 47 ± 14 cm·s, respectively. Although mean CBFVmean did not vary, there was considerable heterogeneity among patients. Twelve patients (23%) experienced reductions of CBFVmean of >20% during HEA intervals (99% lower confidence limit: 9%) and 6 (12%) reductions of >30% (99% lower confidence limit: 1%). There was no correlation between CBFVmean and MAP for MAPs between 100 and 40 mm Hg (R = 0.0015, P = 0.44). There were no instances of gross postoperative neurologic injury. Both hypotheses proved partially correct. CBFV was sometimes well maintained during HEA, despite MAPs well below the commonly accepted lower limit of autoregulation. However, there was considerable interindividual heterogeneity with 23% of subjects having CBFV reductions >20% (99% lower confidence limit: 9%), with some reductions approaching the threshold for ischemic injury. The present data do not allow us to determine whether hypotension would be similarly tolerated in other circumstances.

Ischemia-induced depolarizations and associated hemodynamic responses in incomplete global forebrain ischemia in rats

Spontaneous depolarizations around the core are a consistent feature of focal cerebral ischemia, but the associated regional hemodynamic changes are heterogeneous. We determined how the features of depolarizations relate to subsequent cerebral blood flow (CBF) changes in global forebrain ischemia.Forebrain ischemia was produced in halothane-anesthetized rats (n=13) by common carotid artery occlusion and hypovolemic hypotension. Mean arterial blood pressure (MABP) was monitored via a femoral catheter. Specific illuminations allowed the capture of image sequences through a cranial window to visualize: changes in membrane potential (voltage-sensitive dye method); CBF (laser speckle contrast imaging); cerebral blood volume (intrinsic optical signal, IOS at 540–550nm); and hemoglobin deoxygenation (IOS at 620–640nm).A depolarization occurred (n=9) when CBF fell below 43.4±5% of control (41±4mmHg MABP), and propagated with a distinct wave front at a rate of 2.8mm/min. Depolarizations were either persistent (n=4), intermediate (n=3) or short, transient depolarization (n=2). Persistent and intermediate depolarizations were associated with sustained hypoperfusion (−11.7±5.1%) and transient hypoperfusion (−17.4±5.2, relative to CBF before depolarization). Short, transient depolarizations did not generate clear CBF responses.Depolarizations during incomplete global ischemia occurred at the lower limit of CBF autoregulation, propagated similar to spreading depolarization (SD), and the hemodynamic responses indicated inverse neurovascular coupling. Similar to SDs associated with focal stroke, the propagating event can be persistent or transient.

Bradykinin Antagonist Counteracts the Acute Effect of Both Angiotensin-Converting Enzyme Inhibition and of Angiotensin Receptor Blockade on the Lower Limit of Autoregulation of Cerebral Blood Flow

The lower limit of autoregulation of cerebral blood flow (CBF) can be modulated with both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB). The influence of bradykinin antagonism on ARB-induced changes was the subject of this study. CBF was measured in Sprague-Dawley rats with laser Doppler technique. The blood pressure was lowered by controlled bleeding. Six groups of rats were studied: a control group and five groups given drugs intravenously: an ACE inhibitor (enalaprilat), an ARB (candesartan), a bradykinin-2 receptor antagonist (Hoe 140), a combination of enalaprilat and Hoe 140, and a combination of candesartan and Hoe 140. In the control group, the lower limit of CBF autoregulation was 54±9 mm Hg (mean±s.d.), with enalaprilat it was 46±6, with candesartan 39±8, with Hoe 140 53±6, with enalaprilat/Hoe 140 52±6, and with candesartan/Hoe 140 50±7. Both enalaprilat and candesartan lowered the lower limit of autoregulation of CBF significantly. The bradykinin antagonist abolished not only the effect of the ACE inhibitor but surprisingly also the effect of the ARB on the lower limit of CBF autoregulation, the latter suggesting an effect on intravascular bradykinin.

Effect of Pregnancy and Nitric Oxide on the Myogenic Vasodilation of Posterior Cerebral Arteries and the Lower Limit of Cerebral Blood Flow Autoregulation

Hemorrhage during parturition can lower blood pressure beyond the lower limit of cerebral blood flow (CBF) autoregulation that can cause ischemic brain injury. However, the impact of pregnancy on the lower limit of CBF autoregulation is unknown. We measured myogenic vasodilation, a major contributor of CBF autoregulation, in isolated posterior cerebral arteries (PCAs) from nonpregnant and late-pregnant rats (n = 10/group) while the effect of pregnancy on the lower limit of CBF autoregulation was studied in the posterior cerebral cortex during controlled hemorrhage (n = 8). Pregnancy enhanced myogenic vasodilation in PCA and shifted the lower limit of CBF autoregulation to lower pressures. Inhibition of nitric oxide synthase (NOS) prevented the enhanced myogenic vasodilation during pregnancy but did not affect the lower limit of CBF autoregulation. The shift in the autoregulatory curve to lower pressures during pregnancy is likely protective of ischemic injury during hemorrhage and appears to be independent of NOS.

Assessment of cerebral blood flow autoregulation (CBF AR) with rheoencephalography (REG): studies in animals

The ability of cerebral vasculature to regulate cerebral blood flow (CBF) in the face of changes in arterial blood pressure (SAP) or intracranial pressure (ICP) is an important guard against secondary ischemia in acute brain injuries, and official guidelines recommend that therapeutic decisions be guided by continuous monitoring of CBF autoregulation (AR). The common method for CBF AR monitoring, which rests on real-time derivation of the correlation coefficient (PRx) between slow oscillations in SAP and ICP is, however, rarely used in clinical practice because it requires invasive ICP measurements. This study investigated whether the correlation coefficient between SAP and the pulsatile component of the non-invasive transcranial bioimpedance signal (rheoencephalography, REG) could be used to assess the state and lower limit of CBF AR. The results from pigs and rhesus macaques affirm the utility of REG; however, additional animal and clinical studies are warranted to assess selectivity of automatic REG-based evaluation of CBF AR.

Validation of a Stand-Alone Near-Infrared Spectroscopy System for Monitoring Cerebral Autoregulation During Cardiac Surgery

Individualizing arterial blood pressure (ABP) targets during cardiopulmonary bypass (CPB) based on cerebral blood flow (CBF) autoregulation monitoring may provide a more effective means for preventing cerebral hypoperfusion than the current standard of care. Autoregulation can be monitored in real time with transcranial Doppler (TCD). We have previously demonstrated that near-infrared spectroscopy (NIRS)-derived regional cerebral oxygen saturation (rS(c)O(2)) provides a clinically suitable surrogate of CBF for autoregulation monitoring. The purpose of this study was to determine the accuracy of a stand-alone "plug-and-play" investigational system for autoregulation monitoring that uses a commercially available NIRS monitor with TCD methods. TCD monitoring of middle cerebral artery CBF velocity and NIRS monitoring were performed in 70 patients during CPB. Indices of autoregulation were computed by both a personal computer-based system and an investigational prototype NIRS-based monitor. A moving linear correlation coefficient between slow waves of ABP and CBF velocity (mean velocity index [Mx]) and between ABP and rS(c)O(2) (cerebral oximetry index [COx]) were calculated. When CBF is autoregulated, there is no correlation between CBF and ABP; when CBF is dysregulated, Mx and COx approach 1 (i.e., CBF and ABP are correlated). Linear regression and bias analysis were performed between time-averaged values of Mx and COx derived from the personal computer-based system and from COx measured with the prototype monitor. Values for Mx and COx were categorized in 5 mm Hg bins of ABP for each patient. The lower limit of CBF autoregulation was defined as the ABP where Mx incrementally increased to ≥0.4. There was correlation and good agreement between COx derived from the prototype monitor and Mx (r = 0.510; 95% confidence interval, 0.414-0.595; P < 0.001; bias, -0.07 ± 0.19). The correlation and bias between the personal computer-based COx and the COx from the prototype NIRS monitor were r = 0.957 (95% confidence interval, 0.945-0.966; P < 0.001 and 0.06 ± 0.06, respectively). The average ABP at the lower limit of autoregulation was 63 ± 11 mm Hg (95% prediction interval, 52-74 mm Hg). Although the mean ABP at the COx-determined lower limit of autoregulation determined with the prototype monitor was statistically different from that determined by Mx (59 ± 9 mm Hg; 95% prediction interval, 50-68 mm Hg; P = 0.026), the difference was not likely clinically meaningful. Monitoring CBF autoregulation with an investigational stand-alone NIRS monitor is correlated and in good agreement with TCD-based methods. The availability of such a device would allow widespread autoregulation monitoring as a means of individualizing ABP targets during CPB.

In vivo cerebral blood flow autoregulation studies using rheoencephalography

Acute management of patients with traumatic brain/blast injury is a challenge. To minimize secondary injury and improve outcome, it is critical to detect neurological deterioration early, when it is potentially reversible. One potential monitoring method is cerebral electrical impedance (rheoencephalography-REG) because of its non-invasiveness and good time resolution. Reported here are the results of cerebral blood flow (CBF) manipulations comparing electroencephalogram (EEG) with REG (both intra-cerebral) and measuring with surface and skull REG electrodes. Our hypothesis was that REG would reflect spreading depression and CBF autoregulation. Animal experiments were performed using one rat (four trials with intracerebral electrodes), monkeys (n=8, with surface electrodes) and pigs (n = 24 pigs with skull electrodes; 57 trials, 19 types of liposomes). Challenges included intracranial pressure (ICP) elevation, liposome infusion, and hemorrhage. Data were stored on a PC and evaluated off line. CBF autoregulation was evaluated both by visual inspection and by a Matlab script. These studies confirmed that REG reflects CBF autoregulation and that REG is useful for detecting spreading depression (SD), vasospasm and the lower limit of CBF autoregulation. These findings have clinical relevance for use in noninvasive neuro-monitoring in the neurosurgery intensive care and during transportation of patients with brain injury.

Age-dependent effects of gradual decreases in cerebral perfusion pressure on the neurochemical response in swine

There is still a lack of knowledge on the age-dependent relation between a reduction in cerebral perfusion pressure (CPP) and compromised brain perfusion leading to excessive transmitter release and brain damage cascades. The hypothesis is that an age-dependent lower threshold of cerebral blood flow (CBF) autoregulation determines the amount and time course of transmitter accumulation. This was a prospective randomized, blinded animal study performed in a university laboratory involving eight newborn and 11 juvenile anesthetized pigs. Striatal dopamine, glutamate, glucose, and lactate were monitored by microdialysis. For CPP manipulation, the cisterna magna was infused with artificial cerebrospinal fluid to control intracranial pressure at the maintained arterial blood pressure (stepwise CPP decrease in 15-min stages to 50, 40, 30, and finally 0 mmHg). Juvenile pigs showed a gradual decrease in CBF between 50 mmHg CPP (CPP-50) and 30 mmHg CPP (CPP-30), but a significant CBF reduction did not occur in newborn piglets until CPP-30 (P < 0.05). At CPP-30, brain oxidative metabolism was reduced only in juveniles, concomitantly with elevations in dopamine and glutamate levels (P < 0.05). In contrast, newborn piglets exhibited a delayed and blunted accumulated of transmitters and metabolites (P < 0.05). The lower limit of CBF autoregulation was associated with modifications in neurochemical parameters that clearly occurred before brain oxidative metabolism was compromised. Early indicators for mild to moderate hypoperfusion are elevated levels of lactate and dopamine, but elevated levels of glutamate appear to be an indicator of brain ischemia. The shift to the left of the lower autoregulatory threshold is mainly responsible for the postponed neurochemical response to decrements in the CPP in the immature brain.

Effects of Benidipine, a Long-Lasting Dihydropyridine-Ca2+ Channel Blocker, on Cerebral Blood Flow Autoregulation in Spontaneously Hypertensive Rats

Chronic hypertension shifts cerebral blood flow (CBF) autoregulation towards higher blood pressure. We examined whether or not benidipine, a long-lasting dihydropyridine calcium channel blocker (CCB), improves the CBF autoregulation in spontaneously hypertensive rats (SHRs). CBF was analyzed by laser-Doppler flowmetry during stepwise hypotension by controlled bleeding. The lower limit of CBF autoregulation was calculated as the mean arterial blood pressure at which CBF decreased by 10% of the baseline. Mean arterial blood pressure and cerebral vascular resistance in SHRs were higher than those in normotensive Wistar rats. Oral administration of benidipine (3 mg/kg) for 8 d lowered the mean arterial blood pressure and cerebral vascular resistance, which were equivalent to the effects of amlodipine (3 mg/kg), another CCB, or candesartan (1 mg/kg), an Angiotensin II type-1 receptor blocker. The lower limit of CBF autoregulation in SHRs (142+/-4 mmHg) was significantly shifted to a higher-pressure level compared with Wistar rats (59+/-2 mmHg). The lower limit of CBF autoregulation was significantly lower in the benidipine-treated group (91+/-4 mmHg) than that in the control SHRs, and similar to that of the amlodipine group (97+/-6 mmHg). Benidipine reduced the lower limit of CBF autoregulation more effectively than candesartan (109+/-4 mmHg). In conclusion, benidipine shifted the limit of CBF autoregulation towards lower blood pressure in SHRs under hypotensive conditions by hemorrhage. These results suggest that benidipine may be useful for the treatment of hypertensive patients with the elderly or cerebrovascular disorders, in whom autoregulation of CBF is impaired.

Valsartan Improves the Lower Limit of Cerebral Autoregulation in Rats

The effects of angiotensin II type 1 receptor blockers (ARBs) on cerebral blood flow (CBF) autoregulation have not been fully clarified. Thus, we examined the acute effect of valsartan, the most selective ARB, on CBF autoregulation in spontaneously hypertensive rats. Intravenous administration of valsartan (0.3 mg/kg) reduced the mean arterial pressure (MAP) from 184+/-5 (mean+/-SEM) to 174+/-5 mmHg (p<0.001) without affecting CBF as measured by laser-Doppler flowmetry. The lower limit of CBF autoregulation (the MAP at which the CBF was 80% of the baseline value) in the valsartan-treated group (122+/-3 mmHg) was significantly lower than that in the control group (135+/-4 mmHg, p<0.05). Reverse transcribed-polymerase chain reaction and immunohistochemical staining demonstrated that both angiotensin II type 2 receptors and angiotensin II type 1 receptors (AT1Rs) were expressed in endothelial and smooth muscle cells of the rat cerebral arteries. These results suggest that specific inhibition of AT1Rs in the cerebral circulation causes the leftward shift of the lower limit of autoregulation.

Impaired Cerebral Vasoreactivity in a Transgenic Mouse Model of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Arteriopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease causing stroke and dementia. The disease is caused by highly stereotyped mutations in NOTCH3, which is restrictively expressed in vascular smooth muscle cells (VSMCs). The mechanisms of compromised cerebral hemodynamics in CADASIL remain to be elucidated. We tested the hypothesis that mutant NOTCH3 impairs the vasomotor function of cerebral vessels. Vasomotor function was examined in vivo in transgenic mice expressing a mutant NOTCH3 in VSMCs (TgNotch3R90C). Mice develop an age-dependent arteriopathy similar to that seen in CADASIL, without brain parenchyma lesions. Using laser-Doppler flowmetry, we assessed in awake TgNotch3R90C mice and wild-type littermates the cerebrovascular reactivity to 2 potent vasodilator stimuli (acetazolamide and hypercapnia) and cerebral blood flow (CBF) autoregulation during stepwise blood pressure elevations and reductions. Mice were studied at 18 months of age, when the CADASIL features are apparent, and at 10 months of age, before their appearance. Eighteen-month-old TgNotch3R90C mice showed reduced responses to hypercapnia and acetazolamide, higher cerebrovascular resistance during hypertension, and their lower limit of CBF autoregulation was shifted to higher blood pressures. Cerebrovascular responses were similarly impaired in 10-month-old TgNotch3R90C mice. Cerebrovascular reactivity is compromised early in TgNotch3R90C mice. The data show an impaired autoregulation and are suggestive of a decreased relaxation or increased resistance of cerebral vessels. Our findings indicate that vascular dysfunction is an early pathogenic event that may promote the subsequent development of brain ischemia in CADASIL.

Effects of Porta-Systemic Shunting and Ammonia Infusion on Cerebral Blood Flow Autoregulation in the Rat

Portacaval shunting of blood, hyperammonemia, and impaired cerebral blood flow (CBF) autoregulation are assumed to be involved in the development of high intracranial pressure (ICP) in liver failure. In this study, we determined whether CBF autoregulation is impaired by portacaval anastomosis and hyperammonemia. Four groups of pentobarbital-sedated and mechanically ventilated rats were investigated after construction of a portacaval anastomosis or following sham operation. Half of the rats received either infusion of ammonia (55 micromol/kg/minute) or saline for 180 minutes. Arterial pressure and ICP was monitored, and lower limit of CBF autoregulation was determined. Lower limit of autoregulation was preserved in all four groups of studied animals; vehicle lower limits were 40 +/- 2.3, 40 +/- 2, 54 +/- 1, and 51 +/- 3 mmHg in sham-operated rats, sham rats receiving ammonia infusion, portacaval anastomosis-vehicle animals, and portacaval anastomosis-hyperammonemia animals, respectively. The lower limit of auto regulation was higher in portacaval anastomosis rats (p = 0.01) compared to the sham- operated rats. Hyperammonemia in portacaval anastomosis rats did not aggravate this. Portacaval anastomosis and hyperammonemia does not impair the lower limit of CBF autoregulation. However, shunting of portal blood to the systemic circulation shifts the lower limit of autoregulation to higher blood pressure values, making the brain more sensitive to episodes of arterial hypotension.

Effect of nephrectomy and captopril on autoregulation of cerebral blood flow in rats.

The present study investigated the effect of circulating versus locally present renin on cerebral blood flow (CBF) and its autoregulation in rats. CBF was measured repetitively with the intracarotid 133Xe injection method, whereas blood pressure was lowered to determine the lower limit of autoregulation. To remove renin from the blood, rats were bilaterally nephrectomized and kept alive with peritoneal dialysis for 48 h. Five groups of animals were studied: 1) nephrectomized dialyzed rats, 2) nephrectomized dialyzed rats given a single intravenous dose of the angiotensin-converting enzyme inhibitor captopril (10 mg/kg), 3) sham nephrectomized and dialyzed rats, 4) rats receiving drugs as dialyzed rats but no surgery, and 5) rats given the same diet as the other groups but no drugs and no surgery. Baseline blood pressure was significantly lower in nephrectomized rats compared with controls. Nephrectomy, captopril, sham operation, or dialysis did not influence baseline CBF. The lower limit of CBF autoregulation was significantly lower in nephrectomized (53 +/- 4 mmHg) and sham-operated (58 +/- 4 mmHg) rats compared with diet control rats (78 +/- 3 mmHg). Captopril significantly decreased the lower limit in nephrectomized rats (35 +/- 2 mmHg). Thus removal of circulating renin caused no change in the lower limit of autoregulation. By contrast, captopril lowered the lower limit even in the absence of circulating renin and hence appeared to exert its effect on components of the renin-angiotensin system in the cerebral resistance vessel walls.

Cerebral arteriolar structure and function in pinealectomized rats.

We examined cerebral arteriolar structure and autoregulation of cerebral blood flow (CBF) in control (n = 8), sham-operated (n = 8), pinealectomized (n = 10), and pinealectomized plus melatonin-treated (0.51 +/- 0.01 mg x kg(-1) x day(-1) in drinking water, n = 9) young Wistar rats. The lower limit of CBF autoregulation (LLCBF) was determined by measurement of CBF (in arbitrary units, laser Doppler) during stepwise hypotensive hemorrhage; the arteriolar internal diameter (ID; in microm, cranial window) was also measured. Measurements of ID were repeated during a second stepwise hypotension after smooth muscle cell deactivation (67 mmol/l EDTA). The cross-sectional area (CSA) was measured by histometry. CSA and EDTA-induced vasodilatation decreased after pinealectomy (517 +/- 21 vs. 819 +/- 40 microm(2) in sham and 829 +/- 55 microm(2) in control, P < 0.05, and 81 +/- 4 vs. 102 +/- 5 microm in sham and 104 +/- 4 microm in control, P < 0.05, respectively) and were restored by melatonin (924 +/- 39 microm(2) and 102 +/- 5 microm, respectively). These results suggest that melatonin deprival makes the arteriolar wall thinner and stiffer. However, these changes had little effect on LLCBF. In conclusion, pinealectomy of young rats induces atrophy and decreases distensibility of the cerebral arteriolar wall; these effects are prevented by melatonin. They do not modify LLCBF.

No effect of angiotensin II AT(2)-receptor antagonist PD 123319 on cerebral blood flow autoregulation.

Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral circulation is uncertain. Hence, the present study investigated the effect on CBF autoregulation of blocking of angiotensin AT2-receptors with PD 123319 in spontaneously hypertensive rats (SHR). Anaesthetised and ventilated SHR were given PD 123319, 0.36 mg/kg/min, intravenously, and compared with a control group. CBF was measured by the intracarotid 133xenon injection method and BP was raised by noradrenaline infusion and lowered by controlled haemorrhage in separate groups of rats. The limits of autoregulation were determined by computed least-sum-of-squares analysis. PD 123319 did not influence baseline CBF, but resulted in a minor BP decrease (10 control and 10 treated rats). The lower limit of CBF autoregulation (eight treated and eight control) as well as the upper limit of CBF autoregulation (eight treated and eight control) were not significantly different in PD 123319 and control animals (lower limit treated 102+/-4 mmHg and control 94+/-4; NS, and upper limit treated 171 +/- 10 mmHg and control 162+/-7; NS). These findings indicate that acute AT2-receptor blockade does not influence CBF autoregularion.

Melatonin increases pial artery tone and decreases the lower limit of cerebral blood flow autoregulation.

We studied a possible link between the melatonin-induced increase in cerebral arteriolar tone and the melatonin-induced shift in cerebral blood flow (CBF) autoregulation to a lower pressure level. Using the cranial window technique, we showed that intravenous infusion of melatonin constricted pial arterioles (-5.1 +/- 1.3 and -5.4 +/- 0.7 microm at 60 and 600 ng/kg/h, respectively). Perivascular application of luzindole alone had no significant effect but abolished vasoconstriction induced by melatonin (-0.5 +/- 0.7 and + 3.0 +/- 1.2 microm at 60 and 600 ng/kg/h respectively). Using a combination of the hydrogen clearance and cranial window techniques, we showed that intravenous infusion of melatonin had no effect on baseline CBF but shifted the lower limit (LL) of CBF autoregulation (stepwise hypotension) to a lower pressure (90 +/- 2 mmHg in vehicle vs. 71 +/- 3 and 51 +/- 5 mmHg, both P < 0.05, after melatonin at 60 and 600 ng/kg/h, respectively). As melatonin had no effect on systemic blood pressure yet shifted the LL of CBF autoregulation, the security margin increased (28 +/- 5 in controls vs. 38 +/- 3 and 55 +/- 5% after melatonin at 60 and 600 ng/kg/h, respectively, both P < 0.05). The higher i.v. infusion rate of melatonin increased the relative arteriolar dilatory response to hypotension but did not increase absolute diameter at any given pressure level. Our results show that melatonin shifts the LL of CBF autoregulation to a lower systemic pressure level. This effect does not appear to be explained by the effect of melatonin on cerebral arteriolar diameter.

Restoration of vasodilation and CBF autoregulation by genistein in rat pial artery after brain injury.

This study determined whether, after fluid percussion injury (FPI), tyrosine kinase activation is coupled to inhibition of K(+) channels and alteration in cerebral blood flow (CBF) autoregulation in the rat pial artery. Injury of moderate severity (2--2.5 atm) was produced by FPI in anesthetized rats equipped with a closed cranial window. The suppressed vasodilation of the pial arterioles to calcitonin gene-related peptide (CGRP) and levcromakalim (LMK) and altered lower limit of CBF autoregulation after FPI were restored by genistein but not by daidzein, an inactive analog. Vasodilation to S-nitroso-N-acetyl penicillamine (0.1--10 micromol/l) was, however, little influenced after FPI. The restored vasodilation was decreased by sodium orthovanadate, suggesting the reciprocal action of tyrosine phosphorylation and dephosphorylation. After FPI, CGRP-induced vasodilation restored by genistein (10 micromol/l) was strongly antagonized by iberiotoxin but not by glibenclamide, whereas LMK-induced vasodilation was, in contrast, inhibited by glibenclamide but not by iberiotoxin. Taken together, we suggest that, after FPI, activation of tyrosine kinase links the inhibition of K(+) channels to impaired autoregulatory vasodilation in response to acute hypotension and alteration in CBF autoregulation in the rat pial artery.