Cerebral blood flow autoregulation in early experimental S. pneumoniae meningitis.

We studied cerebral blood flow (CBF) autoregulation and intracranial pressure (ICP) during normo- and hyperventilation in a rat model of Streptococcus pneumoniae meningitis. Meningitis was induced by intracisternal injection of S. pneumoniae. Mean arterial blood pressure (MAP), ICP, cerebral perfusion pressure (CPP, defined as MAP - ICP), and laser-Doppler CBF were measured in anesthetized infected rats (n = 30) and saline-inoculated controls (n = 30). CPP was either incrementally reduced by controlled hemorrhage or increased by intravenous norepinephrine infusion. Twelve hours postinoculation, rats were studied solely during normocapnia, whereas rats studied after 24 h were exposed to either normocapnia or to acute hypocapnia. In infected rats compared with control rats, ICP was unchanged at 12 h but increased at 24 h postinoculation (not significant and P < 0.01, respectively); hypocapnia did not lower ICP compared with normocapnia. Twelve hours postinoculation, CBF autoregulation was lost in all infected rats but preserved in all control rats (P < 0.01). Twenty-four hours after inoculation, 10% of infected rats had preserved CBF autoregulation during normocapnia compared with 80% of control rats (P < 0.01). In contrast, 60% of the infected rats and 100% of the control rats showed an intact CBF autoregulation during hypocapnia (P < 0.05 for the comparison of infected rats at normocapnia vs. hypocapnia). In conclusion, CBF autoregulation is lost both at 12 and at 24 h after intracisternal inoculation of S. pneumoniae in rats. Impairment of CBF autoregulation precedes the increase in ICP, and acute hypocapnia may restore autoregulation without changing the ICP.     

Inhibition of nitric oxide synthase does not alter dynamic cerebral autoregulation in humans

The aim of this study was to determine whether inhibition of nitric oxide synthase (NOS) alters dynamic cerebral autoregulation in humans. Beat-to-beat blood pressure (BP) and cerebral blood flow (CBF) velocity (transcranial Doppler) were measured in eight healthy subjects in the supine position and during 60 degrees head-up tilt (HUT). NOS was inhibited by intravenous NG-monomethyl-L-arginine (L-NMMA) infusion. Dynamic cerebral autoregulation was quantified by transfer function analysis of beat-to-beat changes in BP and CBF velocity. Pressor effects of L-NMMA on cerebral hemodynamics were compared with those of phenylephrine infusion. In the supine position, L-NMMA increased mean BP from 83+/-3 to 94+/-3 mmHg (P < 0.01). However, CBF velocity remained unchanged. Consequently, cerebrovascular resistance index (CVRI) increased by 15% (P < 0.05). BP and CBF velocity variability and transfer function gain at the low frequencies of 0.07-0.20 Hz did not change with L-NMMA infusion. Similar changes in mean BP, CBF velocity, and CVRI were observed after phenylephrine infusion, suggesting that increase in CVRI after L-NMMA was mediated myogenically by increase in arterial pressure rather than a direct effect of cerebrovascular NOS inhibition. During baseline tilt without L-NMMA, steady-state BP increased and CBF velocity decreased. BP and CBF velocity variability at low frequencies increased in parallel by 277% and 217%, respectively (P < 0.05). However, transfer function gain remained unchanged. During tilt with L-NMMA, changes in steady-state hemodynamics and BP and CBF velocity variability as well as transfer gain and phase were similar to those without L-NMMA. These data suggest that inhibition of tonic production of NO does not appear to alter dynamic cerebral autoregulation in humans.     

Gene transfer of Cu/Zn SOD to cerebral vessels prevents FPI-induced CBF autoregulatory dysfunction

The goal of this study was to determine whether gene transfer of human copper-zinc (Cu/Zn) superoxide dismutase (SOD) has preventive effects on cerebral blood flow (CBF) autoregulatory dysfunction after fluid percussion injury (FPI). Rats subjected to FPI (2-2.5 atm) exhibited enhanced activity of reduced NADP (NADPH) oxidase in the cerebral vasculature. In line with these findings, the rats showed not only reduced vasodilation of the pial artery in response to calcitonin gene-related peptide and levcromakalim but also impaired autoregulatory vasodilation in response to acute hypotension. The FPI-induced hemodynamic alterations were significantly prevented by pretreatment with diphenyleneiodonium (10 micromol/l), an NAD(P)H oxidase inhibitor. Intracisternal application of recombinant adenovirus (100 microl of 1 x 10(10) pfu/ml)-encoding human Cu/Zn SOD 3 days before FPI prevented the impairment of vasodilation to hypotension and vasorelaxants, resulting in the restoration of CBF autoregulation. Our findings demonstrate that FPI-induced impairment of CBF autoregulation is closely related with NAD(P)H oxidase-derived superoxide anion, and these alterations can be prevented by the recombinant adenovirus-mediated transfer of human Cu/Zn SOD gene to the cerebral vasculature.     

Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein

The amyloid-beta (A beta) peptide, which is derived from the amyloid precursor protein (APP), is involved in the pathogenesis of Alzheimer's dementia and impairs endothelium-dependent vasodilation in cerebral vessels. We investigated whether cerebrovascular autoregulation, i.e., the ability of the cerebral circulation to maintain flow in the face of changes in mean arterial pressure (MAP), is impaired in transgenic mice that overexpress APP and A beta. Neocortical cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry in anesthetized APP(+) and APP(-) mice. MAP was elevated by intravenous infusion of phenylephrine and reduced by controlled exsanguination. In APP(-) mice, autoregulation was preserved. However, in APP(+) mice, autoregulation was markedly disrupted. The magnitude of the disruption was linearly related to brain A beta concentration. The failure of autoregulation was paralleled by impairment of the CBF response to endothelium-dependent vasodilators. Thus A beta disrupts a critical homeostatic mechanism of the cerebral circulation and renders CBF highly dependent on MAP. The resulting alterations in cerebral perfusion may play a role in the brain dysfunction and periventricular white-matter changes associated with Alzheimer's dementia.     

Relaxant effects of sodium nitroprusside and NONOates in goat middle cerebral artery: delayed impairment by global ischemia-reperfusion.

Global cerebral ischemia and subsequent reperfusion induce early impairment of the vasodilator responses to hypercapnia and vasoactive substances. Nitric oxide (NO) is involved in the regulation of cerebral blood flow (CBF) in both health and disease. The present study was designed to assess possible changes in the cerebrovascular reactivity to NO donors induced by cerebral ischemia-reperfusion in goats. Female goats (n = 9) were subjected to 20 min global cerebral ischemia under halothane/N2O anesthesia. Sixteen additional goats were sham-operated as a control group. One week later the effects of ischemia-reperfusion on relaxations to NO donors sodium nitroprusside (SNP), diethylamine/NO (DEA/NO), diethylenetriamine/NO (DETA/NO), and spermine/NO (SPER/NO) were studied in rings of middle cerebral artery (MCA) isolated in an organ bath for isometric tension recording. SNP, DEA/NO, DETA/NO, and SPER/NO induced concentration-dependent relaxations of MCA precontracted with KCl (DEA/NO > SPER/NO > SNP > DETA/NO) or with endothelin-1 (DEA/NO > SNP > SPER/NO > DETA/NO). Relaxations were always higher in endothelin-1-precontracted arteries. One week after cerebral ischemia concentration-response curves to SNP and DEA/NO were displaced to the right, indicating a reduction in relaxant potency of NO donors. The classical nitrovasodilator SNP and NONOates induce relaxation of isolated goat MCA which is partially inhibited by arterial depolarization. Global cerebral ischemia followed by reperfusion induces delayed impairment of the relaxant effects of NO on cerebrovascular smooth muscle, which results in reduced vasodilatory potency of NO donors in large cerebral arteries.     

Nitrite infusion increases cerebral blood flow and decreases mean arterial blood pressure in rats: A role for red cell NO

It has been proposed that the reduction of nitrite by red cells producing NO plays a role in the regulation of vascular tone. This hypothesis was investigated in rats by measuring the effect of nitrite infusion on mean arterial blood pressure (MAP), cerebral blood flow (CBF) and cerebrovascular resistance (CVR) in conjunction with the accumulation of red cell NO. The relative magnitude of the effects on MAP and CBF as well as the time dependent changes during nitrite infusion are used to distinguish between the effects on the peripheral circulation and the effects on the cerebral circulation undergoing cerebral autoregulation. The nitrite infusion was found to reverse the 96% increase in MAP and the 13% decrease in CBF produced by L-NAME inhibition of e-NOS. At the same time there was a 20-fold increase in oxygen stable red cell NO. Correlations of the red cell NO for individual rats support a role for red cell nitrite reduction in regulating vascular tone in both the peripheral and the cerebral circulation. Furthermore, data obtained prior to treatment is consistent with a contribution of red cell reduced nitrite in regulating vascular tone even under normal conditions.     

Implication of adenosine A2A receptors in hypotension-induced vasodilation and cerebral blood flow autoregulation in rat pial arteries

This study aimed to evaluate the role for adenosine A2A receptors in the autoregulatory vasodilation to hypotension in relation with cerebral blood flow (CBF) autoregulation in rat pial arteries. Changes in pial artery diameters were observed directly through a closed cranial window. Vasodilation induced by adenosine was markedly suppressed by ZM 241385 (1 micromol/l, A2A antagonist) and alloxazine (1 micromol/l, A2B antagonist), but not by 8-cyclopentyltheophylline (CPT, 1 micromol/l, A1 antagonist). CGS-21680-induced vasodilation was more strongly inhibited by ZM 241385 (25.3-fold; P<0.05) than by alloxazine. In contrast, 5'-N-ethylcarboxamido-adenosine (NECA)-induced vasodilation was more prominently suppressed by alloxazine (12.0-fold; P<0.001) than by ZM 241385. The autoregulatory vasodilation in response to acute hypotension of the pial arteries was significantly suppressed by ZM 241385, but not by CPT and alloxazine. Consistent with this finding, the lower limit of CBF autoregulation significantly shifted to a higher blood pressure by 1 micromol/l of ZM 241385 (53.0+/-3.9 mm Hg to 69.2+/-2.9 mm Hg, P<0.01) and 10 micromol/l of glibenclamide (54.7+/-6.5 mm Hg to 77.9+/-4.2 mm Hg, P<0.001), but not by CPT and alloxazine. Thus, it is suggested that adenosine-induced vasodilation of the rat pial artery is mediated via activation of adenosine A2A and A2B receptors, but not by A1 subtype, and activation of adenosine A2A receptor preferentially contributes to the autoregulatory vasodilation via activation of ATP-sensitive K+ channels in response to hypotension and maintenance of CBF autoregulation.     

Critical closing pressure explains cerebral hemodynamics during the Valsalva maneuver

The Valsalvamaneuver (VM), a voluntary increase in intrathoracic pressure of ~40mmHg, has been used to examine cerebral autoregulation (CA). Duringphase IV of the VM there are pronounced changes in mean arterial bloodpressure (MABP), pulse interval, and cerebral blood flow (CBF), but thechanges in CBF are of a much greater magnitude than those seen in MABP,a finding to date attributed to either a delay in activation of the CAmechanism or the inability of this mechanism to cope with the size andspeed of the blood pressure changes involved. These changes in CBF also precede those in MABP, a pattern of events not explained by the physiological process of CA. Measurements of CBF velocity (transcranial Doppler) and MABP (Finapres) were performed in 53 healthy volunteers (aged 31-80 yr). By calculating beat-to-beat values of critical closing pressure (CCP) during the VM, we have found that this parametersuddenly drops at the start of phase IV, providing a coherentexplanation for the large increase in CBF. If CCP is included in theestimation of cerebrovascular resistance, a temporal pattern moreconsistent with an autoregulatory response to the MABP overshoot isalso found. CCP is intricately involved in the control of CBF duringthe VM and should be considered in the assessment of CA.     

Impaired cerebral CO2 vasoreactivity: association with endothelial dysfunction

Conflicting data exist on the role of nitric oxide (NO) in cerebral blood flow (CBF) autoregulation. Previous studies involving human and animal subjects seem to indicate that NO involvement is limited to the CO(2)-dependent mechanism (chemoregulation) and not to the pressure-dependent autoregulation (mechanoregulation). We tested this hypothesis in patients with impaired endothelial function compared with healthy controls. Blood pressure, heart rate, end-tidal Pco(2), CBF velocities (CBFV), forearm blood flow, and reactive hyperemia were assessed in 16 patients with diabetes mellitus and/or hypertension and compared with 12 age- and sex-matched healthy controls. Pressure-dependent autoregulation was determined by escalating doses of phenylephrine. CO(2) vasoreactivity index was extrapolated from individual slopes of mean CBFV during normocapnia, hyperventilation, and CO(2) inhalation. Measurements were repeated after sodium nitroprusside infusion. Indexes of endothelial function, maximal and area under the curve (AUC) of forearm blood flow (FBF) changes, were significantly impaired in patients (maximal flow: 488 +/- 75 vs. 297 +/- 31%; P = 0.01, AUC DeltaFBF: 173 +/- 17 vs. 127 +/- 11; P = 0.03). Patients and controls showed similar changes in cerebrovascular resistance during blood pressure challenges (identical slopes). CO(2) vasoreactivity was impaired in patients compared with controls: 1.19 +/- 0.1 vs. 1.54 +/- 0.1 cm.s(-1).mmHg(-1); P = 0.04. NO donor (sodium nitroprusside) offsets this disparity. These results suggest that patients with endothelial dysfunction have impaired CO(2) vasoreactivity and preserved pressure-dependent autoregulation. This supports our hypothesis that NO is involved in CO(2)-dependent CBF regulation alone. CBFV chemoregulation could therefore be a surrogate of local cerebral endothelial function.     

Effects of combination alfaxalone and alfadolone, anesthetic derivatives of pregnanedione, on cerebral hemodynamics in cats]

Intravenous injection of CT 1341 (a mixture of alphaxalone and alphadolone dissolved in cremophor el) induced a decrease in cerebral blood flow (CBF) measured by 133Xe clearance in cats with artificial respiration (the mean reduction in CBF was 2 ml/100 g/mn for 1,2 mg/kg or CT 1341. So, CBF was decreased by 22% when CT 1341 (7,2 mg/kg) was intravenously injected, (mean Pa CO2 equals 30 mm Hg). Changes in CBF following CT 1341 intravenous injection seems to be caused by cerebral vascular constriction evidenced by the direct observation of pial vessels. Following intravenous injection of CT 1341 (from 7, 2 mg/kg to 19,2 mg/kg), the cerebrovascular reactivity to hypercapnia or hypocapnia was not affected, but autoregulation of cerebral blood flow was transiently abolished. In animals with free respiration, CBF was increased in relation with the elevation in Pa CO2 caused by the depression of respiration.     

Role of bacterial DNA in macrophage activation by group B streptococci

Bacterial DNA (CpG DNA) induces macrophage activation and the production of inflammatory mediators, including tumor necrosis factor (TNF) and nitric oxide (NO) by these cells. However, the role of bacterial DNA in the macrophage response to whole bacteria is unknown. We used overlapping strategies to estimate the relative contribution of bacterial DNA to the upregulation of TNF and NO production in macrophages stimulated with antibiotic-treated group B streptococci (GBS). Selective inhibitors of the bacterial DNA/TLR9 pathway (chloroquine, an inhibitory oligonucleotide, and DNase I) consistently inhibited GBS-induced TNF secretion by 35-50% in RAW 264.7 macrophages and murine splenic macrophages, but had no effect on inducible nitric oxide synthase (iNOS) accumulation or NO secretion. Similarly, splenic and peritoneal macrophages from mice lacking TLR9 expression secreted 40% less TNF than macrophages from control mice after GBS challenge but accumulated comparable amounts of iNOS protein. Finally, studies in both RAW 264.7 cells and macrophages from TLR9-/- mice implicated GBS DNA in the upregulation of interleukins 6 (IL-6) and 12 (IL-12) but not interferon-beta (IFNbeta), a key intermediary in macrophage production of iNOS/NO. Our data suggest that the bacterial DNA/TLR9 pathway plays an important role in stimulating TNF rather than NO production in macrophages exposed to antibiotic-treated GBS, and that TLR9-independent upregulation of IFNbeta production by whole GBS may account for this difference.     

Dopamine does not limit fetal cerebrovascular responses to hypoxia.

Dopamine is used clinically to stabilize mean arterial blood pressure (MAP) in sick infants. One goal of this therapeutic intervention is to maintain adequate cerebral blood flow (CBF) and perfusion pressure. High-dose intravenous dopamine has been previously demonstrated to increase cerebrovascular resistance (CVR) in near-term fetal sheep. We hypothesized that this vascular response might limit cerebral vasodilatation during acute isocapnic hypoxia. We studied nine near-term chronically catheterized unanesthetized fetal sheep. Using radiolabeled microspheres to measure fetal CBF, we calculated CVR at baseline, during fetal hypoxia, and then with the addition of an intravenous dopamine infusion at 2.5, 7.5, and 25 microg.kg(-1).min(-1) while hypoxia continued. During acute isocapnic fetal hypoxia, CBF increased 73.0 +/- 14.1% and CVR decreased 38.9 +/- 4.9% from baseline. Dopamine infusion at 2.5 and 7.5 microg.kg(-1).min(-1), begun during hypoxia, did not alter CVR or MAP, but MAP increased when dopamine infusion was increased to 25 microg.kg(-1).min(-1). Dopamine did not alter CBF or affect the CBF response to hypoxia at any dose. However, CVR increased at a dopamine infusion rate of 25 microg.kg(-1).min(-1). This increase in CVR at the highest dopamine infusion rate is likely an autoregulatory response to the increase in MAP, similar to our previous findings. Therefore, in chronically catheterized unanesthetized near-term fetal sheep, dopamine does not alter the expected cerebrovascular responses to hypoxia.     

Syncope, cerebral perfusion, and oxygenation.

During standing, both the position of the cerebral circulation and the reductions in mean arterial pressure (MAP) and cardiac output challenge cerebral autoregulatory (CA) mechanisms. Syncope is most often associated with the upright position and can be provoked by any condition that jeopardizes cerebral blood flow (CBF) and regional cerebral tissue oxygenation (cO(2)Hb). Reflex (vasovagal) responses, cardiac arrhythmias, and autonomic failure are common causes. An important defense against a critical reduction in the central blood volume is that of muscle activity ("the muscle pump"), and if it is not applied even normal humans faint. Continuous tracking of CBF by transcranial Doppler-determined cerebral blood velocity (V(mean)) and near-infrared spectroscopy-determined cO(2)Hb contribute to understanding the cerebrovascular adjustments to postural stress; e.g., MAP does not necessarily reflect the cerebrovascular phenomena associated with (pre)syncope. CA may be interpreted as a frequency-dependent phenomenon with attenuated transfer of oscillations in MAP to V(mean) at low frequencies. The clinical implication is that CA does not respond to rapid changes in MAP; e.g., there is a transient fall in V(mean) on standing up and therefore a feeling of lightheadedness that even healthy humans sometimes experience. In subjects with recurrent vasovagal syncope, dynamic CA seems not different from that of healthy controls even during the last minutes before the syncope. Redistribution of cardiac output may affect cerebral perfusion by increased cerebral vascular resistance, supporting the view that cerebral perfusion depends on arterial inflow pressure provided that there is a sufficient cardiac output.     

Hemoglobin, NO, and 20-HETE interactions in mediating cerebral vasoconstriction following SAH

Recent studies have indicated that 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to the fall in cerebral blood flow (CBF) after subarachnoid hemorrhage (SAH), but the factors that stimulate the production of 20-HETE are unknown. This study examines the role of vasoactive factors released by clotting blood vs. the scavenging of nitric oxide (NO) by hemoglobin (Hb) in the fall in CBF after SAH. Intracisternal (icv) injection of blood produced a greater and more prolonged (120 vs. 30 min) decrease in CBF than that produced by a 4% solution of Hb. Pretreating rats with N(omega)-nitro-l-arginine methyl ester (l-NAME; 10 mg/kg iv) to block the synthesis of NO had no effect on the fall in CBF produced by an icv injection of blood. l-NAME enhanced rather than attenuated the fall in CBF produced by an icv injection of Hb. Blockade of the synthesis of 20-HETE with TS-011 (0.1 mg/kg iv) prevented the sustained fall in CBF produced by an icv injection of blood and the transient vasoconstrictor response to Hb. Hb (0.1%) reduced the diameter of the basilar artery (BA) of rats in vitro by 10 +/- 2%. This response was reversed by TS-011 (100 nM). Pretreatment of vessels with l-NAME (300 muM) reduced the diameter of BA and blocked the subsequent vasoconstrictor response to the addition of Hb to the bath. TS-011 returned the diameter of vessels exposed to l-NAME and Hb to that of control. These results suggest that the fall in CBF after SAH is largely due to the release of vasoactive factors by clotting blood rather than the scavenging of NO by Hb and that 20-HETE contributes the vasoconstrictor response of cerebral vessels to both Hb and blood.     

The effects of nitric oxide synthase--versus lipoxygenase inhibition on coronary flow and nitrite outflow in isolated rat heart

The aim of this study was to assess the changes of coronary flow (CF) and nitrite outflow under inhibition of nitric oxide synthase (NOS) by Nomega-nitro-L-arginine monomethyl ester (L-NAME) or lipoxygenase (LOX) induced by nordihydroguaiaretic acid (NDGA) in isolated rat heart. The hearts of male Wistar albino rats (n=18, age 8 weeks, body mass 180-200 g) were retrograde perfused according to the Langendorff's technique at gradually increased constant coronary perfusion pressure (CPP) conditions (40-120 cm H2O) which induced flow-dependent nitric oxide (NO) release (nitrite outflow). The experiments were performed during control conditions, in the presence of NO synthesis inhibitor L-NAME (30 micromol/l) or nonspecific LOX inhibitor (NDGA, 0.1 mmol/l) which were administered separately or in combination. CF varied in autoregulatory range from 4.12+/-0.26 ml/min/g wt at 50 cm H2O to 5.22+/-0.26 ml/min/g wt at 90 cm H2O. In autoregulatory range, nitrite outflow varied from 2.05+/-0.17 nmol/min/g wt at 50 cm H2O to 2.52+/-0.21 nmol/min/g wt at 90 cm H2O and was strictly parallel with CPP/CF curve. The autoregulatory range of CF was significantly extended (40-100 cm H2O, 2.22+/-0.12 ml/min/g wt and 2.90+/-0.25 ml/min/g wt, respectively) under the influence of L-NAME. Hemodynamic effects were accompanied by significant decrease in nitrite outflow after L-NAME administration (0.56+/-0.11 nmol/min/g wt at 40 cm H2O to 1.45+/-0.14 nmol/min/g wt at 100 cm H2O). NDGA affected CF in the range of CPP 40-70 cm H2O only (from 42% at 50 cm H2O to 12% at 90 cm H2O, respectively) with no significant changes in nitrite outflow. When L-NAME was applied in combination with NDGA vs. NDGA only, CF was significantly reduced (from 34% at 50 cm H2O to 50% at 90 cm H2O, respectively) with parallel changes in nitrite outflow (from 40% at 50 cm H2O to 51% at 90 cm H2O, respectively). The results showed that CF and nitrite outflow could be decreased under L-NAME administration. Nonselective LOX inhibitor (NDGA) decreased control values of CF only at lower values of CPP but did not change nitrite outflow indicating antioxidant properties of NDGA. In addition, L-NAME decreased the effects induced by NDGA on CF and nitrite outflow indicating the role of NO.     

Cerebral pressure-flow relations in hypertensive elderly humans: transfer gain in different frequency domains.

The dynamics of the cerebral vascular response to blood pressure changes in hypertensive humans is poorly understood. Because cerebral blood flow is dependent on adequate perfusion pressure, it is important to understand the effect of hypertension on the transfer of pressure to flow in the cerebrovascular system of elderly people. Therefore, we examined the effect of spontaneous and induced blood pressure changes on beat-to-beat and within-beat cerebral blood flow in three groups of elderly people: normotensive, controlled hypertensive, and uncontrolled hypertensive subjects. Cerebral blood flow velocity (transcranial Doppler), blood pressure (Finapres), heart rate, and end-tidal CO(2) were measured during the transition from a sit to stand position. Transfer function gains relating blood pressure to cerebral blood flow velocity were assessed during steady-state sitting and standing. Cerebral blood flow regulation was preserved in all three groups by using changes in cerebrovascular resistance, transfer function gains, and the autoregulatory index as indexes of cerebral autoregulation. Hypertensive subjects demonstrated better attenuation of cerebral blood flow fluctuations in response to blood pressure changes both within the beat (i.e., lower gain at the cardiac frequency) and in the low-frequency range (autoregulatory, 0.03-0.07 Hz). Despite a better pressure autoregulatory response, hypertensive subjects demonstrated reduced reactivity to CO(2). Thus otherwise healthy hypertensive elderly subjects, whether controlled or uncontrolled with antihypertensive medication, retain the ability to maintain cerebral blood flow in the face of acute changes in perfusion pressure. Pressure regulation of cerebral blood flow is unrelated to cerebrovascular reactivity to CO(2).     

Methylphenidate decreases regional cerebral blood flow in normal human subjects

To assess the effects of methylphenidate (MP) on cerebral blood flow (CBF), 5 healthy males were studied using ¹⁵O-water and positron emission tomography before and after MP (0.5mg/kg iv). MP significantly decreased whole brain CBF at 5–10 minutes (25±11%) and at 30 minutes (20±10%) after its administration. Decrements in CBF were homogeneous throughout the brain (regional decrements 23–30%) and probably reflect the vasoactive properties of MP. The vasoactive properties of MP should be considered when prescribing this drug chronically and/or when giving it to subjects with cerebrovascular compromise.     

Nitric oxide, atrial natriuretic factor, and dynamic renal autoregulation

Inhibition of nitric oxide (NO) synthase by N(omega)-nitro-L-arginine methyl ester (L-NAME) increases arterial pressure (PA) and profoundly reduces renal blood flow (RBF). Here we report that L-NAME causes changes in the PA-RBF transfer function which suggest augmentation of the approximately 0.2 Hz autoregulatory mechanism. Attenuation of PA fluctuations from 0.06 to 0.11 Hz was enhanced, indicating increased efficacy of autoregulation. Also, the rate of gain reduction between 0.1 and 0.2 Hz increased while the associated phase peak became > or = pi/2 radians, indicating emergence of a substantial rate-sensitive component in this system so that autoregulatory responses to rapid PA changes become more vigorous. Infusion of L-arginine partly reversed the pressor response to L-NAME, but not the renal vasoconstriction or the changes in the transfer function. The ability of atrial natriuretic factor (ANF), which also acts via cGMP, to replace NO was assessed. ANF dose dependently reversed but did not prevent the pressor response to L-NAME, indicating additive responses. ANF did not restore RBF or reverse the changes in the transfer function induced by L-NAME. The rate-sensitive component that was enhanced by L-NAME remained prominent, suggesting that either ANF did not adequately replace cGMP or provision of a basal level of cGMP was not able to replace cGMP generated in response to NO. It is concluded that NO synthase inhibition changes RBF dynamics with the most notable change being increased contribution by a rate-sensitive component of the myogenic system.     

A global mathematical model of the cerebral circulation in man

A mathematical model of the cerebral circulation has been formulated. It was based on non-linear equations of pulsatile fluid flow in distensible conduits and applied to a network simulating the entire cerebral vasculature, from the carotid and vertebral arteries to the sinuses and the jugular veins. The quasilinear hyperbolic system of equations was numerically solved using the two-step Lax-Wendroff scheme. The model's results were in good agreement with pressure and flow data recorded in humans during rest. The model was also applied to the study of autoregulation during arterial hypotension. A close relationship between cerebral blood flow (CBF) and capillary pressure was obtained. At arterial pressure of 80 mmHg, the vasodilation of the pial arteries was unable to maintain CBF at its control value. At the lower limit of autoregulation (60 mm Hg), CBF was maintained with a 25% increase of zero transmural pressure diameter of nearly the whole arterial network.