Impaired cerebral autoregulation in obstructive sleep apnea

Obstructive sleep apnea (OSA) increases the risk of stroke independent of known vascular and metabolic risk factors. Although patients with OSA have higher prevalence of hypertension and evidence of hypercoagulability, the mechanism of this increased risk is unknown. Obstructive apnea events are associated with surges in blood pressure, hypercapnia, and fluctuations in cerebral blood flow. These perturbations can adversely affect the cerebral circulation. We hypothesized that patients with OSA have impaired cerebral autoregulation, which may contribute to the increased risk of cerebral ischemia and stroke. We examined cerebral autoregulation in patients with and without OSA by measuring cerebral artery blood flow velocity (CBFV) by using transcranial Doppler ultrasound and arterial blood pressure using finger pulse photoplethysmography during orthostatic hypotension and recovery as well as during 5% CO(2) inhalation. Cerebral vascular conductance and reactivity were determined. Forty-eight subjects, 26 controls (age 41.0+/-2.3 yr) and 22 OSA (age 46.8+/-2.3 yr) free of cerebrovascular and active coronary artery disease participated in this study. OSA patients had a mean apnea-hypopnea index of 78.4+/-7.1 vs. 1.8+/-0.3 events/h in controls. The oxygen saturation during sleep was significantly lower in the OSA group (78+/-2%) vs. 91+/-1% in controls. The dynamic vascular analysis showed mean CBFV was significantly lower in OSA patients compared with controls (48+/-3 vs. 55+/-2 cm/s; P <0.05, respectively). The OSA group had a lower rate of recovery of cerebrovascular conductance for a given drop in blood pressure compared with controls (0.06+/-0.02 vs. 0.20+/-0.06 cm.s(-2).mmHg(-1); P <0.05). There was no difference in cerebrovascular vasodilatation in response to CO(2). The findings showed that patients with OSA have decreased CBFV at baseline and delayed cerebrovascular compensatory response to changes in blood pressure but not to CO(2). These perturbations may increase the risk of cerebral ischemia during obstructive apnea.     

Impaired endothelium-mediated vasodilation is not the principal cause of vasoconstriction in heart failure

The extent to which abnormal endothelium-dependent vasodilator mechanisms contribute to abnormal resting vasoconstriction and blunted reflex vasodilation seen in heart failure is unknown. The purpose of this study was to test the hypothesis that the resting and reflex abnormalities in vascular tone that characterize heart failure are mediated by abnormal endothelium-mediated mechanisms. Thirteen advanced heart-failure patients (New York Heart Association III-IV) and 13 age-matched normal controls were studied. Saline, acetylcholine (20 microg/min), or L-arginine (10 mg/min) was infused into the brachial artery, and forearm blood flow was measured by venous plethysmography at rest and during mental stress. At rest, acetylcholine decreased forearm vascular resistance in normal subjects, but this response was blunted in heart failure. During mental stress with intra-arterial acetylcholine or L-arginine, the decrease in forearm vascular resistance was not greater than during saline control in heart failure [saline control vs. acetylcholine (7 +/- 3 vs. 6 +/- 3, P = NS) or vs. L-arginine (9 +/- 2 units, P = NS)]. The increase in forearm blood flow was not greater than during saline control in heart failure [saline control vs. acetylcholine (1. 2 +/- 0.3 vs. 1.3 +/- 0.3, P = NS), or vs. L-arginine (1.2 +/- 0.2 ml x min(-1) x 100 ml(-1), P = NS)]. Furthermore, during mental stress with nitroprusside, the decrease in forearm vascular resistance was not greater than during saline control [saline control vs. nitroprusside (7 +/- 3 vs. 5 +/- 4 ml x min(-1) x 100 g(-1), P = NS)], and the increase in forearm blood flow was not greater than during saline control [saline control vs. nitroprusside (1.2 +/- 0.3 vs. 1.3 +/- 0.5 ml x min(-1) x 100 g(-1), P = NS)]. Because the endothelial-independent agent nitroprusside was unable to restore resting and reflex vasodilation to normal in heart failure, we conclude that impaired endothelium-mediated vasodilation with acetylholine-nitric oxide cannot be the principal cause of the attenuated resting- or reflex-mediated vasodilation in heart failure.     

Dynamic cerebral autoregulation remains stable during physical challenge in healthy persons

The effects of physical activity on cerebral blood flow (CBF) and cerebral autoregulation (CA) have not yet been fully evaluated. There is controversy as to whether increasing heart rate (HR), blood pressure (BP), and sympathetic and metabolic activity with altered levels of CO2 might compromise CBF and CA. To evaluate these effects, we studied middle cerebral artery blood flow velocity (CBFV) and CA in 40 healthy young adults at rest and during increasing levels of physical exercise. We continuously monitored HR, BP, end-expiratory CO2, and CBFV with transcranial Doppler sonography at rest and during stepwise ergometric challenge at 50, 100, and 150 W. The modulation of BP and CBFV in the low-frequency (LF) range (0.04-0.14 Hz) was calculated with an autoregression algorithm. CA was evaluated by calculating the phase shift angle and gain between BP and CBFV oscillations in the LF range. The LF BP-CBFV gain was then normalized by conductance. Cerebrovascular resistance (CVR) was calculated as mean BP adjusted to brain level divided by mean CBFV. HR, BP, CO2, and CBFV increased significantly with exercise. Phase shift angle, absolute and normalized LF BP-CBFV gain, and CVR, however, remained stable. Stable phase shift, LF BP-CBFV gain, and CVR demonstrate that progressive physical exercise does not alter CA despite increasing HR, BP, and CO2. CA seems to compensate for the hemodynamic effects and increasing CO2 levels during exercise.     

Cerebral white matter blood flow is constant during human non-rapid eye movement sleep: a positron emission tomographic study.

This study aimed to identify brain regions with the least decreased cerebral blood flow (CBF) and their relationship to physiological parameters during human non-rapid eye movement (NREM) sleep. Using [(15)O]H(2)O positron emission tomography, CBF was measured for nine normal young adults during nighttime. As NREM sleep progressed, mean arterial blood pressure and whole brain mean CBF decreased significantly; arterial partial pressure of CO(2) and, selectively, relative CBF of the cerebral white matter increased significantly. Absolute CBF remained constant in the cerebral white matter, registering 25.9 +/- 3.8 during wakefulness, 25.8 +/- 3.3 during light NREM sleep, and 26.9 +/- 3.0 (ml.100 g(-1).min(-1)) during deep NREM sleep (P = 0.592), and in the occipital cortex (P = 0.611). The regression slope of the absolute CBF significantly differed with respect to arterial partial pressure of CO(2) between the cerebral white matter (slope 0.054, R = - 0.04) and frontoparietal association cortex (slope - 0.776, R = - 0.31) (P = 0.005) or thalamus (slope - 1.933, R = - 0.47) (P = 0.004) and between the occipital cortex (slope 0.084, R = 0.06) and frontoparietal association cortex (P = 0.021) or thalamus (P < 0.001), and, with respect to mean arterial blood pressure, between the cerebral white matter (slope - 0.067, R = - 0.10) and thalamus (slope 0.637, R = 0.31) (P = 0.044). The cerebral white matter CBF keeps constant during NREM sleep as well as the occipital cortical CBF, and may be specifically regulated by both CO(2) vasoreactivity and pressure autoregulation.     

Impaired cerebrovascular autoregulation and reduced CO₂ reactivity after long duration spaceflight

Long duration habitation on the International Space Station (ISS) is associated with chronic elevations in arterial blood pressure in the brain compared with normal upright posture on Earth and elevated inspired CO(2). Although results from short-duration spaceflights suggested possibly improved cerebrovascular autoregulation, animal models provided evidence of structural and functional changes in cerebral vessels that might negatively impact autoregulation with longer periods in microgravity. Seven astronauts (1 woman) spent 147 ± 49 days on ISS. Preflight testing (30-60 days before launch) was compared with postflight testing on landing day (n = 4) or the morning 1 (n = 2) or 2 days (n = 1) after return to Earth. Arterial blood pressure at the level of the middle cerebral artery (BP(MCA)) and expired CO(2) were monitored along with transcranial Doppler ultrasound assessment of middle cerebral artery (MCA) blood flow velocity (CBFV). Cerebrovascular resistance index was calculated as (CVRi = BP(MCA)/CBFV). Cerebrovascular autoregulation and CO(2) reactivity were assessed in a supine position from an autoregressive moving average (ARMA) model of data obtained during a test where two breaths of 10% CO(2) were given four times during a 5-min period. CBFV and Doppler pulsatility index were reduced during -20 mmHg lower body negative pressure, with no differences pre- to postflight. The postflight indicator of dynamic autoregulation from the ARMA model revealed reduced gain for the CVRi response to BP(MCA) (P = 0.017). The postflight responses to CO(2) were reduced for CBFV (P = 0.056) and CVRi (P = 0.047). These results indicate that long duration missions on the ISS impaired dynamic cerebrovascular autoregulation and reduced cerebrovascular CO(2) reactivity.     

Predicting cerebral blood flow response to orthostatic stress from resting dynamics: effects of healthy aging

The transfer function relating arterial pressure (AP) to cerebral blood flow velocity (CBFV) during resting conditions has been used to predict the CBFV response to hypotension. We hypothesized that this approach could predict the CBFV response to posture change in elderly individuals if impaired autoregulation allowed changes in AP to be passively transferred to CBFV. AP (Finapres) and CBFV (middle cerebral artery transcranial Doppler) were measured in 10 healthy young (age 24 +/- 1 yr) and 10 healthy elderly (age 72 +/- 3 yr) subjects during 5 min of quiet sitting and 1 min of active standing while breathing was paced at 0.25 Hz. Transfer functions between AP and CBFV changes during sitting were estimated from each full waveform in both low-frequency (LF; 0.05-0.2 Hz) and heartbeat-frequency (HBF; 0.7-1.4 Hz) ranges. The impulse-response function was used to compute changes in CBFV during posture change. The LF transfer function did not predict orthostatic changes in CBFV in either group, suggesting normal cerebral autoregulation. In the HBF range, the prediction was high in elderly (R = 0.65 +/- 0.23) but not young subjects (R = 0.19 +/- 0.35; P < 0.003, young vs. elderly). Thus rapidly acting regulatory mechanisms that reduce the transmission of beat-to-beat changes in AP to CBFV may be engaged during posture change in young but not elderly subjects.     

Oxypurinol improves coronary and peripheral endothelial function in patients with coronary artery disease

Coronary endothelial dysfunction is a powerful prognostic marker in patients with coronary artery disease (CAD) that is centrally related to oxidative inhibition of nitric oxide (NO)-dependent vascular cell signaling. Xanthine oxidase (XO), which both binds to and is expressed by endothelial cells, generates superoxide and hydrogen peroxide upon oxidation of purines. Whether inhibition of xanthine oxidase activity results in improved coronary vasomotor function in patients with CAD, however, remains unknown. We assessed coronary and peripheral (brachial artery) endothelial function in 18 patients (pts; 65+/-8 years, 86% male) with angiographically documented CAD, preserved left ventricular function, and non-elevated uric acid levels (233+/-10 microM). Patients received incremental doses of intracoronary acetylcholine (ACh; 10(-7) to 10(-5) microM), and minimal lumen diameter (MLD) and coronary blood flow (CBF) were assessed before and after intravenous administration of oxypurinol (200 mg). Oxypurinol inhibited plasma XO activity 63% (0.051+/- 0.001 vs 0.019+/- 0.005 microU/mg protein; p<0.01). In pts who displayed endothelial dysfunction as evidenced by coronary vasoconstriction in response to ACh (n=13), oxypurinol markedly attenuated ACh-induced vasoconstriction (-23+/- 4 vs -15+/- 4% at ACh 10(-5) microM, p<0.05) and significantly increased CBF (16+/-17 vs 62+/-18% at ACh 10(-5) microM, p<0.05), whereas in patients with preserved coronary endothelial function, oxypurinol had no effect on ACh-dependent changes in MLD (+2.8+/- 4.2 vs 5.2+/- 0.7%, p>0.05) or CBF (135+/-75 vs 154+/-61%, p>0.05). Flow-mediated dilation of the brachial artery, assessed in eight consecutive patients, increased from 5.1+/-1.5 before to 7.6+/-1.5% after oxypurinol administration (p < 0.05). Oxypurinol inhibition of XO improves coronary vascular endothelial dysfunction, a hallmark of patients with CAD. These observations reveal that XO-derived reactive oxygen species significantly contribute to impaired coronary NO bioavailability in CAD and that XO inhibition represents an additional treatment concept for inflammatory vascular diseases that deserves further investigation.     

Transcranial Doppler estimation of cerebral blood flow and cerebrovascular conductance during modified rebreathing.

Clinical transcranial Doppler assessment of cerebral vasomotor reactivity (CVMR) uses linear regression of cerebral blood flow velocity (CBFV) vs. end-tidal CO(2) (Pet(CO(2))) under steady-state conditions. However, the cerebral blood flow (CBF)-Pet(CO(2)) relationship is nonlinear, even for moderate changes in CO(2). Moreover, CBF is increased by increases in arterial blood pressure (ABP) during hypercapnia. We used a modified rebreathing protocol to estimate CVMR during transient breath-by-breath changes in CBFV and Pet(CO(2)). Ten healthy subjects (6 men) performed 15 s of hyperventilation followed by 5 min of rebreathing, with supplemental O(2) to maintain arterial oxygen saturation constant. To minimize effects of changes in ABP on CVMR estimation, cerebrovascular conductance index (CVCi) was calculated. CBFV-Pet(CO(2)) and CVCi-Pet(CO(2)) relationships were quantified by both linear and nonlinear logistic regression. In three subjects, muscle sympathetic nerve activity was recorded. From hyperventilation to rebreathing, robust changes occurred in Pet(CO(2)) (20-61 Torr), CBFV (-44 to +104% of baseline), CVCi (-39 to +64%), and ABP (-19 to +23%) (all P < 0.01). Muscle sympathetic nerve activity increased by 446% during hypercapnia. The linear regression slope of CVCi vs. Pet(CO(2)) was less steep than that of CBFV (3 vs. 5%/Torr; P = 0.01). Logistic regression of CBF-Pet(CO(2)) (r(2) = 0.97) and CVCi-Pet(CO(2)) (r(2) = 0.93) was superior to linear regression (r(2) = 0.91, r(2) = 0.85; P = 0.01). CVMR was maximal (6-8%/Torr) for Pet(CO(2)) of 40-50 Torr. In conclusion, CBFV and CVCi responses to transient changes in Pet(CO(2)) can be described by a nonlinear logistic function, indicating that CVMR estimation varies within the range from hypocapnia to hypercapnia. Furthermore, quantification of the CVCi-Pet(CO(2)) relationship may minimize the effects of changes in ABP on the estimation of CVMR. The method developed provides insight into CVMR under transient breath-by-breath changes in CO(2).     

Imaging hemoglobin oxygen saturation in sickle cell disease patients using noninvasive visible reflectance hyperspectral techniques: effects of nitric oxide

Sickle cell disease is characterized by microvascular occlusion and hemolytic anemia, factors that impair tissue oxygen delivery. We use visible reflectance hyperspectral imaging to quantitate skin tissue hemoglobin oxygen saturation (HbO2) and to determine whether changes in blood flow during nitric oxide (NO) stimulation or gas administration (therapies proposed for this disease) improve skin tissue oxygen saturation in five patients with sickle cell disease. Compared with six healthy African-American subjects, sickle cell patients exhibited higher forearm blood flows (7.4 +/- 1.8 vs. 3.2 +/- 0.4 ml.min-1.100 ml tissue-1, P = 0.037) but significantly reduced percentages of skin HbO2 (61.0 +/- 0.2 vs. 77.5 +/- 0.2%, P < 0.001). Administration of acetylcholine to patients increased blood flow by 15.1 +/- 3.8 ml.min-1.100 ml tissue-1 and the percentage of skin HbO2 by 4.1 +/- 0.3% (P = 0.02, P < 0.001, respectively, from baseline values). Sodium nitroprusside, a direct NO donor, increased blood flow by 3.9 +/- 1.1 ml/min and the percentage of skin HbO2 by 2.9 +/- 0.3% (P = 0.02, P < 0.001, respectively). NO inhalation had no effect on forearm blood flow, yet increased the percentage of skin HbO2 by 2.3 +/- 0.3% (P < 0.001). Percentages of skin HbO2 were exponentially related to blood flow (R = 0.97, P < 0.001), indicating a limit to skin tissue oxygen saturation at high blood flows. Thus, for acetylcholine infusion leading to blood flows sevenfold greater than those of healthy resting African-American subjects, patients still exhibited lower percentages of skin HbO2 (65.2 +/- 0.2 vs. 77.5 +/- 0.2%, P < 0.001). Visible reflectance hyperspectral imaging demonstrates that either the stimulation or the administration of NO pharmacologically or by gas inhalation improves, but does not normalize, skin tissue oxygen saturation in patients with sickle cell disease.     

Dynamic cerebral autoregulation during brain activation paradigms

Dynamic cerebral autoregulation (CA) describes the transient response of cerebral blood flow (CBF) to rapid changes in arterial blood pressure (ABP). We tested the hypothesis that the efficiency of dynamic CA is increased by brain activation paradigms designed to induce hemispheric lateralization. CBF velocity [CBFV; bilateral, middle cerebral artery (MCA)], ABP, ECG, and end-tidal Pco(2) were continuously recorded in 14 right-handed healthy subjects (21-43 yr of age), in the seated position, at rest and during 10 repeated presentations (30 s on-off) of a word generation test and a constructional puzzle. Nonstationarities were not found during rest or activation. Transfer function analysis of the ABP-CBFV (i.e., input-output) relation was performed for the 10 separate 51.2-s segments of data during activation and compared with baseline data. During activation, the coherence function below 0.05 Hz was significantly increased for the right MCA recordings for the puzzle tasks compared with baseline values (0.36 +/- 0.16 vs. 0.26 +/- 0.13, P < 0.05) and for the left MCA recordings for the word paradigm (0.48 +/- 0.23 vs. 0.29 +/- 0.16, P < 0.05). In the same frequency range, significant increases in gain were observed during the puzzle paradigm for the right (0.69 +/- 0.37 vs. 0.46 +/- 0.32 cm.s(-1).mmHg(-1), P < 0.05) and left (0.61 +/- 0.29 vs. 0.45 +/- 0.24 cm.s(-1).mmHg(-1), P < 0.05) hemispheres and during the word tasks for the left hemisphere (0.66 +/- 0.31 vs. 0.39 +/- 0.15 cm.s(-1).mmHg(-1), P < 0.01). Significant reductions in phase were observed during activation with the puzzle task for the right (-0.04 +/- 1.01 vs. 0.80 +/- 0.86 rad, P < 0.01) and left (0.11 +/- 0.81 vs. 0.57 +/- 0.51 rad, P < 0.05) hemispheres and with the word paradigm for the right hemisphere (0.05 +/- 0.87 vs. 0.64 +/- 0.59 rad, P < 0.05). Brain activation also led to changes in the temporal pattern of the CBFV step response. We conclude that transfer function analysis suggests important changes in dynamic CA during mental activation tasks.     

Impaired endothelium-dependent vasodilation in overweight and obese adult humans is not limited to muscarinic receptor agonists

Muscarinic receptor agonists have primarily been used to characterize endothelium-dependent vasodilator dysfunction with overweight/obesity. Reliance on a single class of agonist, however, yields limited, and potentially misleading, information regarding endothelial vasodilator capacity. The aims of this study were to determine 1) whether the overweight/obesity-related reduction in endothelium-dependent vasodilation extends beyond muscarinic receptor agonists and 2) whether the contribution of nitric oxide (NO) to endothelium-dependent vasodilation is reduced in overweight/obese adults. Eighty-six middle-aged and older adults were studied: 42 normal-weight (54 +/- 1 yr, 21 men and 21 women, body mass index = 23.4 +/- 0.3 kg/m(2)) and 44 overweight/obese (54 +/- 1 yr, 28 men and 16 women, body mass index = 30.3 +/- 0.6 kg/m(2)) subjects. Forearm blood flow (FBF) responses to intra-arterial infusions of acetylcholine in the absence and presence of the endothelial NO synthase inhibitor N(G)-monomethyl-l-arginine, methacholine, bradykinin, substance P, isoproterenol, and sodium nitroprusside were measured by strain-gauge plethysmography. FBF responses to each endothelial agonist were significantly blunted in the overweight/obese adults. Total FBF (area under the curve) to acetylcholine (50 +/- 5 vs. 79 +/- 4 ml/100 ml tissue), methacholine (55 +/- 4 vs. 86 +/- 5 ml/100 ml tissue), bradykinin (62 +/- 5 vs. 85 +/- 4 ml/100 ml tissue), substance P (37 +/- 4 vs. 57 +/- 5 ml/100 ml tissue), and isoproterenol (62 +/- 4 vs. 82 +/- 6 ml/100 ml tissue) were 30%-40% lower in the overweight/obese than normal-weight adults. N(G)-monomethyl-l-arginine significantly reduced the FBF response to acetylcholine to the same extent in both groups. There were no differences between the groups in the FBF responses to sodium nitroprusside. These results indicate that agonist-stimulated endothelium-dependent vasodilation is universally impaired with overweight/obesity. Moreover, this impairment appears to be independent of NO.     

Effects of chronic sympathectomy on vascular function in the human forearm.

To determine whether endothelial function is altered by chronic surgical sympathectomy, we infused ACh, isoproterenol, nitroprusside (NTP), and the nitric oxide synthase inhibitor NG-mono-methyl-L-arginine (L-NMMA) into the brachial arteries of nine patients 5-64 mo after thoracic sympathectomy for hyperhidrosis. Age- and gender-matched controls were also studied. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Lower body negative pressure was used to assess reflex vasoconstrictor responses. Tyramine, which acts locally and causes norepinephrine release from sympathetic nerves, was also administered via the brachial artery. FBF at rest was 2.5 +/- 0.4 ml x dl-1 x min-1 in the patients and 2.5 +/- 0.3 ml x dl-1 x min-1 in the controls (P = 0.95). The normal vasoconstrictor responses to lower body negative pressure were abolished in the patients. By contrast, tyramine produced dose-dependent vasoconstriction in the patients that was identical to that of controls. The dose-response curves to ACh were similar in patients and controls, with maximum values of 19.3 +/- 4.4 vs. 25.5 +/- 2.8 ml x dl-1 x min-1, respectively. L-NMMA reduced baseline FBF similarly and reduced the maximal FBF response to ACh in both groups (patients 8.9 +/- 3.5 vs. controls 9.7 +/- 2.5 ml x dl-1 x min-1). The vasodilation to isoproterenol was similar and blunted to the same extent in both groups by L-NMMA. The responses to NTP in patients and controls were similar and not affected by L-NMMA. We conclude that, in humans, chronic surgical sympathectomy does not cause major disruptions in vascular function in the forearm. The normal vasoconstrictor responses to tyramine indicate that there were viable sympathetic nerves in the forearm that were not engaged by LBNP.     

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.     

Nitric oxide, prostaglandins, and impaired cerebral blood flow autoregulation in group B streptococcal neonatal meningitis

Impaired autoregulation of cerebral blood flow (CBF) contributes to CNS damage during neonatal meningitis. We tested (i) the hypothesis that cerebrovascular autoregulation is impaired during early onset group B streptococcal (GBS) meningitis, (ii) whether this impairment is regulated by vasoactive mediators such as prostaglandins and (or) nitric oxide (NO), and (iii) whether this impairment is preventable by specific and (or) nonspecific inhibitors: dexamethasone, ibuprofen, and Nomega-nitro-L-arginine, a NO inhibitor. Sterile saline or 10(9) colony-forming units (cfu) of heat-killed GBS was injected into the cerebral ventricle of newborn piglets. CBF autoregulation was determined by altering cerebral perfusion pressure (CPP) with balloon-tipped catheters placed in the aorta. GBS produced a narrow range of CBF autoregulation due to an impairment at the upper limit of CPP. We report that in vivo in the early stages (first 2 h) of induced GBS inflammation (i) GBS impairs the upper limit of cerebrovascular autoregulation; (ii) ibuprofen, dexamethasone, and Nomega-nitro-L-arginine not only prevent this GBS-induced autoregulatory impairment but improve the range of cerebrovascular autoregulation; (iii) these autoregulatory changes do not involve circulating cerebral prostanoids; and (iv) the observed changes correlate with the induction of NO synthase gene expression. Thus, acute early onset GBS-induced impairment of the upper limit of CBF autoregulation can be correlated with increases of NO synthase production, suggesting that NO is a vasoactive mediator of CBF.     

Contribution of arterial blood pressure and PaCO2 to the cerebrovascular responses to motor stimulation

Motor stimulation induces a neurovascular response that can be detected by continuous measurement of cerebral blood flow (CBF). Simultaneous changes in arterial blood pressure (ABP) and Pa(CO(2)) have been reported, but their influence on the CBF response has not been quantified. Continuous bilateral recordings of CBF velocity (CBFV), ABP, and end-tidal CO(2) (ET(CO(2))) were obtained in 10 healthy middle-aged subjects at rest and during 60 s of repetitive, metronome-controlled (1 Hz) elbow flexion. A multivariate autoregressive-moving average model was adopted to quantify the relationship between beat-to-beat changes in ABP, breath-by-breath ET(CO(2)), and the motor stimulus, represented by the metronome on-off signal (inputs), and the CBFV response to stimulation (output). All three inputs contributed to explain CBFV variance following stimulation. For the ipsi- and contralateral hemispheres, ABP explained 20.3 ± 17.3% (P = 0.0007) and 19.5 ± 17.2% (P = 0.01) of CBFV variance, respectively. Corresponding values for ET(CO(2)) and metronome signals were 22.0 ± 24.2% (P = 0.008), 24.0 ± 24.1% (P = 0.037), 32.7 ± 22.5% (P = 0.0015), and 43.2 ± 25.1% (P = 0.013), respectively. Synchronized population averages suggest that the initial sudden change in CBFV was largely due to ABP, while the influence of ET(CO(2)) was more erratic. The component due to elbow flexion showed a well-defined pattern, with rise time slower than the main CBFV change but reaching a stable plateau after 15 s of stimulation. Identifying and removing the influences of ABP and Pa(CO(2)) to motor-induced changes in CBF should lead to more robust estimates of neurovascular coupling and better understanding of its physiological covariates.     

Dissociation between metabolic and vascular insulin resistance in aging

Physiological actions of insulin via activation of the phosphatidylinositol 3-kinase/Akt pathway in the endothelium serve to couple regulation of hemodynamic and metabolic homeostasis. Insulin resistance, endothelial dysfunction, and hypertension increase in prevalence with aging. We investigated the metabolic and endothelial actions of insulin in 24- vs. 3-mo Sprague-Dawley rats. With the use of the hyperinsulinemic euglycemic clamp, the rate of glucose infusion necessary to maintain equivalent plasma glucose (5.5 mmol/l) was similar in 24- vs. 3-mo rats, as was fasting glucose (5.2 +/- 0.33 vs. 4.4 +/- 0.37 mmol/l; mean +/- SE) and insulin (0.862 +/- 0.193 vs. 1.307 +/- 0.230 mg/l). Systolic blood pressure was higher in 24-mo rats (133 +/- 5 vs. 110 +/- 4 mmHg; P = 0.005). Endothelial nitric oxide (NO)-dependent relaxation to insulin was impaired in aortas of 24- vs. 3-mo rats (maximal response 8.9 +/- 4.3 vs. 34.9 +/- 3.9%; P = 0.002); N(G)-nitro-l-arginine methyl ester abolished insulin-mediated relaxation in 3- but not 24-mo rats. Endothelium NO-dependent (acetylcholine) and -independent (sodium nitroprusside) relaxation, as well as NADPH oxidase activity, were similar in 3- and 24-mo rats. Insulin increased aortic serine phosphorylation of Akt in 3-mo rats by 120% over 24-mo rats (P < 0.05) and serine phosphorylation of endothelial NO synthase (eNOS) in 3-mo rats by 380% over 24-mo rats (P < 0.05). Aortic expression of phosphorylated c-Jun NH(2)-terminal kinase-1 and serine phosphorylated insulin receptor substrate-1, known mediators of metabolic insulin resistance, was similar in 3- and 24-mo rats. Expression of caveolin-1, a regulator of eNOS activity and insulin signaling, was 55% lower in 24- than 3-mo rats (P = 0.002). In summary, impaired vasorelaxation to insulin in aging was independent of metabolic insulin sensitivity and associated with impaired insulin-mediated activation of the Akt/eNOS pathway, but intact activation of the acetylcholine-mediated Ca(2+)-calmodulin/eNOS pathway. Vascular insulin resistance in aging may add to the increased susceptibility of this population to vascular injury induced by traditional cardiovascular risk factors.     

Alterations in cerebral dynamics at high altitude following partial acclimatization in humans: wakefulness and sleep.

We tested the hypothesis that, following exposure to high altitude, cerebrovascular reactivity to CO2 and cerebral autoregulation would be attenuated. Such alterations may predispose to central sleep apnea at high altitude by promoting changes in brain PCO2 and thus breathing stability. We measured middle cerebral artery blood flow velocity (MCAv; transcranial Doppler ultrasound) and arterial blood pressure during wakefulness in conditions of eucapnia (room air), hypocapnia (voluntary hyperventilation), and hypercapnia (isooxic rebeathing), and also during non-rapid eye movement (stage 2) sleep at low altitude (1,400 m) and at high altitude (3,840 m) in five individuals. At each altitude, sleep was studied using full polysomnography, and resting arterial blood gases were obtained. During wakefulness and polysomnographic-monitored sleep, dynamic cerebral autoregulation and steady-state changes in MCAv in relation to changes in blood pressure were evaluated using transfer function analysis. High altitude was associated with an increase in central sleep apnea index (0.2 +/- 0.4 to 20.7 +/- 23.2 per hour) and an increase in mean blood pressure and cerebrovascular resistance during wakefulness and sleep. MCAv was unchanged during wakefulness, whereas there was a greater decrease during sleep at high altitude compared with low altitude (-9.1 +/- 1.7 vs. -4.8 +/- 0.7 cm/s; P < 0.05). At high altitude, compared with low altitude, the cerebrovascular reactivity to CO2 in the hypercapnic range was unchanged (5.5 +/- 0.7 vs. 5.3 +/- 0.7%/mmHg; P = 0.06), while it was lowered in the hypocapnic range (3.1 +/- 0.7 vs. 1.9 +/- 0.6%/mmHg; P < 0.05). Dynamic cerebral autoregulation was further reduced during sleep (P < 0.05 vs. low altitude). Lowered cerebrovascular reactivity to CO2 and reduction in both dynamic cerebral autoregulation and MCAv during sleep at high altitude may be factors in the pathogenesis of breathing instability.     

Exogenous NO administration and alpha-adrenergic vasoconstriction in human limbs.

Nitric oxide (NO) is capable of blunting alpha-adrenergic vasoconstriction in contracting skeletal muscles of experimental animals (functional sympatholysis). We therefore tested the hypothesis that exogenous NO administration can blunt alpha-adrenergic vasoconstriction in resting human limbs by measuring forearm blood flow (FBF; Doppler ultrasound) and blood pressure in eight healthy males during brachial artery infusions of three alpha-adrenergic constrictors (tyramine, which evokes endogenous norepinephrine release; phenylephrine, an alpha1-agonist; and clonidine, an alpha2-agonist). To simulate exercise hyperemia, the vasoconstriction caused by the alpha-agonists was compared during adenosine-mediated (>50% NO independent) and sodium nitroprusside-mediated (SNP; NO donor) vasodilation of the forearm. Both adenosine and SNP increased FBF from approximately 35-40 to approximately 200-250 ml/min. All three alpha-adrenergic constrictor drugs caused marked reductions in FBF and calculated forearm vascular conductance (P < 0.05). The relative reductions in forearm vascular conductance caused by the alpha-adrenergic constrictors during SNP infusion were similar (tyramine, -74 +/- 3 vs. -65 +/- 2%; clonidine, -44 +/- 6 vs. -44 +/- 6%; P > 0.05) or slightly greater (phenylephrine, -47 +/- 6 vs. -33 +/- 6%; P < 0.05) compared with the responses during adenosine. In conclusion, these results indicate that exogenous NO sufficient to raise blood flow to levels simulating those seen during exercise does not blunt alpha-adrenergic vasoconstriction in the resting human forearm.     

Myeloperoxidase enhances nitric oxide catabolism during myocardial ischemia and reperfusion

Impaired microvascular function during myocardial ischemia and reperfusion is associated with recruitment of polymorphonuclear neutrophils (PMN) and has been attributed to decreased bioavailability of nitric oxide (NO). Whereas myeloperoxidase (MPO), a highly abundant, PMN-derived heme protein facilitates oxidative NO consumption and impairs vascular function in animal models of acute inflammation, its capacity to function in this regard during human myocardial ischemia and reperfusion remains unknown. Plasma samples from 30 consecutive patients (61 +/- 14 years, 80% male) presenting with acute myocardial infarction were collected 9 +/- 4 h after vessel recanalization and compared to plasma from healthy control subjects (n = 12). Plasma levels of MPO were higher in patients than in control subjects (1.4 +/- 0.9 vs 0.3 +/- 0.2 ng/mg protein, respectively, p < 0.0001). The addition of hydrogen peroxide to patient plasma resulted in accelerated rates of NO consumption compared to control subjects (0.53 +/- 0.25 vs 0.068 +/- 0.039 nM/s/mg protein, respectively, p < 0.0001). Myocardial tissue from patients with the same pathology revealed intense recruitment of MPO-positive PMN localized along infarct-related vessels as well as diffuse endothelial distribution of non-PMN-associated MPO immunoreactivity. Endothelium-dependent microvascular function, as assessed by an acetylcholine-dependent increase in forearm blood flow in 75 patients with symptomatic coronary artery disease, inversely correlated with MPO plasma levels (r = -0.75, p < 0.005). Plasma from patients undergoing myocardial reperfusion contained increased levels of MPO, which catalytically consumed NO in the presence of H(2)O(2). Given the correlation between intravascular MPO levels and forearm vasomotor function in patients with coronary artery disease, MPO appears to be an important modulator of vasomotor function in inflammatory vascular disease and a potential therapeutic target for treatment.     

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.