Role for capillaries in coupling blood flow with metabolism

1. Skeletal muscle blood flow is coupled with metabolism; for this coupling to be effective in matching blood flow to capillary exchange, control of capillary blood flow and recruitment must reside at the capillary level. 2. Capillaries are, indeed, capable of sensing and responding to vasoactive stimuli. We report studies that indicate that contraction of skeletal muscle fibres underneath capillaries is capable of increasing blood flow in those capillaries. 3. This presumed metabolically related signal initiates remote dilations in arterioles upstream of the stimulated capillaries. Our findings indicate that the vasodilatory signal is transmitted along the blood vessel wall. 4. Although we present evidence supporting a role for gap junctionally mediated communication of this vasodilatory signal, it appears unlikely to be primarily electrotonic spread of membrane potential changes. 5. Our studies further indicate that the transmitted signal is not dependent on changes in endothelial cell calcium.     

In vivo monitoring of brain pharmacokinetics and pharmacodynamics with cerebral open flow microperfusion

In vivo investigation of brain pharmacokinetics and pharmacodynamics (PK/PD) is an integral part of neurological drug development. However, drugs intended to act in the brain may reach it at very low concentrations due to the protective effect of the blood–brain barrier (BBB). Consequently, very sensitive measurement methods are required to investigate PK/PD of drugs in the brain. Also, these methods must be capable of continuously assessing cerebral drug concentrations with verifiable intact BBB, as disrupted BBB may lead to compound efflux from blood into brain and to biased results. To date, only a few techniques are available that can sensitively measure drug concentrations in the brain over time; one of which is cerebral open flow microperfusion (cOFM). cOFM's key features are that it enables measurement of cerebral compound concentrations with intact BBB, induces only minor tissue reactions, and that no scar formation occurs around the probe. The membrane-free cOFM probes collect diluted cerebral interstitial fluid (ISF) samples that are containing the whole molecule spectrum of the ISF. Further, combining cOFM with an in vivo calibration protocol (e.g. Zero Flow Rate) enables absolute quantification of compounds in cerebral ISF. In general, three critical aspects have to be considered when measuring cerebral drug concentrations and recording PK/PD profiles with cOFM: (a) the BBB integrity during sampling, (b) the status of the brain tissue next to the cOFM probe during sampling, and (c) the strategy to absolutely quantify drugs in cerebral ISF. This work aims to review recent applications of cOFM for PK/PD assessment with a special focus on these critical aspects.     

彩超直径法和血流速度法评价颈动脉狭窄的临床价值研究

目的 探讨彩超直径法和血流速度法不同的两种方法评估颈动脉狭窄的准确性和临床价值.方法 通过彩色多普勒超声检查分别用直径法和血流速度法诊断颈动脉狭窄51例,评估其程度,并与数字减影血管造影(DSA)作对照,评价彩超两种方法的符合率及其诊断的准确性.结果 直径法灵敏度(Se) 95.35％,假阴性率4.65％,特异度(Sp)75％,假阳性率25％,阳性似然比(LR+)3.81,阴性似然比(LR-)0.06,约登指数0.70.流速法灵敏度(Se) 97.67％,假阴性率2.33％,特异度(Sp) 87.5％,假阳性率12.5％,阳性似然比(LR+)7.81,阴性似然比(LR-)0.03,约登指数0.85.结论 彩超血流速度法和直径法诊断颈动脉狭窄二者有较高的符合率,血流速度法比直径法有较高的灵敏度、特异度和约登指数.     

Long-term measurement of cerebral blood flow and metabolism in a rat chronic hypoperfusion model

1. Rat bilateral common carotid artery occlusion (BCAO) was used as a chronic cerebral hypoperfusion model. We observed autoradiographically the long-term changes in regional cerebral blood flow (rCBF) and regional cerebral glucose utilization (rCGU) after 2 days and 1, 4 and 8 weeks of BCAO and in controls. Regions evaluated included the cerebral cortex, white matter and basal ganglia. Pathological changes were also observed with Klüver-Barrera and haematoxylin-eosin staining. 2. After 2 days, rCBF was significantly reduced to 33-58% in the cortex, white matter and amygdala and similar reductions were observed after 1 week. 3. After 4 weeks, rCBF recovered; however, rCBF remained significantly reduced in the occipital cortex, white matter, globus pallidus and substantia nigra. 4. After 2 days, rCGU was mostly maintained but, after 1 week, rCGU was reduced significantly to 40-70% in the cortex, white matter, basal ganglia and thalamus. Four weeks later, these reductions were no longer seen. 5. Rarefaction of the white matter was observed from 1 week. 6. These results showed that the BCAO in rats is an appropriate model for chronic cerebral hypoperfusion and that uncoupling of rCBF and rCGU was observed from 2 days until 4 weeks in the white matter.     

The continuous and simultaneous blood flow velocity measurement of four cerebral vessels and a peripheral vessel during cigarette smoking

There has been no consensus about the acute effect of cigarette smoking on cerebral blood flow, and the continuous change of flow in four cerebral vessel flow with peripheral flow during different kinds of cigarette smoking has not been reported until now. Our results indicate smoking increases the flow of four cerebral vessels almost at the same time and with the same pattern. Many cerebral vessels began to show increases about 10 s after commencement. In most cases, cerebral blood velocity began to decrease between 10 and 20 s after cessation. Blood flow in peripheral vessels decreases after commencement, which is thought to be the effect of nicotine. The effect of high nicotine cigarettes is greater than that of low nicotine cigarettes. Continuous and simultaneous measurement of cerebral vessels by ultrasonic Doppler is thought to be the only way to establish the detailed blood flow changes during smoking. Received: 4 February 1996/Final version: 8 January 1997     

癫痫患儿发作间期脑血流速度的测定及分析

探讨癫痫患儿脑循环动态的变化。方法：采用经颅超声波多普勒方法对４６例癫痫必发作间期的大脑中动脉血流速度进行测定,并分析其与临床表现的关系。结果表明：症状性癫痫脑血流低下的比率较高,而特发性癫痫则未发现异常。并     

In vivo Cerebral Pharmacokinetics and Pharmaco-dynamics of Diazepam and Midazolam after Short Intravenous Infusion Administration in Sheep

The cerebral pharmacokinetics and pharmacodynamics of midazolam and diazepam were examined in chronically instrumented sheep via measurements of their arterio-venous concentration difference across the brain during and after 2-min iv infusions. Diazepam (30 mg) or midazolam (10 mg) were administered on 5 separate occasions to 4 sheep. For both drugs, rapid cerebral uptake occurred during the infusion, which quickly turned to elution in the postinfusion period. However, this process was more rapid for midazolam than diazepam. The cerebral pharmacokinetics of both was better described by a kinetic model with slight membrane limitation rather than flow limitation. For diazepam, the estimated brain:plasma partition coefficient was 2.67, and the first and second compartments filled with half-lives of 2.2 and 0.5 min, respectively. For midazolam, these values were 0.27, 0.26 and 1.34 min, respectively. In a subset of sheep, pulmonary arterial–arterial gradients were too small to measure suggesting limited metabolism and small distribution volumes for both drugs in the lungs. Simultaneous dynamic measurements of cerebral blood flow and algesimetry lagged behind both the arterial and sagittal sinus blood concentrations. The changes in cerebral blood flow were best described by a previously published a dynamic model that incorporated long half-lives for drug dissociation from the benzodiazepine receptor (13.3 and 5.5 min for midazolam and diazepam, respectively). Effect compartment modeling of the cerebral blood flow data showed apparent effect compartment half-lives (t_1/2,keo) that were longer than the half-lives of cerebral equilibration.     

Cutaneous blood flow changes and weal induced by intradermal bradykinin following pretreatment with indomethacin and captopril

Summary The effects of indomethacin and captopril on local cutaneous blood flow changes and weal induced by intradermal injections of bradykinin were assessed in two randomised, double-blind, placebo-controlled studies in healthy volunteers. Alterations in cutaneous blood flow were estimated by laser Doppler flowmetry (LDF) and erythema area.LDF output, erythema area and weal volume increased with incremental bradykinin dose. Single doses of indomethacin 25 mg and 75 mg did not affect these cutaneous responses compared with placebo. Captopril 25 mg significantly potentiated the increase in local cutaneous blood flow measured by LDF, but not erythema area, and weal volume induced by bradykinin. The effects of the combined treatment of indomethacin 75 mg and captopril 25 mg were not significantly different from those due to captopril alone.The enhanced cutaneous effects of bradykinin following administration of captopril are in keeping with effective kininase II inhibition in the tissues. Cyclo-oxygenase products release does not appear to contribute to the cutaneous actions of bradykinin nor the potentiation of these responses by captopril.     

In vivo relationships between the cerebral pharmacokinetics and pharmacodynamics of thiopentone in sheep after short-term administration

The cerebral kinetics and dynamics of thiopentone after infusions of 250, 500, and 750 mg over 2 min were examined in chronically instrumented sheep (6, 6, and 5 sheep per dose, respectively). The cerebral kinetics were studied by rapid sampling of arterial and dorsal sagittal sinus blood (afferent and efferent blood for the brain, respectively) for 40 min, and could be described by a single flow-limited compartment when arterial concentrations and cerebral blood flow were used as forcing input functions. The half-lives of equilibration between blood and the brain were estimated to be 0.67 (SEM=0.07), 0.57 (0.03) and 0.74 (0.05) min for the 250-, 500- and 750-mg doses, respectively, showing that the cerebral concentrations of thiopentone rapidly equilibrate with the afferent blood concentration. Simultaneous pharmacodynamic measurements included cerebral blood flow via a Doppler flowmeter on the sagittal sinus, and an index of the depth of anesthesia based on an algesimetry method. Thiopentone transiently reduced cerebral blood flow to 82 (SEM=3), 80% (7), and 74% (10) of baseline for the 250−, 500−, and 750-mg doses, respectively, and failure to account for drug-induced changes in cerebral bloof flow in the model overestimated the apparent volume of the brain by 12% for the 500-mg dose. For the 500-mg dose, the changes in cerebral blood flow could be accounted for by an effect compartment with a half-life of 0.82 min for arterial blood, and 0.00 min for sagittal sinus blood, showing the effluent brain concentrations were in equilibrium with this drug effect. The time course of the depth of anesthesia for the 250-mg dose could be accounted for by an effect compartment with a half-life of 1.33 min for arterial blood, and 0.41 min for sagittal sinus blood. Thus, the rate of equilibration between blood and brain could not account for all of this delay. It is concluded that after short-term administration thiopentone equilibrated rapidly with the brain, and that this is consistent with the observation that the magnitude of its clinically relevant effects closely follow the time course of the arterial blood concentrations. Supported by a grant from the National Health and Medical Research Council of Australia     

臭氧治疗对急性脑梗死患者脑血流的影响

目的探讨臭氧治疗对急性脑梗死患者脑血流的影响。方法选择急性脑梗死患者80例,随机分为对照组和治疗组各40例。两组均进行基础用药治疗,治疗组在此基础上加用臭氧治疗。于患者入院时及治疗2周后应用经颅多普勒超声仪（TCD）检测其大脑中动脉（MCA）、基底动脉（BA）、椎动脉（VA）平均血流速度（Vm）。结果治疗组治疗后MCA、BA、VA平均血流速度较对照组有明显改善,两组比较,差异均有高度统计学意义（P〈0．01）。结论臭氧治疗对急性脑梗死患者的脑血流有明显改善作用。     

Cerebral open flow microperfusion: A new in vivo technique for continuous measurement of substance transport across the intact blood–brain barrier

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Experience with a Doppler technique to investigate the interaction of isoprenaline and various B-adrenoceptor blocking drugs on blood vessels in the lower limb

Summary A Doppler technique has been used in three separate studies to measure the changes induced by increasing infusion rates of isoprenaline on blood velocity, blood flow and diameters in the femoral and posterior tibial arteries of normal volunteers and to investigate the effects of various B-adrenoceptor antagonists on these changes. Heart rate and blood pressures were also recorded. Isoprenaline produced the expected changes in heart rates and blood pressures in the volunteers and changes induced in these responses by the B-adrenoceptor antagonist were as seen by previous workers. The only expected finding was that systolic blood pressure at the ankle was decreased compared to that in the arm which was increased. Isoprenaline produced reproducible dose-dependant increases in blood velocity, blood flow and diameters in the femoral artery, but little or no effects in the posterior tibial artery. These differences may reflect the difference in distribution of these arteries, the femoral to large muscular beds and the posterior tibial artery essentially to skin vascular beds. The different effects of the B-adrenoceptor blocking drugs with different actions on B₁- and B₂-adrenoceptors on the responses of the Doppler measurements to isoprenaline would support the differences in distribution of the femoral and posterior tibial arteries and allow a conclusion that the muscle vascular beds contain essentially B₂-adrenoceptors with respect to stimulation by isoprenaline. The results obtained in three separate studies using the Doppler technique do suggest that this non-invasive technique may be of value in investigating the physiology, and/or pharmacology of the peripheral circulation in man.     

高压氧对围生期缺氧缺血事件新生儿脑血流的影响

目的通过检测围生期缺氧缺血事件新生儿高压氧（HBO）治疗前后的脑血流,了解高压氧治疗对有围生期缺氧缺血事件新生儿脑灌注的影响。方法于2008年12月-2010年12月在我院住院的有围生期缺氧缺血病史的新生儿中,随机选取30例,用彩色超声多普勒检测每次HBO治疗前后通过大脑中动脉（McA）脑血流情况,连续检测其大脑前动脉的收缩期峰值（VS）、舒张末期速度（Vd）、阻力指数（RI）。所得数据采用SPSS13．0统计软件进行统计分析。结果脑血流速度的改变：HBO治疗的第1、2天,治疗前后脑血流速度无明显改变;治疗第3天,Vs、Vd较前降低,其中Vs差异有显著性（P〈0．05）,Vd差异有极显著性（P〈0．01）;治疗第4天,Vs、Vd较前降低,Vs、Vd差异有极显著性（P〈0．01）。血管阻力指数的变化：HBO治疗的第1、2天,无明显改变;治疗第3天,RI较前升高,RI差异有极显著性垆〈0．01）治疗第4天,RI较前升高,RI差异有极显著性（P〈0．01）。结论对围生期缺氧缺血事件新生儿进行HBO治疗,初期脑灌注影响不明显,治疗后期产生明显影响,可使脑血管收缩并致血流速度减慢,从而影响脑灌注。     

A placebo-controlled study of retinal blood flow changes by pentoxifylline and metabolites in humans

AIM: To investigate the possible effects of pentoxifylline metabolites on retinal blood flow in humans. METHODS: A randomized, placebo-controlled, four-period cross-over study that was observer blinded and partly blinded for the eight participants. On one occasion a placebo was given as an intravenous (i.v.) infusion over 100 min. On the other three occasions pentoxifylline was administered as i.v. infusions over 100 min at a rate of 3 mg min(-1). Before two of the pentoxifylline infusions the subjects were pretreated with either ciprofloxacin or rifampicin. Retinal blood flow was measured by scanning laser doppler flowmetry (SLDF) in a selected area of the central temporal retina before, during and until 5 h after the end of infusion. Blood samples for concentration analyses of pentoxifyllin, R-M1, S-M1, M4 and M5 were taken serially and areas under the curves (AUCs) were calculated. Linear mixed models were used for the statistical analyses. RESULTS: Mean AUCs (ng h ml(-1)) were significantly increased for pentoxifylline (1964 vs. 1453) and S-M1 (5804 vs. 4227), but not R-M1 when pentoxifylline was co-administered with ciprofloxacin. The mean AUC for M5 was significantly reduced when subjects were pretreated with rifampicin (2041 vs. 3080). Pentoxifylline with and without pretreatment with rifampicin significantly increased retinal blood flow assessed as mean flow, pulsation (i.e. 1-systole/diastole), and diastolic flow (but not during systole), compared with placebo. The increases over placebo were more pronounced on diastolic flow, 9.7% (95% confidence interval 4.2, 15.5) than on mean flow, 4.6% (1.1, 8.3) after pentoxifylline administration. With pentoxifylline after rifampicin pretreatment the corresponding differences were 11.7% (5.8, 17.9) and 5.1% (1.4, 7.8) over placebo, respectively. After co-administration of pentoxifylline and ciprofloxacin we saw only a nonsignificant trend towards increased flow during diastole, but a significant decrease in pulsation. When AUCs for pentoxifylline and its metabolites were used as regressor variables to retinal mean flow we found that pentoxifylline, R-M1 and M5 had coefficients with a positive sign indicating that they enhanced the retinal blood flow. In contrast, S-M1 and M4 had coefficients with negative sign and thus appeared to decrease the blood flow in subjects treated with pentoxifylline. CONCLUSION: The R-M1 and M5 metabolites of pentoxifylline contributed significantly to the effects of pentoxifylline on retinal blood flow.     

彩色多普勒超声结合高分辨率血流显像对胎儿心脏畸形的诊断价值

目的探讨彩色多普勒超声结合高分辨率血流显像对胎儿心脏畸形的诊断价值。方法用彩色多普勒超声结合高分辨率血流显像对本院1360例高危孕妇进行胎儿心脏畸形检查,研究胎儿心脏切面及高分辨率血流对胎儿心脏畸形的诊断价值。结果在1360例胎儿中共发现29例心脏畸形,产前经彩色多普勒结合高分辨率血流显像成功检出26例（占90%）,漏诊3例（占10%）,均经引产后尸检,出生后复查超声心动图,手术及回访,得到证实。结论彩色多普勒超声结合高分辨率血流显像诊断胎儿心脏畸形有较高的敏感性,使胎儿心脏畸形检出率及确诊率有明显提高,对先天性心脏病的产前诊断具有重要价值。     

Acute effects of celiprolol on muscle blood flow and insulin sensitivity: studies using [15O]-water, [18F]-fluorodeoxyglucose and positron emission tomography

Objective: Recently the role of peripheral vasoconstriction in the aetiology of insulin resistance has been proposed. Celiprolol is a β₁-selective adrenoceptor antagonist with partial agonist activity at the β₂-receptor as well as vasodilator properties. The acute effects of celiprolol on skeletal muscle blood flow and insulin sensitivity were measured in this study. Methods: Celiprolol (2 times 0.5 mg · kg⁻¹) or saline was given intravenously to five healthy males in random order. Muscle blood flow was measured in femoral regions using [¹⁵O]-labelled water and positron emission tomography (PET) during euglycaemic hyperinsulinaemia (serum insulin ˜65 mU · l⁻¹) after an overnight fast. Thereafter, skeletal and heart muscle glucose uptake were determined using [¹⁸F]-2-deoxy-d-glucose. Results: Celiprolol increased muscle blood flow by 74%, from 3.4 to 5.9 ml · min⁻¹ · 100 g⁻¹ muscle in the basal state. It decreased peripheral resistance by 40%, from␣32.0 to 19.2 mmHg · ml⁻¹ · min⁻¹ · 100 g⁻¹. Celiprolol significantly decreased diastolic blood pressure from 82 to 73 mmHg and increased heart rate from 61 to 68 beats · min⁻¹, which suggests sympathetic activation. Insulin-stimulated glucose uptake was reduced by 46% in the whole body, from 39 to 21 μmol · kg⁻¹ · min⁻¹ and by 59% in the femoral muscles, from 99 to 41 μmol · kg⁻¹ · min⁻¹, with celiprolol as compared to saline. The effect on heart glucose uptake did not statistically differ between the treatments. Conclusion: Celiprolol given intravenously increased muscle blood flow and decreased peripheral resistance at rest. It also acutely increased heart rate probably via sympathetic activation, and decreased insulin sensitivity in the muscles of healthy male volunteers. The enhanced muscle perfusion when celiprolol is given intravenously does not explain the improved insulin sensitivity seen in the long-term oral use in dyslipidaemic hypertensive patients. Received: 19 September 1996 / Accepted in revised form: 13 November 1996     

Effect of endothelin-1 on regional kidney blood flow and renal arteriole calibre in rabbits

1. Medullary blood flow (MBF) is important in the long-term control of arterial pressure. However, it is unclear which vascular elements regulate MBF. 2. Exogenous endothelin (ET)-1 decreases cortical more than medullary blood flow. We hypothesized that ET-1 would therefore constrict afferent (AA) and efferent arterioles (EA) of juxtamedullary glomeruli less than those of cortical glomeruli. 3. Mean arterial pressure, renal blood flow and cortical (CBF) and medullary (MBF) blood flow, via laser-Doppler flowmetry, were measured before and after intrarenal ET-1 (2 ng/kg per min; n = 6) or vehicle (n = 6) in anaesthetized rabbits. Kidneys were perfusion fixed, vascular casts formed, lumen diameters measured via scanning electron microscopy and relative resistance calculated. 4. Mean arterial pressure was not significantly affected by ET-1 infusion. Cortical glomerular arteriole lumen diameters were significantly reduced in the ET-1-infused group (AA approximately 30%, EA approximately 18%; PA < 0.01), compatible with the decrease in CBF (42 +/- 3%; PGT < 0.01). Juxtamedullary arteriole lumen diameters were also significantly reduced in the ET-1-infused group (AA approximately 34%, EA approximately 21%; PA < 0.01); however, MBF did not decrease. 5. In conclusion, our data suggest that juxtamedullary arterioles are not of primary importance in the regulation of MBF because, despite reductions in juxtamedullary arteriole diameters in response to ET-1, MBF was not decreased.     

养血清脑颗粒对慢性脑缺血大鼠脑血流量及认知功能的影响

目的：观察养血清脑颗粒(YQG)对慢性脑缺血大鼠脑血流量及认知功能的影响。方法：Wistar大鼠双侧颈总动脉永久结扎造成慢性脑缺血模型,激光多普勒血流仪检测额叶皮质局部脑血流量；Morris水迷宫检测认知功能。结果：术后模型组大鼠脑血流量骤降,并呈慢性持续下降趋势(P＜0．05)；大鼠出现认知功能障碍,隐匿平台逃避潜伏期和游泳距离明显延长(P＜0．05,P＜0．01),空间探索实验逃避潜伏期明显延长,穿越次数明显减少(P＜0．01),平台象限游泳时间和距离均缩短(P＜0．01)。YQG 3个剂量组均能明显增加脑血流量,改善认知障碍(P＜0．05或P＜0．01)。结论：YQG能明显改善慢性脑缺血大鼠局部脑血流量,提高学习记忆能力,有随疗程的增加而作用增强的趋势。     

Tissue blood flow and cephalic arteriovenous shunting in cats following administration of indalpine,a selective inhibitor of 5-hydroxytryptamine uptake

A number of observations indicate that a decrease in plasma 5-hydroxytryptamine (5-HT) level may lead to a diminished tissue perfusion and an opening of arteriovenous (AV) anastomoses in the head during migraine headaches. Indeed, some antimigraine drugs and the amine itself decrease the shunting of radioactive microspheres over the cephalic circulation in the experimental animals. Since indalpine selectively inhibits 5-HT uptake mechanisms and increases plasma 5-HT level, we have investigated the effects of the drug (1, 2, and 4 mg·kg^?1) on tissue blood flow and on AV shunting using the radioactive microsphere method in anesthetized cats. Indalpine caused minimal systemic hemodynamic effects; only a moderate (14%) hypotension resulted with the highest dose. Regionally, the drug increased blood flow to brain, intestines, mesentery + pancreas, and skeletal muscles. Both total peripheral AV-shunting (as indicated by the microsphere content of the lungs) and jugular venous AV-shunting (as measured by microspheres in the jugular venous blood) were decreased by the drug. These hemodynamic changes resemble those occurring during 5-Ht infusions. It is suggested that indalpine may be of therapeutic value in migraine since it decreased AV-shunting across the cephalic circulation.