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Recent advances in organ microcirculation research.

This review article dealt with progress in the research of gastroenterological organ microcirculation in Japan. It must be emphasized that this remarkable progress particularly in intravital microcirculatory observations at organ level is attributable to great improvement of microscopic devices combined with computerized system, development of new techniques for measuring microcirculatory blood flow and pioneering of a variety of fluorescent and isotope-labelled tracers. Little attention has been directed toward the fact that microvascular manifestations are perhaps the earliest signs of "cells and tissues" dysfunction in disease processes. The microvasculature undergoes a substantial remodeling not only in vascular wall structures, but also in network characteristics themselves especially in chronic disease. Those microvascular alterations in an organ system, which primarily originate in adaptations to the microenvironmental changes, would lead to the chronicity and self-perpetuation of disease. As has been noted in the IVth World Congress for Microcirculation organized by the Japanese Society for Microcirculation, which was held in Tokyo, July 26-30, 1987, further progress has been made in the research of organ microcirculation in the gastroenterological and other fields. It is the cornerstone for better understanding of the pathogenesis of organ diseases to clarify the earliest alterations in the microvasculature of an organ system from a combined aspect of microhemo- and microlymphocirculation using the newly developed techniques for microcirculation study.

Digestive System↗

Vasodilator effect of terbutaline: in vivo evidence for the existence of beta 2-adrenoceptors in the microcirculation of rats, hamsters, and guinea pigs.

The characteristics of beta 2-adrenoceptors were studied in vivo in the microcirculation of cremaster muscle and mesoappendix in rats, cheek pouch in hamsters, and mesentery in guinea pigs, using a video-microscope technique. Terbutaline (beta 2-selective agonist) caused vasodilatation in all four microcirculation preparations studied, whereas butoxamine (beta 2-selective antagonist) competitively inhibited the terbutaline-induced vasodilatation. The in vivo pA2 values of butoxamine inhibition of terbutaline vasodilator effect were estimated from Schild plots. The pA2 values (6.22-6.31) were statistically identical in all four microcirculations studied and similar to in vitro values reported in other tissues. In contrast, tazolol and prenalterol (both beta 1-selective agonists) did not produce any vasodilatation in the microcirculations studied. These results supported the existence of beta 2-adrenoceptors involved in vasodilatation in the microcirculation.

Animals↗

[Effect of electroacupuncture on peripheral microcirculation in acute experimental arthritic rats].

This paper reports the effect of electroacupuncture (EA) on peripheral microcirculation in 12 acute experimental arthritic rats and 6 healthy rats. The results showed that after EA an obvious improvement in footback-microcirculation of acute experimental arthritic rats appeared, namely, the disturbance of microcirculation on the area of pathological changes was alleviated. The auricular microcirculation was strengthened as well. There were no obvious changes of peripheral microcirculation in healthy rats after EA. That indicates EA has therapeutic effects of promoting blood circulation and reducing extravasated blood, antiphlogosis and detumescence on the area of pathological changes in acute experimental arthritic rat.

Animals↗

[Celiprolol increases the microcirculation in subcutaneous tissue and calf muscles in essential hypertension].

The microcirculation of the subcutaneous tissue and muscles of the extremities is changed already in the early stage of essential hypertension. Insight into the effect of celiprolol, a beta blocker of the third generation, on tissue microcirculation is of both pathogenetic and therapeutic value. On using the method of Na131I tissue clearance, the effect of celiprolol on the microcirculation of subcutaneous tissue and muscles of the extremities was studied in 21 patients with essential hypertension. Celiprolol was administered orally in the daily dose of 300 mg. After one-week administration celiprolol significantly reduced mean arterial pressure and significantly increased the microcirculation in the subcutaneous tissue of the hand and crus as well as in the calf muscle. Celiprolol was thus found to increase the microcirculation in those tissues of the extremities in which its decrease was recorded before onset of the treatment. The obtained results may be of therapeutic value particularly in patients suffering from ischemia of the lower extremities. (Fig. 2, Ref. 19.).

Adult↗

[Objective evaluation of the microcirculation in the skin with indocyanine green angiography (ICGA). A method for the clinic?].

In some cases, assessment of the microcirculation of tissues can be very difficult. Various methods have been proposed for evaluating microcirculation, none of which has so far established itself for clinical use. Indocyanine Green Angiography (ICGA) is a suitable and objective method for quantifying microcirculation and due to the pharmacocinetic properties of this dye the prospects for clinical application of this fluorescence technique are rather promising. In an experimental animal study, postoperative changes of microcirculation were examined in a skin flap. The day of operation, ICGA showed pathophysiologic changes of the microcirculation which was corrected during the postoperative phase. This new state of haemodynamic equilibrium was objectively quantified by ICGA. The objectivity and repeatability within short time intervals speak for clinical application after adequate development and experience. The indication has to be clarified in each case. Rare incidence of negative reactions should be kept in mind.

Animals↗

Hepatic tissue microcirculation, oxygenation and energy charge in ischemia-reperfusion subjected cirrhotic rat liver.

BACKGROUND/AIMS: The hemodynamic disturbances in the cirrhotic liver following severe variceal bleeding and subsequent restoration by blood transfusion is an ischemia/reperfusion injury event which represents the clinical situation of liver dysfunction. Therefore, the aim of this study was to evaluate the microcirculation, oxygenation and energy charge of the cirrhotic rat liver after ischemia/reperfusion. METHODOLOGY: In eight carbon tetrachloride-induced cirrhotic rats and an equal number of controls subjected to 30 minutes of ischemia and 60 minutes of reperfusion by hepatoduodenal ligament clamping, the following parameters were assessed: hepatic microcirculation by laser-Doppler fluxmetry, hepatic tissue oxygenation by a Clark-type electrode, hepatic energy charge by tissue sampling and adenine-nucleotides determination by means of high-performance liquid chromatography. RESULTS: At baseline, liver microcirculation was found to be significantly decreased in the cirrhotics versus controls groups. Ischemia led to a reduction in both groups, while reperfusion improved microcirculation, but not to the baseline level. Oxygenation was reduced during ischemia and restored after reperfusion in both groups. Hepatic energy charge was reduced in the cirrhotics versus controls at baseline, and significantly decreased during ischemia in both groups. At reperfusion, a further reduction was found in the cirrhotic group, while in the control group it was restored to baseline. CONCLUSION: Hepatic microcirculation, oxygenation and energy charge are subjected to different degrees of diminution after ischemia/reperfusion in the cirrhotic rat liver.

Adenine Nucleotides↗

[The effect of nifedipine on the microcirculation in pregnancy-induced hypertension].

OBJECTIVES: To study the effects of nifedipine on the microcirculation in pregnancy-induced hypertension (PIH). METHODS: We observed the microcirculation in nailfold of 30 normal pregnant women and 76 cases of PIH. 20 mg nifedipine was given and nailfold microcirculation was observed after 30 minutes. RESULTS: Nifedipine increased the velocity of blood flow, reduced the aggregation of erythrocytes, and dilated capillaries. After the administration of nifedipine, the total score of the nailfold microcirculation decreased significantly in mild and moderate PIH (P < 0.05), but no marked difference was observed in severe PIH cases (P > 0.05). CONCLUSION: The disorder of the microcirculation of PIH can be improved by nifedipine.

Adult↗

Rotavirus-induced changes in the microcirculation of intestinal villi of neonatal mice in relation to the induction and persistence of diarrhea.

Using a histochemical peroxidase technique, under conditions that preferentially stain erythrocytes, we have shown changes in the microcirculation of villi of neonatal mice infected with murine rotavirus. Between 18 and 48 h postinfection (PI), throughout all areas of the small intestine there occurred, sequentially, a marked ischemia and atrophy of villi. By 72 h PI, villi had recovered their normal height and showed incipient hyperemic microcirculation. At 96 h PI, hyperemic microcirculation was most marked. Between 120 and 144 h PI, a second phase of villus atrophy occurred, which was more attenuated and confined to the upper and middle regions of the intestine. This phase was not accompanied by a wide-spread ischemia of villi: a minority of villi were short and ischemic but many appeared hyperemic. Recovery of villus microcirculation occurred at 168 h PI, which coincided with recovery from diarrhea. These changes in villus microcirculation are discussed in relation to the pathology and pathophysiology of rotavirus infection. We make two novel suggestions. First, the reduction in red cells flowing through villi in the early stages of the infection instigates hypoxia and hence atrophy of villi. The ensuing but ephemeral increase in rate of cell division, necessary for the reconstitution of villi, induces hypersecretion. Second, the increase in numbers of erythrocytes found in villi during their regrowth phase and throughout the remaining time course of the infection perturbs the countercurrent system, lowering the osmolality of the hyperosmotic zone located at villus tips, thereby impairing water absorption and prolonging diarrhea.

Animals↗

Leukocyte accumulation and hemodynamic changes in the cerebral microcirculation during early reperfusion after stroke.

BACKGROUND AND PURPOSE: Leukocytes contribute to cerebral ischemia-reperfusion injury. However, few experimental models examine both in vivo behavior of leukocytes and microvascular rheology after stroke. The purpose of the present study was to characterize patterns of leukocyte accumulation in the cerebral microcirculation and to examine the relationship between leukocyte accumulation and microcirculatory hemodynamics after middle cerebral artery occlusion and reperfusion (MCAO-R). METHODS: Male rats (250 to 350 g) were anesthetized and ventilated. Tail catheters were inserted for measurement of arterial blood gases and administration of drugs. Body temperature was maintained at 37 degrees C. Animals were subjected to 2 hours of MCAO by the filament method. A cranial-window preparation was performed, and the brain was superfused with warm, aerated artificial cerebrospinal fluid. Reperfusion was initiated by withdrawing the filament, and the pial microcirculation was observed by use of intravital fluorescence microscopy. Leukocyte accumulation in venules, arterioles, and capillaries; leukocyte rolling in venules; and leukocyte venular shear rate were assessed during 1 hour of reperfusion. RESULTS: We found significant leukocyte adhesion in cerebral venules during 1 hour of reperfusion after 2 hours of MCAO. Leukocyte trapping in capillaries and adhesion to arterioles after MCAO-R tended to increase compared with controls, but the increase was not significant. We also found that shear rate was significantly reduced in venules during early reperfusion after MCAO. CONCLUSIONS: A model using the filament method of stroke and fluorescence microscopy was used to examine white-cell behavior and hemodynamics in the cerebral microcirculation after MCAO-R. We observed a significant increase in leukocyte rolling and adhesion in venules and a significant decrease in blood shear rate in the microcirculation of the brain during early reperfusion. Leukocytes may activate and damage the blood vessels and surrounding brain cells, which contributes to an exaggerated inflammatory component to reperfusion. The model described can be used to examine precisely blood cell-endothelium interactions and hemodynamic changes in the microcirculation during postischemic reperfusion. Information from these and similar experiments may contribute to our understanding of the early inflammatory response in the brain during reperfusion after stroke.

Animals↗

Pancreatic microcirculation in the monkey with special reference to the blood drainage system of Langerhans islets: light and scanning electron microscopic study.

The microcirculation of the pancreas in 20 monkeys (Macaca mulatta) was further studied by scanning electron microscopy (SEM) of vascular corrosion casts and light microscopy (LM) of Chinese ink-injected/cleared tissues. The results revealed that 91% of islets observed received arterial blood from the terminal branches of the intralobular arteries--the afferent arterioles, and 9% received no arterial blood, being entirely supplied by the efferent vessels of the intermediate or large islets. Some islets received blood from the translobular afferent arterioles of the adjacent lobule. Two patterns of islet drainage channels with different features in the monkey were demonstrated in our study. These patterns might be termed as continuous or convergent portal vessels. All islets possessed continuous portal vessels, 7-8 microns in diameter, which ran a short distance (approximately 100 microns) and then drained into the peri-islet acinar region, forming a typical continuous insulo-acinar portal system. About 21% of the islets possessed one or two convergent portal vessels, occasionally more. This was first observed in the monkey. These vessels were relatively long and/or thick and drained into different regions: (1) the acinar region far from the islet in the lobule, forming a convergent insulo-acinar portal system, (2) crossed the interlobular septum into an adjacent lobule where sometimes no islet existed and then drained into the exocrine acinar region, forming a translobar convergent insulo-acinar portal system, (3) drained into an adjacent small islet through the insulo-insular drainage vessels--one part of the drainage system of the islets. Translobular vascular anastomoses observed between the microcirculation of pancreatic lobules in the monkey formed a new arrangement of pancreatic microcirculation-translobular pancreatic microcirculation. The functional and clinical significance of the pancreatic portal circulation and translobular circulation is discussed in this report.

Animals↗

Sarpogrelate, a specific 5HT2-receptor antagonist, improves the coronary microcirculation in coronary artery disease.

BACKGROUND: Serotonin (5-hydroxytryptamine: 5-HT) reduces the coronary blood flow (CBF) as a product of aggregating platelets. Sarpogrelate, a specific 5HT2-receptor antagonist, has been reported to increase the coronary collateral flow in humans: however, its effect on the microcirculation is still not fully understood. HYPOTHESIS: This study was undertaken to determine whether sarpogrelate might improve the microcirculation in coronary artery disease (CAD). METHODS: To investigate the effect of sarpogrelate on the microcirculation in CAD, we measured CBF in 15 patients with CAD but no significant stenosis in the left anterior descending artery (LAD). The patients were randomly allocated to two groups, including those receiving oral administration of 200 mg of sarpogrelate (SPG, 8 patients, age 61 +/- 6 years) and those receiving no medication (controls, 7 patients, age 57 +/- 8 years). Prior to and 1 h after the administration of sarpogrelate, or in controls at 1-h intervals, the average peak velocity (APV) at baseline and hyperemia was measured by an intracoronary Doppler guidewire. Systemic blood pressure (SBP) and cardiac output (CO) were also measured. RESULTS: In the patients receiving SPG, the medication significantly increased the baseline (18 +/- 9 to 19 +/- 10 cm/s, p < 0.05) and maximal APV (55 +/- 9 to 64 +/- 31 cm/s, p<0.05). However, no significant changes were observed in SBP and CO after the administration of SPG. In the control group, there were no significant differences in baseline and hyperemic APV. CONCLUSION: Sarpogrelate increased both baseline and maximal CBF without changing the systemic hemodynamics. These findings thus support that SPG improves the microcirculation by antagonizing the vasoconstrictive products of the aggregating platelets in CAD.

Aged↗

Effects of extended cold preservation and transplantation on the rat liver microcirculation.

Liver sinusoidal endothelial cell impairment and/or microcirculatory disturbances are thought to induce storage-related graft failure; however, the respective roles of changes induced by extended cold preservation and transplantation, as well as their interactions, are still unknown. To this end, the alterations of the liver microcirculation and of hepatocyte and sinusoidal endothelial cell functions induced by extended cold preservation and/or transplantation were assessed using an isolated perfused rat liver model combined to an orthotopic rat liver transplantation model. Liver microcirculation remained minimally altered following extended cold ischemia alone, despite a marked deterioration of sinusoidal endothelial cell function, while liver microcirculation alterations were mainly characterized by areas of no-reflow following transplantation alone. It was only when both procedures were associated that hepatocyte function became markedly compromised, without further deterioration in liver microcirculation. It is concluded that extended cold preservation and transplantation as such are not associated with lethal liver injury. However, the sinusoidal cell impairment and the liver microcirculatory disturbances, induced by both conditions combined, are important factors leading to secondary hepatic nonfunction, which might be triggered by extrahepatic events.

Animals↗

Modulation of endothelin and nitric oxide: a rational approach to improve canine hepatic microcirculation.

ET receptor blocker (TAK-044) and NO donor (FK409) were used to improve the hepatic microcirculation following ischemia-reperfusion injury. In the first experiment (60 minutes of ischemia), 15 dogs were divided into three groups: group A (control), saline; group B, TAK 5 mg/kg; and group C, FK 0.4 mg/kg. In the second experiment (90 minutes of ischemia), 38 dogs were divided into six groups that underwent 90 minutes of hepatic ischemia followed by reperfusion: group I (control), saline only; group II, TAK 5 mg/kg and FK 3.2 mg/kg; group III, TAK 5 mg/kg and FK 0.4 mg/kg; group IV, TAK 5 mg/kg; group V, FK 0.4 mg/kg; and group VI, FK3.2 mg/kg. All drugs were administered through the portal vein. Following 60 minutes of ischemia, both FK and TAK produced significant improvement in hepatic microcirculation and enzymatic status when compared with the control group. After 90 minutes of ischemia, low doses of FK and TAK significantly improved hepatic microcirculation and reduced portal pressure following reperfusion in group III compared with group I. Leakage of hepatic enzymes was prevented and tissue injury score was significantly lower in group III. In group VI, early protection was obtained to some extent; however, blood pressure was reduced significantly following reperfusion compared with group I. In contrast, hepatocellular function deteriorated and the tissue injury score was higher in group II animals. TAK pretreatment with low doses of FK provided the best protection for the hepatic microcirculation in ischemia-reperfusion injury of the liver.

Animals↗

In vivo model for visualizing flap microcirculation of ischemia-reperfusion.

Since ischemia-reperfusion injury continues to be a major problem in reconstructive microsurgery, improvement of experimental models is still desirable. We developed a model that allows direct visualization of flap microcirculation in mice by intravital microscopic techniques. A newly designed skinfold chamber was installed on the dorsum of mice, and microcirculation was inspected with an intravital microscope. An island flap, nourished by the deep circumflex iliac arteries, was elevated after implantation of the chamber, allowing visualization of the microcirculation in the island flap. The island flap was exposed to global ischemia by clamping the pedicles, and the clamps were then released to allow reperfusion. Various microcirculatory responses induced by ischemia-reperfusion were visualized. This model accurately simulated the clinical situation in reconstructive surgery and successfully realized chronic visualization of the flap microcirculation in vivo.

Animals↗

Monitoring blood oxygen state in muscle microcirculation with transverse relaxation.

Oxygen uptake from the microcirculation is a direct measure of tissue function. Magnetic resonance is capable of detecting differences between oxygenated and deoxygenated blood due to the paramagnetic properties of deoxyhemoglobin. At the level of the microcirculation, however, imaging methods cannot directly visualize the vessels. Instead, bulk MR parameters are investigated for their ability to monitor blood oxygen saturation (%O(2)) changes in the microcirculation of tissue, specifically skeletal muscle. Experiments in an in vitro model verified the feasibility of detecting changes in exponential decay signals, and also verified the prediction of only two distinct decay components. Experiments in a rabbit model demonstrate that T(2)' and monoexponential T(2) decay are not sensitive to blood oxygen changes, but that the long-T(2) component in a biexponential fit is correlated to the blood oxygen state. Assuming a two-pool model for water protons in muscle, and with knowledge of the T(2)-%O(2) relation, estimates of the microcirculation blood oxygen state can be made with some reasonable assumptions. Magn Reson Med 45:662-672, 2001.

Animals↗

Age-related changes in the microcirculation of skeletal muscle.

The age-related reduction in exercise capacity is associated with a reduction in cardiac output and maximal oxygen consumption (VO2max). The loss of muscle mass explains a large portion of the age-related decline in VO2max. The capillary supply to a muscle fibre is primarily determined by its size, but also by its metabolic profile and the metabolic profile of surrounding fibres. Thus the age-related fibre atrophy and changes in the fibre type composition are expected to be accompanied by changes in the capillarisation. The exchange of oxygen, blood-borne energy sources, metabolites and heat between the blood and muscle tissue takes place in the microcirculation. Changes in the microcirculation may thus affect the functioning and viability of the muscle. The resting blood flow is minimally affected by age, but blood flow during or following exercise is generally reduced. This may in part be due to a reduced vasodilatory capacity and a decreased capillarisation. However, the coupling between capillary supply to a fibre and its metabolic profile or the profile of the surrounding fibres is maintained. There are some changes in ultrastructure of the endothelium. The age-related changes in the microcirculation are associated with a reduced VO2max and exercise capacity. The adaptability of the microcirculation is maintained at old age.

Aging↗

The effect of 5-hydroxytryptamine and arterial blood withdrawal on cerebral microcirculation in the cat, arterial permeability in the rabbit.

Studies dealing with the effect of 5-HT on cerebral cortical microcirculation of cats and on permeability of femoral arteries to RISA of rabbits are presented. The effect of 5-HT on cerebral cortical microcirculation was compared to that of arterial blood withdrawal and blood reinfusion. The effect of topical administration of 5-HT was also studied. Cortical microcirculation was observed by transillumination using a microtransilluminator. Motion pictures were taken at a speed of 400 frames/sec. and a magnification of 3000X. Permeability was investigated using arterial RISA uptake in vessels perfused in vitro, with continuous recording of perfusion pressure. Microcirculatory studies revealed that arterial blood withdrawal and injection of 5-HT diminished red cell velocity, although to a different degree. With blood withdrawal and reinjection, good correlation existed between blood pressure and red cell velocity. In contrast, no correlation between blood pressure and red cell velocity was found after intracarotid injection of 5-HT. Reactive hyperemia was noted during reinfusion of blood. Both arterial blood withdrawal and 5-HT injection resulted in disappearance of red cells in individual vessels (unperfused channels). Good correlation of blood pressure with capillary red cell velocity during arterial blood withdrawal suggests absence of autoregulation in this portion of the microcirculation. Topical administration of 5-HT caused general vasoconstriction. Permeability to 5-HT to RISA followed a parabolic curve. With slight arterial vasoconstriction, permeability declined, while it rose with severe vasoconstriction.

Animals↗

A new model for photochemically induced thrombosis in the inner ear microcirculation and the use of hearing loss as a measure for microcirculatory disorders.

A new photochemical method was employed to cause disorders in the inner ear's microcirculation, using the rat as an animal model. Hearing loss was used as a measure for establishing the altered microcirculation. Under pentobarbital anesthesia, the middle ear was opened by a ventral approach. The lateral wall of the cochlea was then illuminated with a filtered xenon lamp (wavelength 540 nm) while rose bengal was infused intravenously. Photoactivated rose bengal produces oxygen radicals and oxygen singlets, which subsequently damage the vascular epithelium to cause the adhesion and aggregation of platelets in the small vessels. Disintegration of the inner ear hair cells at the irradiated site became evident 24 h after the illumination. These findings further suggest that the photochemical occlusion in the inner ear's microcirculation led to ischemic damage of the stria vascularis and the hair cells in the inner ear. When the action potential (AP) of the cochlea was measured with an electrocochleogram a gradual decrease occurred after the illumination. When acetylsalicylic acid was injected intravenously before treatment, the time required to completely suppress the AP was prolonged in a dose-dependent manner. Findings indicate that our method causes a photochemically induced occlusion in the inner ear's microcirculation and is therefore potentially useful for evaluating the various effects of drugs on the ear.

Action Potentials↗