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Effect of aspirin plus hydrochloric acid on the gastric mucosal microcirculation.

The effect of topically applied aspirin or HCl, or both, on gastric mucosal blood flow was studied by in vivo microscopy in the rat. Ten minutes after the topical application of 20 mM aspirin in 50 mM HCl, red blood cell flow ceased and red blood cells were no longer present in the superficial mucosal microvessels in 76.8% +/- 7.7% of the microscopic field. Hydrochloric acid (50 mM) alone caused this effect in only 12.8% +/- 12.8% of the field, whereas 20 mM aspirin alone had no effect. During this microcirculatory change, white thrombi were observed flowing through mucosal microvessels. Later, mucosal hemorrhages developed in areas where flow had ceased. Study of the submucosal microcirculation suggested that high concentrations of HCl are responsible for thrombus formation and low concentrations of HCl for submucosal arteriolar constriction. These results suggest that aspirin-induced acid back-diffusion causes thrombus formation in mucosal microvessels and submucosal arteriolar constriction. These microcirculatory changes might play a causative role in the cessation of mucosal blood flow, mucosal injury, and focal hemorrhage.

Animals↗

Effect of exogenous acid on the rat gastric mucosal microcirculation in hemorrhagic shock.

In vivo microscopy and histology were used to study the effect of exogenous acid (0.1 N HCl) on the rat corpus mucosal microcirculation and bleeding in hemorrhagic shock. Systemic blood pressure was reduced stepwise by bleeding. Mucosal blood flow showed a significant linear correlation with mean systemic blood pressure. The flow stopped in half of the rats at 25% of control blood pressure, but red blood cells were always present within the microvessels. In contrast, the topical application of 0.1 N HCl accelerated the decrease of blood flow with graded hypotension and caused progressive disappearance of the honeycomblike network of red blood cell-filled superficial mucosal microvessels. After retransfusion, mucosal bleeding occurred in the area in which the blood-filled microvessels had disappeared. Histology revealed that the bleeding extended from the middle of the depth of the mucosa and was associated with tissue necrosis. These results indicate that exogenous acid in hemorrhagic shock causes increased mucosal ischemia and tissue damage with bleeding on retransfusion.

Animals↗

Impaired vasodilatory responses in the gastric microcirculation of anesthetized rats with secondary biliary cirrhosis.

BACKGROUND/AIMS: The increased susceptibility of the stomach to injury observed in portal hypertension may be related to a defect in the hyperemic response to luminal irritants. The aim of this study was to evaluate the components that mediate this hyperemic response in a rat model of cirrhosis and portal hypertensive gastropathy. METHODS: Cirrhosis was induced by bile duct ligation, whereas controls underwent sham operation. Gastric blood flow responses to topical application of acid, capsaicin, nitrovasodilators, misoprostol, 8-bromo-cyclic guanosine monophosphate, and 8-bromo-cyclic adenosine monophosphate were measured by laser Doppler flowmetry using an ex vivo gastric chamber preparation. Calcitonin gene-related peptide immunoreactivity was used as an index of the anatomic integrity of the sensory afferent neurons of the stomach. RESULTS: Blood flow responses to acid, capsaicin, nitrovasodilators, and 8-bromo-cyclic guanosine monophosphate were significantly depressed in cirrhotic rats, whereas they were augmented after topical application of misoprostol and 8-bromo-cyclic adenosine monophosphate. Calcitonin gene-related peptide immunoreactivity was similar in the stomachs of cirrhotic and control rats. CONCLUSIONS: Gastric vasodilation after stimulation of sensory afferent neurons is impaired in cirrhotic rats despite the normal anatomic distribution of these nerves. This effect seemed to be related to a depressed response of the gastric microcirculation to cyclic guanosine monophosphate-dependent vasodilators. This alteration may contribute to the increased susceptibility to gastric ulceration in cirrhotics.

8-Bromo Cyclic Adenosine Monophosphate↗

Low molecular weight dextran in experimental pancreatitis: effects on pancreatic microcirculation.

UNLABELLED: Although low molecular weight (LMW) dextran has been said to decrease the lethality of experimental acute pancreatitis (AP) by reversing stasis in the pancreatic microcirculation, the actual mechanism(s) of action is unknown. This investigation was designed to measure the effects of low molecular weight dextran on pancreatic capillary flow (QCAP) and arteriovenous shunt flow (QAVS), and on pancreatic oxygen consumption (O2CP) following bile-trypsin-induced AP in dogs. Total pancreatic blood flow (QT) was measured with an electromagnetic flow probe on the superior pancreaticoduodenal artery (SPDA). QAVS was measured by liver trapping of 99mTc-albumin microspheres after SPDA injection. QCAP was calculated as QT minus QAVS. Seventeen dogs were treated with lactated Ringer's (LR) solution at 6.5 ml/kg/hr; 10 dogs were treated with LMW dextran 10% in normal saline at 1.5 ml/kg/hr plus LR at 5.0 ml/kg/hr. Mean arterial and central venous pressures remained constant throughout the 4-hr experiment. In the dogs receiving LR only, QT decreased from 42.7 to 24.4 ml/min (P less than 0.001); QAVS remained constant at 1.35 +/- 0.04 ml/min. During the first 30 min O2CP decreased from 1.17 to 0.76 ml O2/min (P less than 0.05) and remained constant thereafter. LMW dextran treatment altered none of these hemodynamic or metabolic parameters significantly. CONCLUSIONS: bile trypsin AP in the dog causes significant decreases in QT and QCAP without altering QAVS. The decrease in O2CP in association with a constant QAVS suggests a metabolic block to oxygen uptake at the cellular level. Continuous infusion of LMW dextran at a dose of 1.5 ml/kg/hr in the dog does not reverse these abnormalities.

Acute Disease↗

Adrenergic and dopaminergic control of the canine paw microcirculation.

Basal isolated canine paw blood flow was equally distributed between arteriovenous anastomosis (AVA) and capillary circulations. Norepinephrine decreased AVA flow by 92% and capillary flow by 41%. Dopamine significantly reduced AVA flow by 94% compared to baseline with a 37% reduction in capillary flow. However, with alpha-adrenergic blockade dopamine decreased AVA flow 66% while capillary flow increased 42%. Isoproterenol increased capillary flow almost twofold and appeared to decrease AVA flow, although the latter was statistically insignificant. Differential effects of adrenergic and dopaminergic agonists on canine paw AVA and capillary blood flow suggest the existence of independent regulation of these components of the microcirculation.

Animals↗

The effect of photodynamic therapy on the microcirculation.

Photodynamic therapy (PDT) is a new form of cancer therapy involving tumor localization by photosensitizing drugs such as dihematoporphyrin ether (DHE). Light irradiation of drug-sensitized tissue results in photoactivation of DHE and tumor necrosis. The mechanism of action is incompletely understood but involves the generation of singlet oxygen which produces cytotoxic effects on tissues containing the compound. In addition, microcirculatory aberrations have been described during PDT. We have studied the acute effects of PDT on the microcirculation using in vivo television microscopy of the rat cremaster. This has enabled us to observe the effects of PDT on both paired and unpaired arterioles and venules using two different wavelengths of activating light (blue, 450-490 nm, and green, 530-560 nm). For both wavelengths of activating light, significant reduction in blood flow of all vessels was seen during PDT. This, in combination with the formation and embolization of platelet thrombi, resulted in stasis of blood flow in 80% of arterioles and 90% of venules. Observation for 2 hr after the completion of photoactivation revealed reperfusion in 20% of the arterioles but none of the venules. Blood flow was reduced by a combination of vasoconstriction and platelet thrombus formation. Reducing the total activating energy from 120J/cm2 to 24J/cm2 significantly reduced the response in venules and the incidence of stasis in both arterioles and venules. We conclude that the photoactivation of DHE results in significant vasoconstriction and thrombosis of normal vessels and that if these effects are seen at later times after DHE administration and in tumor neovasculature they may contribute to the mechanism by which PDT results in tumor necrosis.

Animals↗

Interleukin-2 acutely induces protein leakage from the microcirculation.

Interleukin-2 has been shown to mediate the regression of metastatic cancer. However, therapeutic application has been limited by the induction of dose-dependent toxicities in normal tissues secondary to a vascular leak syndrome. To better understand the pathophysiology of this vascular leak syndrome, the earliest microvascular effects of interleukin-2 were directly observed and quantitated by intravital microscopy. The cremaster muscle of anesthetized Sprague-Dawley rats was prepared for in vivo microvascular observation. Animals were injected with fluorescein isothiocyanate-labeled albumin, and the interstitial emission intensity was used to assess macromolecular leakage. Both the intravenous injection and topical application of interleukin-2 to the cremaster muscle acutely induced the leakage of macromolecules from the microcirculation. The topical application of interleukin-2 induced macromolecular leakage without changes in central hemodynamic parameters. Furthermore, topically applied interleukin-2 did not produce changes in arteriolar or venular diameters, or in regional microvascular blood flow, which could have influenced the protein leakage. These data support the hypothesis that the acute increase in macromolecular leakage produced by interleukin-2 occurs secondary to an increase in endothelial porosity and not as a result of changes in hemodynamic or hydrostatic forces.

Administration, Topical↗

Influence of early phases of paralysis on microcirculation of rat skeletal muscle.

By combining tissue pO2 measurements with morphological visualization and counting of perfused capillaries, early microvascular changes were investigated in paralysis of skeletal muscle of the rat. The models included experimental allergic encephalomyelitis (EAE), experimental allergic neuritis (EAN), 6-aminonicotinamide intoxication, and peripheral denervation. The results showed that in all models tissue oxygenation was either normal or elevated. In most cases this was accompanied by a reduced perfusion of the capillary bed, supporting the hypothesis of a dysfunction in oxidative metabolism. The effects of paralysis on capillary perfusion were more marked in red than in white muscles, except in spastic paresis. Flaccid paralysis had more deleterious effects on muscle microcirculation than spastic paralysis. Our data suggest that: (1) microvascular changes occur very early after the onset of paralysis and (2) later developing changes in the skeletal muscle such as atrophy cannot be ascribed to a lack of oxygen supply but rather, at least in part, to a dysfunction in oxidative metabolism.

6-Aminonicotinamide↗

Differential serotonin responses in the skeletal muscle microcirculation.

Closed circuit television microscopy was used to quantitate in vivo responses of small vessels in the rat cremaster muscle to topically applied serotonin. Sprague-Dawley rats were anesthetized with a combination of urethane (800 mg/kg) and alpha-chloralose (60 mg/kg). The cremaster muscle with intact circulation and innervation was suspended in a bath which had controlled pH, pCO2, and pO2. Microvascular diameters of first order arterioles and venules and fourth-order arterioles were measured from the television monitor while serotonin (10(-9)M-10(-4)M) was added to the bath. Fourth-order arterioles (3-11 micron diameter) dilated to a maximum of 267% of their control value with a serotonin concentration of 10(-6)M. Serotonin (10(-4)M) constricted first-order arterioles (78-121 micron) to 61% of their control value. The threshold concentration (10(-8)M) for a serotonin-induced dilation of fourth-order arterioles was 1000 fold less than the threshold concentration (10(-5)M) for serotonin-induced constriction of first-order arterioles. Serotonin (10(-8)M - 10(-4)M) did not alter the diameter of first-order venules (115-195 micron) from the control value. The dose-dependent constriction of first-order arterioles and dose-dependent dilation of fourth-order arterioles by serotonin appear to be independent of each other. In addition, the lack of constriction of first-order venules suggests a heterogenous distribution of serotonin receptors and that the predominate control mechanisms are different at different levels of the arteriolar and venous microcirculation of rat skeletal muscle.

Animals↗

Relationship between endothelin and thromboxane A2 in rat liver microcirculation.

In our previous study, we determined changes in hepatic blood flow using a Laser Doppler blood flow meter after i.v. injection of endothelin-1 (ET-1) or endothelin-3 (ET-3) at 2 nmol/kg in rats and found that ET-3 caused greater decreases in blood flow than ET-1. In the present study, we determined how the arachidonic acid cascade, mainly thromboxane A2 (TXA2), is related to ET-1 and ET-3 using indomethacin (INDO), which inhibits the biosynthesis of prostaglandin (PG), and OKY-046, a selective inhibitor of TXA2 synthesis. In the first series of experiments, ET-1 and ET-3 were administered after inhibiting the biosynthesis of PG by s.c. injection of 2 mg/kg of INDO. While INDO failed to inhibit the slight decrease in hepatic blood flow induced by ET-1, it significantly inhibited the marked decrease in hepatic blood flow elicited by ET-3. In the next series of experiments, ET-1 and ET-3 were administered after administration of 20 mg/kg of OKY-046. OKY-046 showed no effects in animals treated with ET-1, as in those pre-treated with INDO, while it significantly inhibited the decreases in hepatic blood flow induced by ET-3. These findings suggest that ET-1 decreases hepatic blood flow due to its direct effects although to a lesser extent than ET-3, while ET-3 does so due not only to its direct effects but also to TXA2-mediated effects. It is therefore likely that in addition to ET family peptides, PG-mediated mechanisms are involved in the regulation of hepatic microcirculation by ETs.

Animals↗

Functional and morphological changes in the microcirculation of the dog following acute coronary artery ligation.

Acute ligation of the anterior descending coronary artery in the dog had little immediate effect on heat clearance but immediately lowered heat production, which fell to its minimum level in 1/2 hr, after which it began to recover; recovery was complete in 6 hr. After 1/2 hr heat clearance also began to fall and reached a minimum level in 1 1/2 hr. Ligation increased oxygen extraction but reduced oxygen consumption markedly though temporarily. Complete recovery followed. After 3 months, there was full recovery in flow, oxygen extraction ratio, and oxygen consumption mVO2. In morphological studies using Microfil injections soon after ligation, capillaries failed to fill retrogradely, though network vessels were perfused. After 1 hr of acute artery ligation, capillaries still did not perfuse but by 3 hr there was some reperfusion. After 6 hr there was marked capillary reperfusion. In dogs kept for 3 months after ligation the microcirculation was normal. These studies confirm that immediate circulatory failure occurred in capillaries (probably critical closure) which accounts for the immediate fall in venous outflow, heat production, and mVO2. Flow continued in network vessels which traversed the ischemic zone without perfusing capillaries. These results are contrasted with the findings of some other workers who found a continued functional decline leading to infarction. The present results were accounted for by closure and reopening to capillaries.

Animals↗

Response of the rabbit cutaneous microcirculation to prostanoid modifiers as determined by laser Doppler flowmetry.

The cutaneous microvascular flow of the rabbit epigastric island flap under the influence of various prostanoid modifiers has been determined semiquantitatively with a Laser Doppler flowmeter. Infused prostacyclin, diluted with arterial blood to an estimated concentration of 2.5 ng/ml in the microvasculature, increased the microvascular blood flow to approximately 130% of the buffer control. The three thromboxane synthetase inhibitors tested--dazoxiben hydrochloride, UK-38,485, and 7-(1-imidazolyl) heptanoic acid--at concentrations up to 3 X 10(-5) M in the microvasculature, failed to induce any change in blood flow compared to a control neutral-buffered saline infusion. Preliminary results also found that the lipoxygenase inhibitor Bay g6575 did not alter microvascular flow up to 7 X 10(-6) M, but the prostacyclin analog carbacyclin at 30 ng/ml in the microvasculature induced a similar response to 2.5 ng/ml prostacyclin. While such responses are well known for the major vessels, this is one of the few reports with semiquantitative data on the influence of prostanoid synthesis modifiers on blood flow for the microcirculation.

Animals↗

Surgical exposure induces formation of an arteriovenous permeability gradient for macromolecules in the microcirculation of muscle.

Rous and his colleagues (P. Rous, H. P. Gilding, and F. Smith, 1930, J. Exp. Med. 51, 807-830, F. Smith and P. Rous, 1931, J. Exp. Med. 53, 195-217) uncovered evidence for an arteriovenous gradient of permeability in exchange vessels of muscle. After injecting vital dyes intravenously in laboratory animals, including mice and rats, they examined escape of the dyes from exchange vessels of abdominal muscles, prepared for observation by reflection of the overlying skin. They noted that a particular class of dyes, termed "poorly diffusible," escapes from venules but not from arterioles and capillaries a few minutes after injection. We now assume that the "poor" diffusibility of the dyes stems from their binding to plasma proteins. We repeated similar experiments in mice and rats, using Evans blue as tracer, and also observed leakage of Evans blue from venules but not from other exchange vessels. We made three additional observations. (1) Evans blue leaks from venules only after the skin overlying the abdominal muscles is reflected. (2) Reflection of the skin initiates degranulation of mast cells in the muscles. (3) Leakage of Evans blue from venules is inhibited by administration of promethazine, a histamine and serotonin antagonist, to the animals prior to reflection of the skin. On the basis of our observations, we conclude that the arteriovenous permeability gradient for poorly diffusible dyes in the microcirculation of muscle represents response to tissue injury resulting from reflection of overlying skin.

Abdomen↗

Human malignant ascites and histamine-induced protein leakage from the normal microcirculation.

The accumulation of malignant ascites is a significant cause of morbidity and mortality in patients with intraabdominal malignancies. However, the cause of malignant ascites is unknown. In this study, we used the rat cremaster muscle preparation to determine if and how malignant ascites could produce protein leakage from normal blood vessels which would lead to fluid accumulation in the peritoneal cavity. The rat cremaster muscle, with nerves and blood vessels to the animal intact, was prepared for microscopic observations of the microcirculation. Serum albumin was tagged to fluorescein isothiocyanate and injected into the rat. Fluorescent microscopy was used to quantitate leakage of the tagged albumin into the interstitial tissue. Malignant ascites was collected from a patient with metastatic breast cancer. The ascites fluid was placed on the cremaster muscle and it induced protein leakage from the normal blood vessels of this tissue. Protein leakage was partially blocked by diphenhydramine (10(-4) M) and by mast cell depletion with compound 48/80. There was a high level of C3a in the malignant ascites solution but C3a did not increase during the exposure period. These data suggest that activated complement in malignant ascites may release histamine from mast cells to cause protein leakage of the normal vasculature. The movement of protein into the peritoneal cavity would be followed by water, thus increasing the volume of the ascites and exacerbating the clinical condition.

Animals↗

Noradrenergic and peptidergic innervation of the extrinsic vessels and microcirculation of the rat cremaster muscle.

The noradrenergic and peptidergic innervation of the extrinsic vessels and microcirculation of the rat cremaster muscle was examined. Catecholamine-containing nerves were identified histochemically by glyoxylic acid-induced fluorescence and tyrosine hydroxylase immunoreactivity (TH-IR). The extrinsic pudic-epigastric artery and vein as well as the entire intramuscular arteriolar network was innervated by noradrenergic axons. The capillaries and intramuscular venules of the cremaster muscle were devoid of a noradrenergic innervation. Immunohistochemical double-labeling demonstrated that most, if not all, of the TH-IR axons also possessed neuropeptide Y immunoreactivity (NPY-IR), implying colocalization of the norepinephrine and NPY in the perivascular nerves. No vasoactive intestinal peptide immunoreactivity (VIP-IR) was found, except for occasional VIP-IR axons associated with the pudic-epigastric artery. Substance P immunoreactive (SP-IR) axons formed a sparse plexus around the arteries and larger arterioles. Calcitonin gene-related peptide immunoreactivity (CGRP-IR) had a similar distribution to the SP-IR axons. CGRP-IR was also observed in axons alongside some smaller arterioles and capillaries. The extrinsic vessels and intramuscular arteriolar network of the rat cremaster muscle are innervated by noradrenergic axons which contain NPY and by presumed sensory nerves containing SP and/or CGRP. Both types of nerves may contribute to regulation of microvascular function.

Adrenergic Fibers↗

Mapping of the microcirculation in the chick chorioallantoic membrane during normal angiogenesis.

The microcirculation within the chorioallantoic membrane (CAM) of the chick is particularly well suited for in vivo observation and has been used extensively as an assay to detect angiogenic activity. Although progressive chronological expansion of the CAM capillary network occurs normally during embryogenesis, descriptions of the branching patterns of CAM pre- and postcapillary microvessels during embryonic development have not been recorded. In the present study chick embryos were incubated, using an established shell-less culture technique, and observed in vivo at Days 6, 10, and 14 of embryonic development. Morphometric analyses of photomicrographs of CAM microvessels were based upon the centripetal ordering method of microvascular mapping of the first three orders of pre- and postcapillary microvessels with the capillaries serving as the initial point of reference. For both pre- and postcapillary vessels, the number of first-order vessels exceeded the number of second-order vessels which, in turn, outnumbered third-order vessels during each observation period. First- and second-order vessels progressively increased in number from Day 6 to Day 14; however, the number of third-order vessels remained essentially constant during this period. Further, the number of precapillary vessels was greater than postcapillary vessels in their respective orders at Days 6 and 10; however, by Day 14 the numbers were comparable. Average diameters and lengths of the third-order vessels were greater than the second-order vessels which, in turn, were greater than the first-order vessels in both the pre- and postcapillary compartments. Further, mean lengths of each of the three vessel orders in both compartments decreased progressively and by Day 14 were significantly less than at Day 6. Average diameters of each vessel order, on the other hand, remained unchanged from Day 6 to Day 14. Finally, intercapillary distances, based on measurements from fluorescent micrographs obtained after microinjections of fluorescein isothiocyanate (FITC)-dextran, were substantially less at Day 10 and 14 than at Day 6. Based on these morphometric data, the endothelial precursor responsible for continuous neoformation of first- and second-order microvessels during embryogenesis remains uncertain. Whether existing first-, second-, or third-order vessel endothelia serve as this precursor or histodifferentiation of existing capillaries enables continuous expansion of the first- and second-order microvessels remains to be tested.

Allantois↗

Leukocyte flow dynamics in the rat liver microcirculation.

The flow dynamics of leukocytes in the rat liver microcirculation was studied in the sinusoids in the three zones of the liver acinus (zone 1, periportal; zone 2, mid; and zone 3, pericentral) by means of in vivo fluorescence microscopy. Leukocytes were labeled in vivo with acridine orange. The microscopic image was videotaped and on playback of the videotapes, leukocyte velocity, leukocyte flux, erythrocyte velocity, sinusoid diameter, and sinusoid tortuosity were measured. Blood flow and flow resistance were calculated from these data. The leukocyte velocity, erythrocyte velocity, sinusoid diameter, and blood flow in the liver sinusoids in zone 3 were significantly greater than those in zone 2, which in turn were also significantly greater than those in zone 1. There were significant positive correlations between leukocyte and erythrocyte velocity, between leukocyte velocity and sinusoid diameter, and between leukocyte velocity and blood flow. Sinusoid tortuosity in zone 1 was significantly larger than that in zone 2 and zone 3. Flow resistance in zone 1 was significantly greater than that in zone 2, which was also significantly greater than that in zone 3. These results provide evidence for a "zonal gradient" of leukocyte velocity in the liver sinusoids, with increasing velocity from zone 1 to zone 3. The morphological (narrow diameter and tortuous path) and resistance factors appear to contribute to the slow velocity in zone 1.

Animals↗

Interaction between adenosine and angiotensin II in renal microcirculation.

In order to examine the possibility of an interaction between adenosine and angiotensin II (A II) in the control of the renal microcirculation, we studied the effects of agonists and antagonists of both substances by means of in vivo microscopy in the split hydronephrotic rat kidney. In a first series of experiments (n = 6), local application of the A II receptor antagonist saralasin (10(-6) mol.liter-1 abolished the vasoconstriction and the reduction of glomerular blood flow induced by the A1-adenosine receptor agonist N6-cyclohexyladenosine (CHA, local concentration 10(-7) mol.liter-1). Without saralasin (second series, n = 6), CHA reduced glomerular blood flow and decreased vessel diameters as previously reported from our laboratory. In a third series of experiments (n = 6), A II significantly reduced vessel diameters and glomerular blood flow both alone and during blockage of the A1-adenosine receptor by the selective antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10(-5) mol.liter-1). In additional experiments, we excluded nonspecific receptor effects of saralasin and confirmed the inhibitory action of DPCPX on the adenosine-induced vasoconstriction. We suppose that adenosine needs a functioning A II receptor system for its vasoconstrictor action, whereas A II can induce a nonadenosine-dependent vasoconstriction.

Adenosine↗