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Biomedical subjects

F N Miller

Publications and source records attributed to F N Miller.

At least 91 records · Page 5Linked to original sources
PubMed1988

Protein leak from normal vasculature due to human malignant ascites.

Malignant ascites is an accumulation of protein rich fluid (a filtrate of whole blood) in the peritoneal cavity of patients with abdominal malignancies. The normal peritoneal microvasculature of the cremaster muscle of rats, with the nerve and blood supply intact, was visualized before and after exposure of the tissue to human malignant ascites fluid and to human plasma. In vivo fluorescent microscopy was used to quantitate leakage of fluorescent-tagged albumin. Exposure of the abluminal side of the vasculature to malignant ascitic fluid and plasma causes significant protein leakage from the small veins to the interstitial space. This suggests that the continued production of malignant ascites may be caused by a positive feedback system, which is related to factors present in a normal plasma filtrate. These factors can induce leakage of protein by an effect on the abluminal side of the normal peritoneal microvasculature.

Adenocarcinoma↗
PubMed1987

In vivo arteriolar reactivity to norepinephrine and calcium in one-kidney, one-clip Goldblatt hypertensive rats.

The in vivo reactivity of small arterioles to norepinephrine and to changes in external calcium was investigated in normotensive (NT) and one-kidney, one-clip Goldblatt hypertensive rats (1K1C). Rats were anesthetized with sodium pentobarbital (50 mg/kg) and arterioles in the cremaster muscle were exposed to increasing concentrations of either norepinephrine (10(-10) to 10(-5) M) or of bath calcium (0 to 5.1 mM). Third-order arterioles of 1K1C showed almost a ten-fold increased reactivity to NE compared to arterioles of NT rats (pD2 values of 7.88 +/- .43 vs 6.92 +/- .30). Arterioles of 1K1C rats showed an increased reactivity to re-exposure to calcium (0.65 to 5.10 mM). Following exposure to phentolamine this hyper-reactivity was abolished and arterioles of 1K1C and NT exhibited similar responses to changes in bath calcium concentrations, suggesting that the increased reactivity in the 1K1C was due to stimulation of endogenous norepinephrine release. When arterioles were exposed to increasing bath concentrations of the calcium entry blockers, verapamil and diltiazem, dilator responses were similar for 1K1C and NT groups. Collectively, these data suggest that during the development of renovascular hypertension, observed increases in arteriolar reactivity involve an increase in the receptor mediated entry of extracellular calcium into vascular smooth muscle and no change in non-receptor-mediated entry of calcium.

Animals↗
PubMed1986

Differential macromolecular leakage from the vasculature of tumors.

Tumor-induced neovascularization is essential for invasion, metastases, and exponential growth of solid tumors. The authors studied the differences in macromolecular leakage from the neovasculature of a fast-growing, early-metastasizing tumor, the Walker 256 carcinosarcoma, and a slow-growing, nonmetastasizing tumor, a rat chondrosarcoma. A 1-mm3 piece of the Walker 256 carcinoma or the chondrosarcoma was implanted in the cremaster muscle of rats. Five days after surgery the cremaster muscle with the implanted tumor was placed in a special bath containing Krebs solution such that the circulation and nerves from the animal to the cremaster were intact. Fluorescein isothiocyanate-labeled rat serum albumin (FITC-RSA) was injected (intra-arterially) into each rat to permit visualization of the vasculature by fluorescent microscopy. A closed-circuit television system was used to quantitate macromolecular leakage as a change in interstitial fluorescent intensity. Data are given as a relative fluorescent intensity (mean +/- standard error of the mean) in an area of the cremaster with tumor-induced neovascularization. These studies demonstrated that the vasculature induced by rapidly growing Walker 256 carcinosarcoma leak albumin freely when compared with the vasculature induced by the slow-growing chondrosarcoma. Furthermore, there was a significant increase in fluorescent intensity (albumin leakage) in the Walker tumor from 1 minute (24 +/- 3.0) to 30 minutes (49 +/- 5.6). In the normal cremaster area there was a significantly lower fluorescent intensity in the interstitium and a very slight increase with time (4 +/- 1.5 at 1 minute vs. 7 +/- 1.4 at 30 minutes). One interpretation of these data is that the mechanisms responsible for protein leakage from the vasculature of the Walker tumor may be involved in the fast growth and metastases of this tumor as compared with slower-growing tumors such as the chondrosarcoma.

Animals↗
PubMed1986

Mechanism by which methylprednisolone inhibits acute immune complex-induced changes in vascular permeability.

Intravital microscopy was used to quantitate protein leakage which resulted from the deposition of immune complexes in the vasculature of the rat cremaster muscle. Immune complex deposition was initiated by the addition of 80 micrograms/ml of ovalbumin to the bath surrounding the muscle, followed by the intravenous administration of antiovalbumin. Administration of 25 mg/kg of antiovalbumin produced significant leakage of protein from the third-order venules, while 7.5 and 2.5 mg/kg had no effect. Administration of methylprednisolone (MP), 30 mg/kg, 1 h prior to the deposition of immune complexes significantly inhibited protein leakage. In separate experiments, MP inhibited intradermal edema formation and protein exudation induced in rats by histamine, platelet activating factor, or C5a. However, MP had no effect on protein exudation or edema produced by xanthine oxidase or glucose oxidase. Intravenous administration of MP inhibited the ability of polymorphonuclear leukocytes (PMNs) to phagocytize bacteria, but failed to alter hydrogen peroxide production. These results suggest that MP prevents acute changes in vascular permeability following immune complex deposition by inhibiting the effects of soluble mediators of edema on vascular endothelium and by inhibiting PMN phagocytosis.

Animals↗
PubMed1986

Histamine-induced protein leakage in hypertensive rats: inhibition by verapamil.

Hypertension has been associated with an enhanced transport of macromolecules from the vasculature to the interstitium. The first objective of this study was to determine if, under control conditions, there is an enhanced leakage of macromolecules from the cremaster vasculature of the hypertensive rat. The second objective was to determine if the response to a mediator of macromolecular leakage (histamine) was altered in the renovascular hypertensive rat. A third objective was to determine if a calcium entry blocker, verapamil, could inhibit histamine-induced leakage and, if so, was the sensitivity to verapamil different in the renovascular hypertensive rat. Rats were anesthetized with pentobarbital, and the cremaster preparation was used for in vivo television microscopy studies. Fluorescein isothiocyanate was tagged to rat serum albumin (FITC-RSA), and the leakage of this albumin from the vasculature to the interstitium was quantitated by the use of fluorescent microscopy techniques. There was no difference during control conditions in macromolecular leakage between the normotensive and hypertensive rats. However, histamine induced a greater leakage in the renovascular hypertensive rat than in the normotensive controls. In addition, verapamil, in the presence of normal calcium levels, inhibited the histamine-induced leakage in the hypertensive rats but not in the normotensive controls. These data suggest that enhanced macromolecular leakage during hypertension may be due to an increased sensitivity to mediators of protein leakage. These agents may produce protein leakage by enhancing entry of extracellular calcium into endothelial cells.

Animals↗
PubMed1986

In vivo venular changes with the development of one-kidney, one-clip hypertension in the rat.

Television microscopy was used to quantify in vivo resting venular diameters and the responses to topically applied norepinephrine in the cremaster muscle of two groups of urethanchloralose anesthetized rats: normotensive rats (NT) and one-kidney, one-clip Goldblatt hypertensive rats (1K1C). Observations were made two weeks after the surgery which was used to induce renovascular hypertension. At this stage, we have previously observed an increase in arteriolar reactivity (1). In the current study, mean arterial blood pressures for 1K1C (149 +/- 5 mmHg) were significantly higher than pressures for NT (102 +/- 3 mmHg). Venules were categorized by branching order and venular diameters were measured at three different levels of the microcirculation: first (1V), second (2V), and third order (3V) venules. Reactivity to norepinephrine at all venular levels in the 1K1C group was similar to that recorded for the NT group. Resting venular luminal diameters, however, were significantly smaller (20%) for large (1V) venules of the HT group (137 +/- 9 micron) compared to those for the NT group (171 +/- 10 micron). Thus, in contrast to previously reported data for arterioles, a structural venoconstriction and not an increase in venular reactivity appears to characterize the early vascular changes associated with this form of renovascular hypertension.

Abdominal Muscles↗
PubMed1986

Contractile elements in the regulation of macromolecular permeability.

The leakage of macromolecules from the vasculature to the interstitium is greatly accentuated by mediators of edema such as histamine and bradykinin. The mechanism for this effect is not well delineated although many agents that affect smooth muscle tone may also affect macromolecular leakage. Leakage occurs primarily from the small venules. The demonstration that mediators of edema produce interendothelial gaps in the venules as well as changes in the shape of the endothelial nuclei has led to the hypothesis that a contraction of a vascular wall component may be responsible for the observed leakage of macromolecules. This component does not appear to be the vascular smooth muscle itself. Two other elements of the vascular wall, the endothelium and the pericytes, have been shown to contain many of the same elements of the contractile machinery present in smooth muscle. Most recent studies have presumed that endothelial cell contraction is responsible for the formation of the interendothelial gaps through which the macromolecules move. However, endothelial contraction has been difficult to demonstrate experimentally. Alternatively, inasmuch as pericytic processes can end near endothelial junctions and there is an abundance of fibronectin between the pericytes and the endothelium, it may be a pericytic contraction that causes the interendothelial gap formation.

Actins↗
PubMed1984

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↗
PubMed1984

Inhibition of histamine-induced protein leakage in rat skeletal muscle by blockade of prostaglandin synthesis.

The effects of two prostaglandin synthesis blockers, indomethacin and mefenemic acid, on both histamine-induced extravasation of albumin and arteriole dilation were studied using intravital fluorescent microscopy. Sprague-Dawley rats (140-180 g) were anesthetized with pentobarbital (50mg/Kg) and the cremaster muscle was positioned in a Krebs bath (pH = 7.4, PCO2 = 40 mm Hg, PO2 = 35 mm Hg, temp = 34 degrees). Fluorescein isothiocyanate-labeled albumin was injected intravascularly and the fluorescent image of the cremaster microcirculation was produced by illumination from an argon laser (488 nm). Videotape analysis of the experiments showed that increasing concentrations of histamine in the bath produced both a concentration-dependent arteriole dilation and a concentration-dependent leakage of labeled albumin into the interstitium. Adding indomethacin (10 or 100 micrograms/ml) or mefenemic acid (10 micrograms/ml) to the Krebs bath significantly diminished the protein leakage induced by histamine but did not alter the arteriole dilation. These results indicate that prostaglandins may be directly involved in the histamine-induced increase in vascular permeability to macromolecules but not in the arteriole dilation histamine produces.

Animals↗
PubMed1984

Protein loss induced by complement activation during peritoneal dialysis.

A variable loss of macromolecules during peritoneal dialysis has been noted in both humans and experimental animals. We investigated the potential role of the complement system for inducing protein loss during peritoneal dialysis, both to shed light on clinical variability of protein loss and to develop a model for quantitatively studying complement-induced microvascular protein leakage. Rats received intra-arterial injections of a fluorescent dye conjugated to rat serum albumin and underwent a 3.5-hr series of 15-min peritoneal dialysis exchanges. After the control exchanges, rats received either intra-arterial zymosan-activated rat serum, saline, unactivated rat serum, or endotoxin; other rats received an intraperitoneal injection of endotoxin, histamine, phenylephrine, or nitroprusside. The drainage volume from each exchange was measured, and the concentrations of labeled albumin, total protein, and urea were determined by spectroscopy. Zymosan-activated rat serum and endotoxin injections (both intraperitoneal and intra-arterial), each of which may activate the alternative pathway of complement, produced a dramatic increase in dialysate protein concentrations. In addition, histamine, which is a vasodilator but which may also be involved as a mediator of the activated complement system and/or endotoxemia, also produced an increase in dialysate protein concentrations. On the other hand, drugs which may alter peritoneal blood flow such as the vasodilator nitroprusside or the vasoconstrictor phenylephrine, did not affect dialysate protein concentrations. These data suggest that activation of the alternative pathway of complement may cause variation in protein loss during peritoneal dialysis and that in some situations, pharmacological control of this system could be an important therapeutic consideration.

Animals↗
PubMed1981

Hyperosmolality, acetate, and lactate: dilatory factors during peritoneal dialysis.

Factors that alter peritoneal blood flow may influence the clearance of solutes during peritoneal dialysis. Arteriolar vasodilation, for instance, could increase the delivery of solutes to the capillaries and venules leading to an increase in solute transport into the peritoneal cavity. This study was designed to identify the vasoactive effects of several major components of McGaw and Dianeal peritoneal dialysis solutions to understand how the composition of these solutions may alter in vivo blood flow in the peritoneum. Because the major differences between these solutions and Krebs solution are a high osmolality, a high dextrose concentrations, and an acetate or lactate buffer system, we investigated the effects of these components. Rats were anesthetized with the combination of urethane and chloralose. The cremaster muscles, with the nerve and blood supplies from the rat still intact, was placed in a specially designed tissue chamber that was filled with Krebs solutions. A port permitted microscopic observations of the blood vessels. In vivo television microscopy observations was used to quantitate changes in small arteriole diameters induced by changes in the composition of the solution bathing the cremaster or by the addition of nitroprusside. Hyperosmolality produced by the addition of dextrose, sucrose, or sodium chloride to the Krebs solution induced a submaximal dilation of the small arterioles of the cremaster. The rate of dilation differed depending on the substance used to increase osmolality. A normal osmolality acetate (74 mM) or lactate (45 mM) solution produced a slow, submaximal dilation of the cremaster arterioles. Hyperosmolar acetate (37 or 74 mM) or lactate (45 mM) solutions produced a rapid, maximal dilation of these vessels. Because the rate of dilation and maximal effect produced by the commercial dialysis solutions were similar to these same parameters produced by the high-osmolality acetate or lactate solutions, the dilatory effects of McGaw and Dianeal solutions appear to be due to the combinations of high osmolality and the buffer anion acetate or lactate.

Acetates↗
PubMed1981

An hypothesis to explain the ultrafiltration characteristics of peritoneal dialysis.

We present an hypothesis that could account for many characteristics of ultrafiltration and solute movement during peritoneal dialysis. The hypothesis describes transcapillary ultrafiltration and can account for (1) the osmotic effectiveness of rapidly absorbed glucose, (2) small solute sieving in a system permitting protein loss, (3) functional estimates of effective pore sizes as low as 11 A for urea and as high as 62 A for proteins from hydrodynamic analyses, (4) isolated loss of ultrafiltration without loss of clearance, (5) decreased ultrafiltration with decreased clearances, and (6) increased ultrafiltration with decreased clearances. Mechanisms for fluid movement from the peritoneal interstitium into the peritoneal cavity may involve both hydrostatic and osmotic pressure. Interstitial water pathway dimensions, interstitial gel surface charges, mesothelial cell surface charges, and transmesothelial-cell water movement might also account for sieving effects during peritoneal ultrafiltration.

Animals↗
PubMed1981

muscle microcirculation: effects of tissue pH, PCO2, and PO2 during systemic hypoxia.

The responses of arterioles and venules to systemic hypoxia (fractional inspired O2 concentration 0.10) were determined for the rat cremaster muscle that was positioned with intact nerve and vascular supplies in a tissue bath that had controlled pH, O2 tension (PO2), CO2 tension (PCO2), and temperature. Blood pressure and heart rate were decreased significantly during systemic hypoxia. First- and second-order arterioles actively constricted during systemic hypoxia, whereas most first-, second-, and third-order venules had biphasic responses (dilation followed by constriction). There were no significant differences in the active arteriolar responses to systemic hypoxia when cremaster bath pH was altered from 6.9 to 7.2, or when bath PCO2 was changed from 60 +/- 2.2 to less than 5 mmHg; but, there was significantly greater arteriolar constriction with high bath PO2 (139 +/- 1.3 mmHg) in comparison to low bath PO2 (4.5 +/- 0.5 mmHg). Decreased bath pH, decreased PO2, and increased PCO2 had no effect on the dilation responses of first-, and second-, and third-order venules to systemic hypoxia; however, these bath alterations attenuated the constriction responses of third-order venules. alpha-Adrenergic receptor blockade did not alter the arteriolar responses to systemic hypoxia. Our data indicate 1) that there is a centrally mediated stimulus for constriction of first-order arterioles during systemic hypoxia, 2) that changes in local cremaster PO2, but not PCO2 or pH, can attenuate this centrally mediated arteriolar constriction, and 3) that the centrally mediated arteriolar constriction does not involve alpha-adrenergic receptors.

Animals↗
PubMed1981

Decreased vascular sensitivity to norepinephrine following exercise training.

Twenty Sprague-Dawley rats (230 +/- 9 g; mean +/- SE) were exercised daily for 6 wk by swimming 1 h/day with weights (5% of body wt) attached to their tails. Nineteen additional rats (237 +/- 8 g) remained sedentary in their cages. All animals were anesthetized with urethan (800 mg/kg) and alpha-chloralose (60 mg/kg). In the first series of experiments, increasing doses of norepinephrine were injected into the jugular vein and the responses in mean arterial blood pressure was recorded from a cannulated femoral artery. Exercise training had no effect on the maximal increase in blood pressure, but significantly decreased blood pressure sensitivity to norepinephrine, expressed as a pD2 value (=-log ED 50), from 5.64 +/- 0.07 to 5.20 +/- 0.06. In the second series, the cremaster muscle with intact circulation and innervation was suspended in a tissue bath and norepinephrine in increasing concentrations was added to the cremaster bath. The responses of the main arteriole (approximately 110 micron) and venule (approximately 170 micron) were recorded by television microscopy. Exercise training had no effect on vessel diameters of resting muscle or on the maximal vessel constrictions obtained in response to high concentrations of norepinephrine. Arteriole sensitivity to norepinephrine was significantly decreased (pD2 of 6.69 +/- 0.24 vs. 5.96 +/- 0.18) and there was some tendency for reduced venule sensitivity. These data suggest that exercise training in rats produces a decrease in alpha- or an increase in beta-adrenergic receptor sensitivity.

Animals↗