Effects of local mast cell degranulation on vascular permeability to macromolecules.

The suffused noneverted cheek pouch of pentobarbital anesthetized hamsters was used to study the effects of localized, selective mast cell degranulation on vascular permeability. Fluorescein isothiocynate dextran (FITC-D, 70,000 Da) was utilized as a tracer, and intra-vital light microscopy was employed to monitor the formation of vascular leakage sites while direct measurement of plasma and suffusate tracer concentrations were used to monitor tracer clearance. Varying the time at which the FITC-D tracer was injected i.

Differential effects of inhibitors of cellular function on inflammatory mediator-stimulated increases in vascular permeability.

The suffused noneverted cheek pouch of pentobarbital anesthetized hamsters was used to study the effects of various inhibitors of receptor/cellular function on inflammatory mediator stimulated increases in vascular permeability. Fluorescein isothiocynate dextran (FITC-D, 70,000 Da) was utilized as a tracer, and intra-vital light microscopy was employed to monitor the formation of vascular leakage sites while direct measurement of plasma and suffusate tracer concentrations were used to monitor tracer clearance. Vascular permeability increases were triggered by suffusing the cheek pouch with histamine, bradykinin, or Compound 48/80 which stimulated the formation of focal FITC-D leakage sites in the postcapillary venules resulting in marked increases in [FITC-D]S, [FITC-D]S/[FITC-D]p.

Contribution of kininase II to the waning of vascular actions of bradykinin.

The mechanism(s) of the waning of the vasodilation and increase in vascular permeability during prolonged local intraarterial infusions of bradykinin (BK) was investigated in this study. Treatment with phentolamine or saralasin failed to prevent the waning of the vasodilation during the prolonged infusion of BK into forelimbs perfused at constant flow. In contrast, BK produced a sustained vasodilator response after treatment with captopril.

The role of venular endothelial cells in the regulation of macromolecular permeability.

It is well documented that inflammatory mediators produce increases in fluid filtration promoting massive edema formation in limb skin and skeletal muscle. The edema is attributable to an increase in the transmural hydrostatic pressure gradient subsequent to an increase in microvascular pressure (Pmv) and, more importantly, to a decrease in the transmural colloid osmotic pressure gradient subsequent to an increase in vascular permeability to macromolecules. The mediators produce increases in net fluid filtration, protein clearance, the L/P total protein ratio, and edema formation in the absence of increases in blood flow and Pmv demonstrating that increases in vascular permeability are not dependent on changes in blood flow, Pmv, or surface area per se.

Modulation of macromolecular permeability by immune-complexes and a beta-adrenoceptor stimulant.

The suffused, noneverted cheek pouch of ovalbumin (OA)-immunized hamsters was employed to study changes in vascular permeability utilizing intravital light microscopy and direct measurements of plasma to suffusate tracer efflux. Suffusion of the cheek pouches of immunized animals with OA for 10 min stimulated the formation of focal venular fluorescein isothiocyanate dextran (FITC-D, 70,000 Da) leakage sites and produced increases in the plasma to suffusate FITC-D efflux resulting in marked increases in concentration of FITC-D in suffusate ([FITC-D]s). The intravenous injection of the FITC-D 15 to 60 min after the start of the OA suffusion failed to reveal the formation of vascular FITC-D leakage sites or increases in [FITC-D]s.

Patterns of constriction produced by vasoactive agents.

The patterns of vasoconstriction produced by local infusions of constrictor agents and neurogenic stimuli are unique and varied. Although vasoconstrictors or neurogenic stimuli may produce similar increases in total resistance to blood flow, the effects on consecutive vascular segments may differ dramatically. Vasoconstrictors may affect primarily small vessels, large vessels, or a combination of both.

Evidence that prolonged histamine suffusions produce transient increases in vascular permeability subsequent to the formation of venular macromolecular leakage sites. Proof of the Majno-Palade hypothesis.

The aim of this study was to determine whether histamine-stimulated increases in macromolecular efflux are dependent on the formation of specific vascular leakage sites, or whether other mechanisms need to be invoked to explain the increase in macromolecular efflux produced by this inflammatory mediator. Intravital light microscopy was used to localize and quantitate vascular macromolecular leakage sites in the noneverted hamster cheek pouch. Fluorimetric measurements of plasma and suffusate tracer (FITC-D 70,000 mol wt) concentrations were utilized to quantitate changes in macromolecular efflux.

Physiological and pharmacological evidence for the regulation of permeability.

Local intraarterial infusions of histamine-type mediators produce increases in microvascular pressure (Pmv), protein efflux, and net fluid filtration that promote edema formation. The rise in Pmv is not the primary determinant of edema formation inasmuch as mediator-stimulated edema formation develops without an increase in Pmv. The inflammatory mediators increase the hydraulic conductivity of the microvascular membrane as evidenced by a large increase in the capillary filtration coefficient (CFC) subsequent to an increase in permeability.

Evidence for endothelial cell-mediated regulation of macromolecular permeability by postcapillary venules.

Local application of inflammatory mediators to the hamster cheek pouch produces an immediate increase in the number of leaking postcapillary venules as observed by intravital light microscopy. Leaks are illuminated by using fluorescein-labeled dextran given i.v.

Is there evidence for venular large junctional gap formation in inflammation?

Inflammatory edema is associated with vascular macromolecular leakage. Various patterns of vascular macromolecular leakage may be produced depending on the severity and nature of the inflammatory stimulus resulting in transient and/or sustained increases in macromolecular permeability. Inflammatory stimuli which cause endothelial cell damage or destruction induces non-specific increases in macromolecular permeability in all injured microvessels.

Effects of dopamine and vasopressin on histamine-induced increases in macromolecular permeability in the canine forelimb.

Local intra-arterial infusions of histamine, 16 micrograms base/min, for 60 minutes produced increases in lymph flow, lymph total protein concentration, the lymph/plasma total protein ratio, and weight in canine forelimbs perfused at constant flow. The weight gains were far greater than can be accounted for by an increase in vascular volume, and must, therefore, be attributed to edema formation. Treatment with dopamine (2, 4, or 8 micrograms base/min) or arginine vasopressin (AVP) initially produced an increase in perfusion pressure reflecting constriction of the forelimb vasculature.

Effects of AVP and DDAVP on histamine-induced increases in macromolecular permeability in the hamster cheek pouch.

The effects of histamine alone and in the presence of AVP or DDAVP on microvascular permeability to macromolecules was evaluated in the superfused hamster cheek pouch. FITC-Dextran (MW 70,000) was employed as a macromolecular tracer to quantitate the increase in macromolecular permeability produced by the topical application of histamine. Intra-vital light microscopy was utilized to quantitate and localize FITC-D extravasation sites along the vascular tree, and fluorimetric measurement of the FITC-D concentration in the suffusate (S) and plasma (P) was used to calculate the FITC-D S/P ratio to quantitate the increase in macromolecular permeability.

Effects of dopamine (DA) and SKF 82526, a selective DA1-receptor agonist, on vascular resistances in the canine forelimb.

This study was performed to determine the presence of vascular dopamine (DA1) receptors in the canine forelimb. Local i.a.

Evidence that serotonin receptors mediate the cutaneous vasoconstriction produced by 5-hydroxytryptamine in canine forelimbs.

The effects of local intra-arterial infusions of serotonin (5 or 25 micrograms base/min) or norepinephrine (1 or 5 micrograms base/min) on cutaneous (skin) and skeletal muscle vasculatures were investigated in canine forelimbs perfused at constant flow in dogs anesthetized with pentobarbital. Norepinephrine produced dose-related constriction of the skin and skeletal muscle vasculatures. In the cutaneous vascular circuit, norepinephrine produced large artery, small vessel, and large vein constriction.

Effects of captopril and propanolol on bradykinin-induced changes in vascular pressures, lymph total protein concentration, and weight in canine forelimbs.

Sixty-minute local intraarterial infusions of bradykinin (0.8, 5, or 10 micrograms base/min) produced transient forelimb vasodilation and dose-related increases in lymph flow, lymph total protein concentration, total protein transport, and weight in forelimbs perfused at a controlled flow rate. Mean aortic pressure was not affected by these infusion rates of bradykinin.

Effect of norepinephrine on lymph flow and edema formation in the canine forelimb.

In the present study we sought evidence for the hypothesis that norepinephrine (NE) can cause constriction of lymph vessels in the canine forelimb perfused at constant flow. Mechanical venous compression (small-vein pressure approximately equal to 45 mmHg), intra-arterial infusion of histamine (16 micrograms base/min), and intra-arterial infusion of NE (16 micrograms base/min) caused the limbs to gain weight at similar rates due to edema formation; the first two maneuvers caused a sustained increase in skin lymph flow, but the increase in lymph flow with NE was only transient. Similar changes were seen during infusion of NE at 1 and 2 micrograms/min, and studies with radioactive microspheres indicated that NE increased capillary blood flow.

Pharmacological modification of the edema produced by combined infusions of prostaglandin E1 and bradykinin in canine forelimbs.

In dogs anesthetized with pentobarbital, 60 min local i.a. infusions of prostaglandin E1 (4 micrograms/min) together with bradykinin (10 micrograms base/min) into forelimbs perfused at a constant pump controlled flow rate produced decreases in perfusion pressure and very marked increases in lymph flow, lymph total protein concentration, total protein transport and weight (266 g).

Interactions among inflammatory mediators on edema formation in the canine forelimb.

Prostaglandin E1, 4 microgram/min, infused locally intra-arterially (ia) for 60 minutes into forelimbs perfused at constant pump controlled inflow produced decreases in perfusion pressure, increases in lymph total protein concentration (approximately equal to g/100 ml), and small increases in weight (23 g) owing to edema formation. Histamine, 16 microgram base/min, or bradykinin, 10 microgram base/min, infused locally ia for 60 minutes produced large increases in lymph flow, lymph total protein concentration, total protein transport, and weight (70 g and 130 g, respectively). However, the local ia infusion of prostaglandin E1, 4 microgram/min, together with histamine, 16 microgram base/min, or bradykinin, 10 microgram base/min, produced weight increases of 180 g and 236 g, respectively, and the rate of weight gain during the combination infusions greatly exceeded that produced by infusions of histamine or bradykinin alone.

Effects of intravenously infused histamine on canine forelimb transvascular protein efflux following adrenergic receptor blockade.

The intravenous infusion of high doses of histamine (400 micrograms base/min) produced only small increases in weight (approximately equal to +30 g) and lymph total protein concentration (+ 0.9 g/100 ml) in canine forelimbs perfused at constant inflow. The weight gain was associated with profound decreases in aortic pressure (112 to 30 mm Hg) and in forelimb perfusion pressure (105 to 75 mm Hg) and marked increases in forelimb skin small-vein pressure (from 12 to 25 mm Hg).