On the Mechanism of Vascular Leakage Caused by Histamine-Type Mediators

Abstract

A current hypothesis maintains that the vascular leakage induced by histamine, serotonin, and bradykinin is brought about by a hydrostatic mechanism: The larger veins are said to contract; the venules are therefore submitted to an increase in pressure, which causes their wall to give way. To test this hypothesis, vessels of an exposed striated muscle (rat and rabbit cremaster) were photographed while treated with the above-mentioned substances; the occurrence of vascular leakage was tested by the intravenous injection of carbon black (carbon labeling). All animals were under barbiturate anesthesia, given a neuromuscular blocking agent (gallamine triethiodid), and were maintained by artificial respiration, according to a technique previously described. In 72 rats and 4 rabbits, the first event observed was arteriolar dilatation. Constriction of a small vein was observed in only 1 in 76 experiments (in two other cases it was doubtful). It is concluded that venous spasm cannot account for the leakage induced by the mediators of the histamine type, though such leakage may be enhanced by venous spasm whenever it may occur. An alternative mechanism is proposed and discussed: Histamine-type mediators cause vascular leakage by a direct effect on the venular endothelium, which is induced to contract. FIGURE 2 Effect of bradykinin, 0.01 mg/ml, on rat oremaster. (1) 26 min after a first injection of carbon, a second one was given; 40 sec later, no vessels are labeled. Note caliber of arteriole A. (V = venule; large vessel is a vein.) (2) 20 sec after bradykinin (and 3 min after the second carbon injection). The arteriole has greatly dilated. (3) 50 sec after bradykinin. Arteriole is still dilated; venule V has begun to label. (4) 66 sec after bradykinin. Venule V is strongly labeled. The large vein has not become constricted throughout the sequence. Downloaded from 838 MAJNO, GILMORE, LEVENTHAL FIGURE 3 Sequence illustrating venular labeling after histamine, in the absence of venous contraction, and with minimal oenular dilatation. (1) 6 sec after carbon. Note laminar flow (x) in small vein. The carbon is unevenly distributed. (2) 11 sec after carbon. Laminar flow (x) is now apparent in other vessels. (3) 2 min after carbon. The blood is dark, but no venular labeling has developed. (4) 4 min, 5 sec after carbon and 1 min, 35 sec after Downloaded from 840 MAJNO, GILMORE, LEVENTHAL FIGURE 4 Effect of bradykinin, 0.01 mg/ml, on rat cremaster. (1) 2 min, 8 sec after carbon. Arrow points to a leukocyte "rolling" along the wall of the small vein. V = venule. (2) 5 min after carbon; decreased perfusion of the capillaries during a "resting phase." (3) 23 min after the first injection of carbon a second one was given: 1 min, 45 sec later, there is no vascular labeling at all; circulation is lively. (4) 2 min, 15 sec after the second carbonFIGURE 5 Effect of bradykinin, 0.01 mg/ml, on rat cremaster. (1) Normal circulation. (2) 15 sec after carbon. Note laminar flow (x). (3) 35 sec after bradykinin and 3 min after carbon. No labeling ...

Passage of low density lipoproteins through monolayers of human arterial endothelial cells. Effects of vasoactive substances in an in vitro model.

“…20 ' 40 By the fura-2 assay, we found a basal level of 0.11 ±0.05 fiM calcium ions in the endothelial cells. After addition of histamine, an immediate increase in cytoplasmic calcium concentration was observed, as detected fluorimetrically by an increase in fluorescence at excitation 340 nm and emission at 510 nm ( Figure 5A).…”

“…The unexpected finding that histamine increases the passage of macromolecules through monolayers of cultured endothelial cells of human aorta and carotid artery may suggest this, but it may also reflect an in vitro activation of these cells. From in vivo experiments, Majno et al 20 postulated that histamine acted on a contractile mechanism of rat and rabbit venule endothelial cells. In favor of this, Rotrosen et al 84 demonstrated an increase in cytoplasmatjc calcium concentration after stimulation of suspended human umbilical vein endothelial cells, which coincided with a change in F-actin content.…”

“…Histamine and thrombin have large effects on the permeability of postcapillary venules in vtvo, 18 ' 19 a process that may be mediated by endothelial cell contraction. 20 AJso, the passage of albumin through bovine aorta 21 ' 22 and human umbilical vein 23 endothelial cells in vitro is changed after a stimulation by vasoactive substances. Since H1 receptors are present on human coronary arteries 24 and on guinea pig endothelial aortic cells, 25 we wondered whether histamine could also have effects on the permeability characteristics of endothelial cell monolayers of human arteries.…”

Fibrinogen-Induced Increased Pial Venular Permeability in Mice

“…Histamine released from nerve terminals, transiently 'opens' BBB (Abbott, 2000). It has been shown that histamine increases vascular permeability via contraction of ECs (Majno et al, 1967) and increases formation of pinocytotic vesicles in ECs (Gross et al, 1982). Thus, histamine affects both transcellular and paracellular pathways, and as such was an appropriate tool in the study.…”

Histamine receptors of the microvascular endothelium revealed in situ with a histamine-ferritin conjugate: characteristic high-affinity binding sites in venules.

“…VENULAR LEAKAGE : As shown by Majno et al (24)(25)(26) the topical or systemic administration of histamine is followed by vascular leakage characteristically restricted to venules . The capability of HF to induce a histammelike effect was assessed through two lines of experiments testing: (a) HF monomers' capability to induce the extravasation of previously injected carbon black particles, and (b) extravasation at the level of venules of some of the intravascularly administered HF aggregates (HFa).…”