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. In some experiments, the FITC-D was injected intravenously either at the start of or after the start of a prolonged histamine suffusion for estimation of the duration of the vascular FITC-D leakage response. In saline control cheek pouches there were few, if any, visible FITC-D vascular leakage sites and only small increases in the [FITC-D]s. The arteriolar vasodilators papaverine (1 X 10(-5) M) and isoproterenol (1 X 10(-5) M) failed to increase the formation of vascular FITC-D leakage sites, and the magnitude of the increase in [FITC-D]s produced by these agents was similar to that observed in saline controls. Histamine (1 X 10(-5) M) suffused for either 15, 60, or 120 minutes produced marked increases in [FITC-D]s and in the number of venular FITC-D leakage sites. The venular FITC-D leakage sites began to fade after 10-20 minutes, eventually disappearing altogether. In contrast, the [FITC-D]s was markedly increased throughout the 120-minute observation period. Treatment with papaverine prior to and during the 60-minute histamine suffusion failed to prevent the mediator-stimulated vascular leakage response. In contrast, similar treatment with isoproterenol inhibited the histamine-stimulated increases in [FITC-D]s and the formation of venular FITC-D leakage sites. When the tracer was injected intravenously at the start of the 60-minute histamine suffusion (1 X 10(-5) M), the [FITC-D]s and the number of vascular leakage sites were markedly increased. However, when the tracer was injected intravenously 30 minutes after the start of the 60-minute histamine suffusion, there were only minimal increases in [FITC-D]s and the formation of venular leakage sites. These findings suggest that prolonged suffusions of histamine produce transient increases in macromolecular efflux which are dependent on the formation of discrete venular macromolecular leakage sites.(ABSTRACT TRUNCATED AT 400 WORDS)