Abstract
We tested the hypothesis that the anti‐inflammatory actions of atrial natriuretic peptide (ANP) result from the modulation of leukocyte adhesion to inflamed endothelium and not solely ANP ligation of endothelial receptors to stabilize endothelial barrier function. We measured vascular permeability to albumin and accumulation of fluorescent neutrophils in a full‐thickness skin wound on the flank of LysM‐EGFP mice 24 h after formation. Vascular permeability in individually perfused rat mesenteric microvessels was also measured after leukocytes were washed out of the vessel lumen. Thrombin increased albumin permeability and increased the accumulation of neutrophils. The thrombin‐induced inflammatory responses were attenuated by pretreating the wound with ANP (30 min). During pretreatment ANP did not lower permeability, but transiently increased baseline albumin permeability concomitant with the reduction in neutrophil accumulation. ANP did not attenuate acute increases in permeability to histamine and bradykinin in individually perfused rat microvessels. The hypothesis that anti‐inflammatory actions of ANP depend solely on endothelial responses that stabilize the endothelial barrier is not supported by our results in either individually perfused microvessels in the absence of circulating leukocytes or the more chronic skin wound model. Our results conform to the alternate hypothesis that ANP modulates the interaction of leukocytes with the inflamed microvascular wall of the 24 h wound. Taken together with our previous observations that ANP reduces deformability of neutrophils and their strength of attachment, rolling, and transvascular migration, these observations provide the basis for additional investigations of ANP as an anti‐inflammatory agent to modulate leukocyte–endothelial cell interactions.
Highlights
The primary homeostatic action of atrial natriuretic peptide (ANP) in the microcirculation is to increase endothelial barrier permeability to plasma proteins when plasma volume is increased
We have recently demonstrated that ANP reduced accumulation of polymorphonuclear leukocytes (PMNs) in a mouse skin wound after exogenous thrombin was added to the wound (Morikis et al 2015)
The fact that we found no evidence that the endothelial barrier was stabilized by ANP, taken with our previous observations that ANP attenuated thrombin-induced PMN accumulation, indicated that at least part of the action of ANP in attenuation of thrombin-induced permeability increase depicted in Figure 2 was attributable to a reduction in leukocyte/ endothelial interaction in the vasculature surrounding the wound
Summary
The primary homeostatic action of atrial natriuretic peptide (ANP) in the microcirculation is to increase endothelial barrier permeability to plasma proteins when plasma volume is increased. These microvascular actions act in parallel with the well-known renal functions as a natriuretic and diuretic. Recent published data has drawn attention to additional actions of ANP which may be vasoprotective. These include actions of ANP as a vasodilator to improve perfusion and as a modulator of the immune system. Several investigations, those using cultured endothelial cell monolayers as model systems, suggest ANP may activate anti-
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