Summary:
Τhis study investigated, for the first time, the potential autoregulatory
action of histamine in the rat large peripheral vessels and the contribution of
histamine receptors, both under physiological conditions and in systemic
inflammation. The selection of the abdominal aorta and the inferior vena cava
as experimental tissues was based on their vital role in the pathophysiology of
the cardiovascular system and on the existing indications of the putative
autoregulatory action of histamine in peripheral tissues. Therefore, various
doses of histamine receptor antagonists were administered intraperitoneally in
normal animals and in a rat model of experimental arthritis. Histamine levels
were quantified in the blood vessels and the optimum dose of histamine receptor
antagonists was determined from the resulting dose-response curve. The
histamine receptor ligands were selected according to their pharmacological
properties. The H1 receptor antagonist dimethindene was mostly used as a
control agent based on the accepted, but not fully elucidated role of the H1
receptors in the functionality of blood vessels, as well as in numerous
inflammatory processes. GSK334429 and JNJ7777120 have been recently developed
and chatacterised as selective Η3 and Η4 antagonists/reverse agonists,
respectively. Statistical analysis of the results showed that histamine exerts
autoregulatory actions in the peripheral blood vessels of normal rats via
binding to the H3 and H4 receptors. In experimental arthritis, Η1 and Η3
receptors seemed to underlie the autoregulatory properties of histamine in the
rat abdominal aorta and inferior vena cava, respectively. Considering that the
endothelium regulates the vascular tone and the release of histamine and other
vasoactive substances, preliminary studies were performed in the rat blood
vessels where the vascular endothelium was removed ex vivo. The results
provided evidence towards the implication of the endothelium in the histamine
autoregulatory action in the rat large blood vessels. In conclusion, the
findings revealed new roles of histamine in the peripheral blood vessels, with
the possible involvement of the vascular endothelium. In particular, the
results demonstrated that the histamine levels are regulated through the H3 and
H4 receptors in the peripheral blood vessels of normal rats, whereas a
differential regulation was observed in systemic inflammation that was elicited
via the H1 and H3 receptors in veins and arteries, respectively. Considering
the contribution of the H1 receptors in inflammation, the neuroregulatory
properties of the H3 receptors and the immunomodulatory characteristics of the
H4 receptors, these results will contribute to the future evaluation of the
interaction of the histamine receptors in peripheral blood vessel homeostasis
and in the vascular involvement in systemic inflammation. The final aim is the
pharmacological evaluation of novel and more beneficial therapeutic
interventions in systemic vascular inflammation.
Keywords:
Histamine, Receptors, Inflammation, Blood vessels, Endothelium
