PHARMACOLOGICAL AND IMMUNOHISTOCHEMICAL CHARACTERIZATION OF DOPAMINE D4 RECEPTOR IN HUMAN UMBILICAL ARTERY AND VEIN.

Abstract

Aims - To investigate the effects of the dopamine D4 receptor agonist A-412997 and the D4 antagonist sonepiprazole in human isolated umbilical artery (HUA) and vein (HUV) and the expression of the D4 receptor by immunohistochemistry in these vessels. Main methods - A segment of the umbilical cord (10-20 cm) from the insertion point in the placenta and 5 cm from the umbilicus was removed by the obstetrician and placed in a container with Krebs-Henseleit's solution (KHS). The Wharton's jelly was removed and HUA and HUV and rings (3-mm) of HUA and HUV were suspended in 10-mL organ baths containing oxygenated (95%O2:5%CO2) and heated (37°C) KHS. For immunohistochemistry, the vessels were fixed in 10% formalin, embedded in paraffin wax and sectioned (4µm). Key findings - A-412997 did not induce contractions in the HUA rings. In HUA pre-contracted rings, A-412997 induced concentration-dependent relaxations, which were reduced when the HUA rings were pre-incubated with L-NAME. A-412997 caused concentration-dependent contractions of HUV rings, which were potentiated by pre-treatment with L-NAME, and reduced by pre-incubation with 6-nitrodopamine. In HUV pre-contracted rings, A-412997 failed to induce relaxations. Sonepiprazole antagonized A-412997 induced contractions in HUV rings and provoked concentration-dependent relaxations in pre-contracted HUA and HUV rings. Dopamine receptor D4 was positive in both HUA and HUV, especially in the endothelium, and detected only in HUV smooth muscle cells. Significance - Activation of HUA D4 receptor is associated with relaxation, whereas in HUV, it leads to contraction. Differential expression of D4 receptors may modulate umbilical-placental blood flow.