Cyclic nucleotide-dependent relaxation in human umbilical vessels.

Umbilical vessels have a low sensitivity to dilate, and this property is speculated to have physiological implications. We aimed to investigate the different relaxing responses of human umbilical arteries (HUAs) and veins (HUVs) to agonists acting through the cAMP and cGMP pathways. Vascular rings were suspended in organ baths for isometric force measurement. Following precontraction with the thromboxane prostanoid (TP) receptor agonist U44069, concentration-response curves to the nitric oxide (NO) donor sodium nitroprusside (SNP), the soluble guanylate cyclase (sGC) stimulator BAY 41-2272, the adenylate cyclase (AC) activator forskolin, the ß-adrenergic receptor agonists isoproterenol (ADRB1), salmeterol (ADRB2), and BRL37344 (ADRB3), and the phosphodiesterase (PDE) inhibitors milrinone (PDE3), rolipram (PDE4), and sildenafil (PDE5) were performed. None of the tested drugs induced a relaxation higher than 30% of the U44069-induced tone. Rings from HUAs and HUVs showed a similar relaxation to forskolin, SNP, PDE inhibitors, and ADRB agonists. BAY 41-2272 was significantly more efficient in relaxing veins than arteries. ADRB agonists evoked weak relaxations (< 20%), which were impaired in endothelium-removed vessels or in the presence of the NO synthase inhibitor L-NAME, sGC inhibitor ODQ. PKA and PKG inhibitors impaired ADBR1-mediated relaxation but did not affect ADRB2-mediated relaxation. ADRB3-mediated relaxation was impaired by PKG inhibition in HUAs and by PKA inhibition in HUVs. Although HUA and HUV rings were relaxed by BRL37344, immunohistochemistry and RT-qPCR analysis showed that, compared to ADRB1 and ADRB2, ADRB3 receptors are weakly or not expressed in umbilical vessels. In conclusion, our study confirmed the low relaxing capacity of HUAs and HUVs from term infants. ADRB-induced relaxation is partially mediated by endothelium-derived NO pathway in human umbilical vessels.

Vasomotor effects of hydrogen sulfide in human umbilical vessels.

Hydrogen sulfide (H2S) has recently emerged as a biologically active gas with multiple effects on the cardiovascular system. We aimed to investigate the vasomotor actions of sodium sulfide (Na2S), which forms H2S and HS- in solution, in human umbilical artery (HUA) and vein (HUV) rings. In addition, we examined by immunocytochemistry the expression and localization of cystathionine ß-synthase (CBS), cystathionine lyase (CSE), and 3-mercaptopyruvate sulphurtransferase (MPST), the enzymes responsible for endogenous H2S production. Human umbilical vessels were compared with chicken embryo umbilical vessels. HUA and HUV expressed a robust signal for CSE, CBS, and 3-MPST in both endothelial and smooth muscle cells. However, HUA rings did not respond to Na2S (10-6M-10-3M) either at resting tone or during contraction evoked by serotonin or KCl. Similarly, the extraembryonic part of chicken allantoic artery did not respond to Na2S. In contrast, Na2S induced a concentration-dependent contraction in HUV rings under resting tone and a concentration-dependent relaxation when the H2UV rings were contracted with serotonin (42 ± 5% relaxation) or KCl (12 ± 5% relaxation). Na2S-induced contraction of HUV was impaired following removal of extracellular Ca2+, endothelial denudation, NO synthase inhibition (L-NAME), or soluble guanylate cyclase (sGC) inhibition (ODQ). Na2S-induced relaxation of HUV was impaired by the KATP channel inhibitor glibenclamide. In conclusion, H2S does not have vasomotor effects on HUA but induced contraction (mediated through inactivation of the NO/sGC axis) and relaxation (mediated through KATP channels) in HUV. Our data suggest a role for H2S in the venous side of human umbilical circulation.