Because adenosine is a vascular tone modulator, we examined the effect of adenosine and congeners in the vascular reactivity of isolated human placental vessels and in perfused cotyledons. We characterized its vasomotor action and tentatively identified the receptor subtypes and their intracellular signaling mechanisms. We recorded isometric tension from the circular layer of chorionic vessel rings maintained under 1.5 g of basal tension or precontracted with KCl. The relative order of potency of adenosine and structural analogs is consistent with the expression of A2B receptors, 5'-(N-ethylcarboxamido)adenosine (NECA) being the most potent. The maximal contraction ranged from 45% to 60% of the KCl standard response, except for an A2A receptor agonist that did not exceed 15%. Consistently, NECA was 100-fold more potent than adenosine to raise the perfusion pressure of ex vivo perfused cotyledons. In contrast, a selective A3 receptor agonist relaxed precontracted rings of chorionic vessels. Whereas a selective A3 receptor antagonist was ineffective to antagonize adenosine-induced contraction, A2 or A1 receptor antagonists reduced adenosine-induced vasoconstriction concentration-dependently. Denudation of the endothelial layer reduced adenosine- and NECA-induced contractions by 50-70%. Furthermore, indomethacin reduced adenosine- or NECA-induced contractions concentration-dependently in intact and endothelium-denuded rings. A thromboxane receptor antagonist blocked adenosine- and NECA-induced contractions in intact and endothelium-denuded rings, suggesting the involvement of an arachidonic acid metabolite as the mediator of the vasoconstriction. We propose that adenosine A2B receptors mediate the adenosine-induced contraction vasomotor effect in human chorionic vessels and that this involves synthesis of a thromboxane receptor activator or a related prostanoid.
Neuropeptide Y (NPY) appears to be involved in the sympathetic regulation of vascular tone. To assess the putative role of NPY in mesenteric circulation, the release and biological effect of NPY were examined after electrical stimulation of perimesenteric arterial nerves. Nerve stimulation with trains of 2–30 Hz increased the perfusion pressure of the arterially perfused rat mesenteric bed in a frequency‐ and time‐dependent fashion. Trains of 15–30 Hz significantly displaced to the left, approximately threefold, the noradrenaline (NA)‐induced pressor concentration‐response curve, in addition to increasing significantly its efficacy. Perfusion with 10 nM exogenous NPY mimicked the electrical stimulation effect, causing a threefold leftward shift of the NA concentration‐response curve and increasing the maximal NA response. These effects were antagonized by 100 nM BIBP 3226, indicating the activity of NPY‐Y1 receptors. Electrical stimulation of the perimesenteric nerves released immunoreactive NPY (ir‐NPY) in a frequency‐dependent fashion; the ir‐NPY coelutes with synthetic NPY as confirmed by HPLC. Both the electrically induced pressor response and the calcium‐dependent release of NPY were obliterated in preparations perfused with 1 µM guanethidine or in rats pretreated intravenously for 48 h with 6‐hydroxydopamine, thus revealing the sympathetic origin of these phenomena. Only a small proportion of the total NPY content in the perimesenteric arterial nerves is released after electrical stimulation. Chromatographic studies of the physiological sources of the ir‐NPY support that NPY fragments are generated via peptidase degradation. The present findings demonstrate that NPY is released from the perimesenteric arterial sympathetic nerves and acts, via the activation of NPY‐Y1 receptors, as the mediator responsible for the potentiation of NA's effect on perfusion pressure in the isolated rat mesenteric bed.
The expression of purinergic P2Y receptors (P2YRs) along the cord, superficial chorionic vessels and cotyledons of the human placenta was analysed and functional assays were performed to determine their vasomotor activity. Immunoblots for the P2Y 1 R and P2Y 2 R revealed a 6-to 8-fold increase in receptor expression from the cord to the chorionic or cotyledon vessels. In the cord and chorionic vessels the receptor distribution was mainly in the smooth muscle, whereas in the cotyledon vessels these receptors were equally distributed between the endothelium and smooth muscle cells. An exception was the P2Y 2 R at the umbilical artery, which was distributed as in the cotyledon. mRNA coding for the P2Y 1 R and P2Y 2 R were detected by RT-PCR and the mRNA coding for the P2Y 4 R, P2Y 6 R and P2Y 11 R was also identified. Application of 2-MeSADP and uridine triphosphate (UTP), preferential P2Y 1 R and P2Y 2 R ligands, respectively, resulted in contraction of isolated rings from umbilical and chorionic vessels.
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