title: Augmented sensory-motor vasodilatation of the rat mesenteric arterial bed after chronic infusion of the P1-purinoceptor antagonist, DPSPX.
abstract: 1. The effect of long-term antagonism of P1-purinoceptors on vascular function was examined in the perfused mesenteric arterial bed isolated from rats which had received constant infusion of either the non-selective P1-purinoceptor antagonist, 1-3-dipropyl-8-sulphophenylxanthine (DPSPX, 30 micrograms kg-1 h-1, i.p.) or saline for seven days. Sympathetic and sensory-motor neurotransmission, smooth muscle and endothelial function were assessed. 2. Basal tone was similar in mesenteric arterial preparations from control and DPSPX-treated rats. Continuous perfusion with methoxamine (7-70 microM) induced similar increases in tone in control and DPSPX-treated preparations. In the presence of guanethidine (5 microM), electrical field stimulation (EFS; 1-12 Hz, 60V, 0.1 ms, 30 s) elicited frequency-dependent vasodilatation due to activation of sensory-motor nerves. In tissues from DPSPX-treated rats the nerve-mediated vasodilator responses were markedly augmented at all frequencies. Maximal relaxation at 8 Hz was 38.34 +/- 4.76% (n = 5) in controls and 65.92 +/- 3.68% (n = 5) after DPSPX-treatment (P < 0.01). Adenosine (3 microM) inhibited the frequency-dependent sensory-motor neurotransmission similar in preparations from controls and DPSPX-treated rats. 3. In raised-tone preparations calcitonin gene-related peptide (CGRP; 5,15 and 50 pmol), the principal vasodilator transmitter of sensory-motor nerves in rat mesenteric arteries, produced similar relaxations in control and DPSPX-treated preparations. Vasodilator responses to the sensory neurotoxin capsaicin (50 and 500 pmol) were also similar between the groups. 4. Assay of tissue CGRP levels of the superior mesenteric artery by enzyme-linked immunosorbent assay showed no significant difference in tissue levels of CGRP in controls, 120.25 +/- 26.34 pmol g-1 tissue (n = 6) and with DPSPX-treatment, 82.12 +/- 24.42 pmol g-1 tissue (n = 6). 5. In raised-tone preparations dose-dependent endothelium-dependent vasodilatation to acetylcholine and ATP, and endothelium-independent vasodilatation to sodium nitroprusside were similar in control and DPSPX-treated preparations. 6. EFS (4-32 Hz, 90V, 1 ms, 30 s) elicited frequency-dependent vasoconstriction due to activation of sympathetic nerves which was similar in controls and in DPSPX-treated preparations. Adenosine (10 and 30 microM) inhibited sympathetic neurotransmission similarly in control and DPSPX-treated preparations. Dose-dependent vasoconstriction to noradrenaline (NA) and ATP, and to KCI (0.15 mmol) was similar between the groups. 7. High performance liquid chromatographic analysis of tissue NA showed no significant difference in NA content of the superior mesenteric artery from DPSPX-treated (1.38 +/- 0.09 ng mg-1, n = 6) and control rats (1.46 +/- 0.17 ng mg-1, n = 6). 8. In conclusion, in rats with hypertension due to 7 days treatment with the P1-purinoceptor antagonist, DPSPX, there is an increase in sensory-motor vasodilatation of the mesenteric arterial bed. There is no change in sympathetic nerve, endothelial or smooth muscle function. Augmented sensory-motor neurotransmission, which does not involve a change in postjunctional responsiveness to CGRP or in the CGRP content of sensory-motor nerves, could be a compensatory change in response to the DPSPX- induced hypertension.
authors.affiliation: Department of Anatomy and Developmental Biology, University College London.
authors.forename: V
authors.initials: V
authors.lastname: Relevic
authors.forename: A
authors.initials: A
authors.lastname: Rubino
authors.forename: G
authors.initials: G
authors.lastname: Burnstock
mesh_terms: D000241:Adenosine / Q000502:physiology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004558:Electric Stimulation; D006973:Hypertension / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000378:metabolism; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines; C053896:1,3-dipropyl-8-(4-sulfophenyl)xanthine; D015740:Calcitonin Gene-Related Peptide; D000241:Adenosine; D009638:Norepinephrine