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 μg 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 μM) induced similar increases in tone in control and DPSPX-treated preparations. In the presence of guanethidine (5 μM), 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 μM) inhibited the frequency-dependent sensory-motor neurotransmission similarly 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 μM) inhibited sympathetic neurotransmission similarly in control and DPSPX-treated preparations. Dose-dependent vasoconstriction to noradrenaline (NA) and ATP, and to KCl (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.