Heterogeneity in mechanisms underlying vasodilatory responses in small arteries of the rat hepatic mesentery (original) (raw)
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British Journal of Pharmacology, 2000
In the presence of ouabain (1 mM), acetylcholine and KCl (5 mM) evoked endothelium-independent relaxations in rat hepatic arteries. Treatment with capsaicin (10 mM), scopolamine (1 mM) or CGRP 8 ± 37 (3 mM) prevented these relaxations. Acetylcholine-induced relaxations in intact arterial segments in the presence of indomethacin (10 mM) and N G -nitro-L-arginine (0.3 mM) were only partially inhibited by ouabain plus BaCl 2 (30 mM). However, ouabain plus BaCl 2 almost abolished such relaxations in capsaicin-pre-treated preparations. In arteries without endothelium, the neurosecretagogue a-latrotoxin (1 nM) induced complete relaxations, which were abolished by CGRP 8 ± 37 or pre-treatment with capsaicin. a-Latrotoxin also induced a smooth muscle hyperpolarization (12+2 mV), which was abolished by CGRP 8 ± 37 . The ability of ouabain to disclose a CGRP-mediated neurogenic relaxation must be considered when this agent is used as a pharmacological tool. The results further suggest that CGRP is a nerve-derived hyperpolarizing factor in the rat hepatic artery.
Receptors involved in nerve-mediated vasoconstriction in small arteries of the rat hepatic mesentery
British Journal of Pharmacology, 1998
1 We have investigated the neurotransmitters and receptor subtypes involved in nerve-mediated vasoconstriction in small arteries of the rat hepatic mesentery. 2 A dense sympathetic innervation was demonstrated using catecholamine histochemistry and antibodies against the synaptic vesicle protein synaptophysin. 3 Reverse transcription-polymerase chain reaction (RT ± PCR) demonstrated very strong expression of the a 1A -adrenergic, neuropeptide Y (NPY) Y 1 , P 2X1 -and P 2X4 -purinergic receptors, moderate expression of the a 2B -adrenergic receptor and the purinergic P 2X5 -and P 2X7 -receptors and weak expression of the a 1B -, a 1D -, a 2A -and a 2C -adrenergic receptors and the P 2X2 -and P 2X3 -purinergic receptors. NPY 2 and P 2X6 receptor expression was absent. 4 Electrical ®eld stimulation (10 Hz, 10 s) produced contractions which were abolished by tetrodotoxin (10 76 M) and/or guanethidine (GE, 5610 76 M) and a combination of benextramine (10 75 M) and a,bmethylene ATP, (a,b-mATP, 3610 76 M) or PPADS (10 75 M). Selective a 1 -adrenergic receptor antagonists showed the potency order of prazosin4WB-410145-methyl-urapidil4BMY 7378. Yohimbine (10 78 M, 10 77 M), a,b-mATP (3610 76 M) and PPADS (10 75 M) each enhanced the response to nerve stimulation. 5 Some experiments demonstrated a slow neurogenic contraction which was abolished by GE or the selective NPY 1 receptor antagonist 1229U91 (6610 77 M).
British Journal of Pharmacology, 1991
1 Acetylcholine causes a concentration-dependent hyperpolarization of the rat small mesenteric artery (diameter at 100mmHg, 200-400,um). In the absence of tone the average potential change was from approximately -60 to -75mV. In the presence of tone induced by endothelin-1 (20nM), acetylcholine caused vasorelaxation in association with a marked hyperpolarization; from approximately -32 to -71mV. 2 A number of compounds known to antagonize the actions of cromakalim were tested for their ability to block responses to acetylcholine. Glibenclamide (0.1-3pM), phentolamine (10-100pM) and alinidine
Effect of endothelium on the actions of sympathetic and sensory nerves in the perfused rat mesentery
European Journal of Pharmacology, 1992
We and others have previously demonstrated that pretrcalment with capsaicin produces an augmentation of vasoconstrictor responses to transmural nerve stimulation. In the present study, removal of endothelium by saponin or inhibition of nitric oxide synthesis by N"-nitro-L-arginine methyl ester produced an augmentation of vasoconstrictor responses to transmural ncrvc stimulation, responses which were further potentiated after treatment with capsaicin to desensitize sensory nerves. Capsaicin treatment decreased vasodilator responses to acetylcholine, but only at low acetylcholine concentrations. Potentiation by capsaicin of vasoconstrictor responses to transmural nerve stimulation was not affected by indomethacin. In the presence of guanethidinc and methoxamine, transmural nerve stimulation caused vasodilator responses in the perfused rat mesentery. Thcse responses were unaffected by removal of endothelium, as were vasodilator responses to exogenous calcitonin gcne-rclated peptidc (CGRP). In contrast, substance P did not produce any relaxation in the methoxamine-contracted mesentery. This study suggests that facilitation of vasoconstrictor responses to transmural nerve stimulation after capsaicin treatment primarily reflects inhibition of sensory nerve effects resulting in an increase of sympathetic vasoconstrictor actions. The prescnt results also suggest that vasodilator responses to sensory nerve activation or exogenous CGRP are endothelium-independent and that substance P does not significantly contribute to modulation of vascular tone in the rat mescntery. Mesentery (rat); Capsaicin; CGRP (calcitonin gene-related peptide); Saponin; L-Argininc; N'"-Nitro-L-argininc methyl estcr
The Journal of Physiology, 2007
In rat tail artery, activation of postjunctional α 2 -adrenoceptors by noradrenaline (NA) released from sympathetic axons produces a slow depolarization (NAD) of the smooth muscle through a decrease in K + conductance. In this study we used intracellular recording to investigate whether the K + channel involved is the ATP-sensitive K + (K ATP ) channel. Changes in membrane resistance were monitored by measuring the time constant of decay of excitatory junction potentials. The K ATP channel blockers, glibenclamide (10 μM) and PNU 37883A (5 μM), depolarized the smooth muscle and increased membrane resistance. Conversely, the K ATP channel openers, pinacidil (0.1 and 0.5 μM) and levcromakalim (0.1 μM), hyperpolarized the smooth muscle and decreased membrane resistance. Activation of K ATP channels with calcitonin gene-related peptide (CGRP; 10 nM) also hyperpolarized the smooth muscle and decreased membrane resistance. The NAD was abolished by both glibenclamide and PNU 37883A but was potentiated by CGRP. However, unlike CGRP, the directly acting K ATP channel openers, pinacidil and levcromakalim, inhibited the NAD. The effects of other K + channel blockers were also determined. A high concentration of Ba 2+ (1 mM), which would be expected to block K ATP channels, abolished the NAD, whereas teteraethylammonium (1 mM) and 4-aminopyridine (1 mM) increased its amplitude. Apamin (0.5 μM) and a lower concentration of Ba 2+ (0.1 mM) did not affect the NAD. These findings indicate that activation of α 2 -adrenoceptors by neurally released NA depolarizes the membrane of vascular smooth muscle by inhibiting K ATP channels open in the resting membrane.
The Journal of Physiology, 2007
In rat tail artery, activation of postjunctional α 2 -adrenoceptors by noradrenaline (NA) released from sympathetic axons produces a slow depolarization (NAD) of the smooth muscle through a decrease in K + conductance. In this study we used intracellular recording to investigate whether the K + channel involved is the ATP-sensitive K + (K ATP ) channel. Changes in membrane resistance were monitored by measuring the time constant of decay of excitatory junction potentials. The K ATP channel blockers, glibenclamide (10 μM) and PNU 37883A (5 μM), depolarized the smooth muscle and increased membrane resistance. Conversely, the K ATP channel openers, pinacidil (0.1 and 0.5 μM) and levcromakalim (0.1 μM), hyperpolarized the smooth muscle and decreased membrane resistance. Activation of K ATP channels with calcitonin gene-related peptide (CGRP; 10 nM) also hyperpolarized the smooth muscle and decreased membrane resistance. The NAD was abolished by both glibenclamide and PNU 37883A but was potentiated by CGRP. However, unlike CGRP, the directly acting K ATP channel openers, pinacidil and levcromakalim, inhibited the NAD. The effects of other K + channel blockers were also determined. A high concentration of Ba 2+ (1 mM), which would be expected to block K ATP channels, abolished the NAD, whereas teteraethylammonium (1 mM) and 4-aminopyridine (1 mM) increased its amplitude. Apamin (0.5 μM) and a lower concentration of Ba 2+ (0.1 mM) did not affect the NAD. These findings indicate that activation of α 2 -adrenoceptors by neurally released NA depolarizes the membrane of vascular smooth muscle by inhibiting K ATP channels open in the resting membrane.
British Journal of Pharmacology, 2003
1 The present study addressed whether endothelium-dependent vasodilatation evoked by acetylcholine and flow are mediated by the same mechanisms in isolated rat mesenteric small arteries, suspended in a pressure myograph for the measurement of internal diameter. 2 In pressurized arterial segments contracted with U46619 in the presence of indomethacin, shear stress generated by the flow evoked relaxation. Thus, in endothelium-intact segments low (5.170.6 dyn cm À2 ) and high (1972 dyn cm À2 ) shear stress evoked vasodilatations that were reduced by, respectively, 68711 and 6878% (Po0.05, n ¼ 7) by endothelial cell removal. Acetylcholine (0.01 -1 mM) evoked concentration-dependent vasodilatation that was abolished by endothelial cell removal.
Potentiation by vasopressin of adrenergic vasoconstriction in the rat isolated mesenteric artery
British Journal of Pharmacology, 1997
1The aim of the present study was to investigate in rat mesenteric artery rings whether low concentrations of vasopressin could modify the contractile responses to noradrenaline and electrical stimulation of perivascular nerves.2Vasopressin (10−10–10−7 M) caused concentration-dependent contractions (pD2=8.36±0.09). The V1-receptor antagonist d(CH2)5Tyr(Me)AVP (10−9–10−8 M) produced parallel rightward shifts of the control curve for vasopressin. Schild analysis yielded a pA2 value of 9.83 with a slope of 1.10±0.14.3Vasopressin (3×10 −10 and 10−9 M) caused concentration-dependent potentiation of the contractions elicited by electrical stimulation (2–8 Hz; 0.2 ms duration for 30 s) and produced leftward shifts of the concentration-response curve for noradrenaline. The V1-receptor antagonist induced concentration-dependent inhibitions of potentiation induced by vasopressin. The selective V1-receptor agonist [Phe*, Orn8]-vasotocin (3×10 −10 and 10−9 M) induced potentiation of electrical stimulation-evoked responses which was also inhibited in the presence of the V1 antagonist (10−8 M). In contrast, the V2-receptor agonist deamino-8-D-arginine vasopressin (desmopressin 10−8–10−7 M) did not modify the electrical stimulation-induced responses and the V2-receptor antagonist [d(CH2)5, D-Ile*, Ile4, Arg8]-vasopressin (10−8–10−7 M) did not affect the potentiation evoked by vasopressin.4In artery rings contracted by 10−6 M noradrenaline in the presence of 10−6 M guanethidine and 10−6 M atropine, electrical stimulation (2, 4 and 8 Hz) produced frequency-dependent relaxations which were unaffected by 10−9 M vasopressin but abolished by 10−6 M tetrodotoxin.5Vasopressin also potentiated contractions elicited by KCl and contractions induced by addition of CaCl2 to KCl depolarized vessels. The augmenting effects were inhibited by the V1 antagonist.6In the presence of the calcium antagonist nifedipine (10−6 M), vasopressin failed to enhance the contractile responses to electrical stimulation, noradrenaline and KCl.7The results demonstrate that low concentrations of vasopressin strongly potentiate the contractions to adrenergic stimulation and KCl depolarization. This effect appears to be mediated by V1 receptor stimulation which brings about an increase in calcium entry through dihydropyridine-sensitive calcium channels.The aim of the present study was to investigate in rat mesenteric artery rings whether low concentrations of vasopressin could modify the contractile responses to noradrenaline and electrical stimulation of perivascular nerves.Vasopressin (10−10–10−7 M) caused concentration-dependent contractions (pD2=8.36±0.09). The V1-receptor antagonist d(CH2)5Tyr(Me)AVP (10−9–10−8 M) produced parallel rightward shifts of the control curve for vasopressin. Schild analysis yielded a pA2 value of 9.83 with a slope of 1.10±0.14.Vasopressin (3×10 −10 and 10−9 M) caused concentration-dependent potentiation of the contractions elicited by electrical stimulation (2–8 Hz; 0.2 ms duration for 30 s) and produced leftward shifts of the concentration-response curve for noradrenaline. The V1-receptor antagonist induced concentration-dependent inhibitions of potentiation induced by vasopressin. The selective V1-receptor agonist [Phe*, Orn8]-vasotocin (3×10 −10 and 10−9 M) induced potentiation of electrical stimulation-evoked responses which was also inhibited in the presence of the V1 antagonist (10−8 M). In contrast, the V2-receptor agonist deamino-8-D-arginine vasopressin (desmopressin 10−8–10−7 M) did not modify the electrical stimulation-induced responses and the V2-receptor antagonist [d(CH2)5, D-Ile*, Ile4, Arg8]-vasopressin (10−8–10−7 M) did not affect the potentiation evoked by vasopressin.In artery rings contracted by 10−6 M noradrenaline in the presence of 10−6 M guanethidine and 10−6 M atropine, electrical stimulation (2, 4 and 8 Hz) produced frequency-dependent relaxations which were unaffected by 10−9 M vasopressin but abolished by 10−6 M tetrodotoxin.Vasopressin also potentiated contractions elicited by KCl and contractions induced by addition of CaCl2 to KCl depolarized vessels. The augmenting effects were inhibited by the V1 antagonist.In the presence of the calcium antagonist nifedipine (10−6 M), vasopressin failed to enhance the contractile responses to electrical stimulation, noradrenaline and KCl.The results demonstrate that low concentrations of vasopressin strongly potentiate the contractions to adrenergic stimulation and KCl depolarization. This effect appears to be mediated by V1 receptor stimulation which brings about an increase in calcium entry through dihydropyridine-sensitive calcium channels.British Journal of Pharmacology (1997) 122, 431–438; doi:10.1038/sj.bjp.0701397
In vivo mechanisms of acetylcholine-induced vasodilation in rat sciatic nerve
American Journal of Physiology-Heart and Circulatory Physiology
We examined the importance of nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), and neurogenic activity in agonist-induced vasodilation and baseline blood flow [i.e., nerve microvascular conductance (NMVC)] in rat sciatic nerve using laser Doppler flowmetry. Agonists were acetylcholine (ACh) and 3-morpholinosydnonimine (SIN-1). Vasodilation occurring despite NO synthase (NOS) and cyclooxygenase inhibition and showing dependence on K+ channel activity was taken as being mediated by EDHF. NOS and cyclooxygenase inhibition with N ω-nitro-l-arginine (l-NNA) + indomethacin (Indo) revealed two phases of ACh-induced vasodilation: an initial, transient l-NNA + Indo-resistant vasodilation, peaking at 23 ± 6 s and lasting 145 ± 69 s, followed by sustainedl-NNA + Indo-sensitive vasodilation. l-NNA alone did not affect sustained ACh-induced vasodilation but decreased baseline NMVC by 55%. In the presence of l-NNA + Indo, the K+ channel blocker tetraethylammonium (TEA) inhibi...
The Journal of Physiology, 2005
Vasodilatation initiated on arterioles of skeletal muscle ascends into the proximal feed arteries through cell-to-cell conduction along the endothelium and into smooth muscle. Whereas perivascular sympathetic nerve activity (SNA) can inhibit conducted vasodilatation and restrict muscle blood flow, the signalling events mediating this interaction are poorly defined. Therefore, using isolated pressurized (75 mmHg) feed arteries (diameter (µm) at rest = 53 ± 3; maximum = 99 ± 2; n = 86) of the hamster retractor muscle, we tested the hypothesis that distinct yet complementary signalling pathways underlie the ability of SNA to inhibit conduction. Conducted vasodilatation was initiated using ACh microiontophoresis (1 µA; 250, 500 and 1000 ms) and SNA was initiated using local field stimulation (30-50 V; 1 ms at 2, 8 and 16 Hz). With vasodilatations of 5-20 µm, conduction increased with ACh pulse duration and was inhibited progressively as the frequency of SNA increased. During SNA, conduction was partially restored with inhibition of α 1 -(0.1 µM prazosin) or α 2 -(0.1 µM RX821002) adrenoreceptors and fully restored with both antagonists present. Activating α 1 -(50 nM phenylephrine) or α 2 -(1 µM UK 14,304) adrenoreceptors inhibited conduction partially and their simultaneous activation inhibited conduction cumulatively (P < 0.05). Elevated [K + ] o (30 or 40 mM) or phorbol esters (0.5 µM) also inhibited conduction yet similar constriction with L-NNA (50 µM) or Bay K 8644 (10 nM) did not. Thus, the activation of α 1 -and α 2 -adrenoreceptors inhibits conducted vasodilatation through complementary signalling events. With robust coupling along the endothelium, our modelling predicts that the inhibition of conduction by SNA can be explained by reduced electrical coupling through myoendothelial gap junctions or greater current leak across smooth muscle cell membranes.