Isoflurane Anesthesia Attenuates Endothelium-dependent Pulmonary Vasorelaxation by Inhibiting the Synergistic Interaction between Nitric Oxide and Prostacyclin 

1997 ◽  
Vol 86 (4) ◽  
pp. 936-944 ◽  
Author(s):  
Linda M. Gambone ◽  
Paul A. Murray ◽  
Nicholas A. Flavahan
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Arteries ◽  
Inhibitory Effect ◽  
Isometric Tension ◽  
Synergistic Interaction ◽  
Nitric Oxide Synthase Inhibitor ◽  
Channel Dependent ◽  
The Individual ◽  
Synthase Inhibitor ◽  
Endothelium Dependent Relaxation

Background Endothelium-derived nitric oxide causes vasodilation in part by increasing the dilator activity of other endothelium-derived mediators, including prostacyclin and a K+ATP channel-dependent hyperpolarizing factor. Although previous studies have proposed that isoflurane (ISO) depresses endothelium-dependent vasorelaxation by inhibiting endothelium-derived nitric oxide activity, the effects of ISO on the interactions among endothelium-derived dilators have not been characterized. The aim of this study was to determine the mechanisms underlying the inhibitory effect of ISO on endothelium-dependent relaxation in canine pulmonary arteries. Specifically, the goal was to assess the effects of ISO on the individual actions and on the synergistic interactions of these endothelium-derived mediators. Methods Canine pulmonary arterial rings were suspended for isometric tension recording. The effects of 1 minimum alveolar concentration ISO (0.4 mM) on vasorelaxation responses to bradykinin, A23187, acetylcholine, cromakalim, and SIN-1 were assessed in phenylephrine-precontracted rings with and without pretreatment with a nitric oxide synthase inhibitor (N omega-nitro-L-arginine methyl ester; L-NAME), a cyclooxygenase inhibitor (indomethacin), or a K+ATP channel inhibitor (glybenclamide). Results Isofluane attenuated pulmonary vasorelaxation induced by bradykinin, A23187, and cromakalim but had no effect on relaxation induced by acetylcholine or SIN-1. Neither the nitric oxide-mediated nor the prostacyclin-mediated components of relaxation induced by bradykinin and A23187 were altered by ISO. However, ISO abolished the K+ATP-mediated component of relaxation and the K+ATP-dependent synergistic interaction between nitric oxide and prostacyclin. Conclusions These results suggest that ISO selectively attenuates endothelium-dependent relaxation in canine pulmonary arteries. It exerts its inhibitory effect by interfering with a synergistic interaction between nitric oxide and prostacyclin, possibly via an effect on K+ATP channels.

scholarly journals Inhibitory effect of valves on endothelium-dependent relaxations to calcium ionophore in canine saphenous vein

2001 ◽  
Vol 280 (2) ◽  
pp. H892-H898 ◽  
Author(s):  
Daihiko Eguchi ◽  
Zvonimir S. Katusic
Keyword(s):  
Nitric Oxide ◽  
Soluble Guanylate Cyclase ◽  
Isometric Force ◽  
Calcium Ionophore ◽  
Inhibitory Effect ◽  
Nitric Oxide Synthase Inhibitor ◽  
A 23187 ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
Endothelium Dependent Relaxation

The present study was designed to evaluate endothelium-dependent relaxation to the calcium ionophore A-23187 in isolated canine saphenous veins. Isometric force recordings and cGMP measurements using isolated veins with and without valves were performed. During contractions to U-46619 (3 × 10−7 M), endothelium-dependent relaxations to A-23187 (10−9–10−6 M) were significantly reduced in rings with valves compared with rings without valves. Endothelial removal abolished A-23187-induced relaxation. Relaxations to forskolin (FK; 10−8–10−5 M) and diethylaminodiazen-1-ium-1,2-dionate; DEA-NONOate, 10−9–10−5 M) were identical in rings with and without valves. In rings without valves, a nitric oxide synthase inhibitor, N G-nitro-l-arginine methyl ester (l-NAME; 3 × 10−4 M), and a cyclooxygenase inhibitor, indomethacin (10−5 M), partially reduced A-23187-induced relaxation. However, in rings with valves,l-NAME had no effect, whereas indomethacin abolished the relaxation to A-23187. A selective soluble guanylate cyclase inhibitor, 1 H-[1,2,4]-oxadiazolo [4,3-a]quinoxalin-1-one (ODQ; 3×10−6 M), had no effect on the relaxation to A-23187 in either group. In contrast, ODQ abolished the A-23187-induced increase in cGMP levels, suggesting that relaxation to nitric oxide released by A-23187 is independent of increases in cGMP. These results demonstrate that endothelium-dependent relaxation to A-23187 is reduced in regions of veins with valves compared with relaxation in the nonvalvular venous wall. Lower production of nitric oxide in endothelial cells of valvular segments appears to be a mechanism responsible for reduced reactivity to A-23187.

Endothelium-derived contracting and relaxing factors contribute to hypoxic responses of pulmonary arteries

1993 ◽  
Vol 265 (4) ◽  
pp. H1139-H1148 ◽  
Author(s):  
K. L. Kovitz ◽  
T. D. Aleskowitch ◽  
J. T. Sylvester ◽  
N. A. Flavahan
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Arteries ◽  
Initial Response ◽  
Isometric Tension ◽  
No Synthase ◽  
Moderate Hypoxia ◽  
Relaxing Factor ◽  
Endothelium Derived Relaxing Factor ◽  
Increased Activity ◽  
Endothelium Dependent Relaxation

The response of porcine pulmonary arteries to hypoxia depended on their location in the vasculature and the degree and duration of the hypoxic challenge. In rings of pulmonary artery suspended for isometric tension recording (37 degrees C, 16% O2 and 5% CO2), moderate hypoxia (10% and 4% O2) caused endothelium-dependent relaxation in distal arteries but transient endothelium-dependent contraction in proximal arteries. In both proximal and distal arteries, the initial response to anoxia (0% O2) was a transient endothelium-dependent contraction. This was followed by a slowly developing, sustained endothelium-dependent contraction in proximal arteries, or by an endothelium-independent relaxation in distal arteries. The endothelium-dependent relaxation to moderate hypoxia in distal arteries was inhibited only by combined inhibition of endothelium-derived relaxing factor (EDRF)-nitric oxide (NO) synthase [N omega-nitro-L-arginine methyl ester (L-NAME)] and cyclooxygenase (indomethacin), suggesting mediation by EDRF-NO and prostacyclin. Transient endothelium-dependent contractions to moderate hypoxia (proximal arteries) or anoxia (all arteries) were abolished by L-NAME, but the late endothelium-dependent anoxic contraction observed in proximal arteries was not reduced by L-NAME and/or indomethacin. Therefore, hypoxia/anoxia may initiate contraction of pulmonary arteries by decreasing the activity of EDRF-NO, but the contractions appear to be maintained by an increased activity of an endothelium-derived contracting factor.

Alterations of endothelium and smooth muscle function in monocrotaline-induced pulmonary hypertensive arteries

2000 ◽  
Vol 279 (4) ◽  
pp. H1786-H1795 ◽  
Author(s):  
Kaoru M. Ito ◽  
Miharu Sato ◽  
Keiko Ushijima ◽  
Masaaki Nakai ◽  
Katsuaki Ito
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Artery ◽  
Single Injection ◽  
Early Stage ◽  
Pulmonary Arteries ◽  
Nitric Oxide Synthase Inhibitor ◽  
Basal Tone ◽  
Smooth Muscle Function ◽  
Synthase Inhibitor ◽  
Oxide Synthase

We examined how monocrotaline (MCT), which impairs the endothelium and causes pulmonary hypertension, altered the endothelial regulation of pulmonary artery functions. Rats were given a single injection of MCT (60 mg/kg sc). Pulmonary arteries were depolarized to −48.3 ± 2.6 and −39.8 ± 2.2 mV at 2 and 3 wk after treatment with MCT, respectively (control arteries −59.9 ± 1.9 mV). The basal tone in the resting state was only slightly elevated at 3 wk in endothelium-intact arteries. Removal of the endothelium caused further depolarization in MCT-affected arteries at 2 wk, but not at 3 wk, and greatly elevated the basal tone at 2 and 3 wk. N ω-nitro-l-arginine (200 μM), a nitric oxide synthase inhibitor, also caused depolarization in endothelium-intact arteries in both groups and elevated the basal tone of MCT-affected arteries. The relaxant responses of pulmonary arteries to ACh and A-23187 were depressed at 2 and 3 wk after MCT treatment. Thus chronic impairment of the endothelium altered the property of the pulmonary artery leading to depolarization. During the early stage of depolarization, a rise in the basal tone was offset by nitric oxide released from the injured endothelium.

Contribution of NK2 tachykinin receptors to propulsion in the rabbit distal colon

2000 ◽  
Vol 278 (1) ◽  
pp. G137-G147 ◽  
Author(s):  
L. Onori ◽  
A. Aggio ◽  
G. Taddei ◽  
M. Tonini
Keyword(s):  
Nitric Oxide ◽  
Circular Muscle ◽  
Distal Colon ◽  
Inhibitory Effect ◽  
Facilitatory Effect ◽  
Nitric Oxide Synthase Inhibitor ◽  
Excitatory Transmission ◽  
The Difference ◽  
High Concentrations ◽  
Synthase Inhibitor

The role of the tachykinin neurokinin (NK)2 receptors on rabbit distal colon propulsion was investigated by using two selective NK2-receptor antagonists, MEN-10627 and SR-48968. Experiments on colonic circular muscle strips showed that contractile responses to [β-Ala8]NKA-(4—10) (1 nM–1 μM), a selective NK2-receptor agonist, were competitively antagonized by MEN-10627 (1–100 nM), whereas SR-48968 (0.1–10 nM) caused an insurmountable antagonism, thus confirming the difference in the mode of action of the two compounds. Colonic propulsion was elicited by distending a mobile rubber balloon with 0.3 ml (submaximal stimulus) or 1.0 ml (maximal stimulus) of water. The velocity of anal displacement of the balloon (mm/s) was considered the main propulsion parameter. At low concentrations (1.0–100 nM and 0.1–10 nM, respectively), MEN-10627 and SR-48968 facilitated the velocity of propulsion, whereas at high concentrations (100 nM and 1 μM, respectively) they decelerated propulsion. The excitatory and inhibitory effects of both antagonists were observed only with submaximal stimulus. We focused on the hypothesis that the facilitatory effect on propulsion may result from blockade of neuronal NK2 receptors and the inhibitory effect from suppression of the excitatory transmission mediated by NK2 receptors on smooth muscle cells. In the presence of N G-nitro-l-arginine (300 μM), a nitric oxide synthase inhibitor, MEN-10627, at a concentration (10 nM) that was found to accelerate propulsion in control experiments inhibited the velocity of propulsion. In the presence of threshold (1–10 nM) or full (1 μM) concentration of atropine, which inhibited to a great extent the velocity of propulsion, the inhibitory effect of MEN-10627 (1 μM) was markedly increased. In conclusion, in the rabbit distal colon NK2 receptors may decelerate propulsion by activating a nitric oxide-dependent neuronal mechanism and may accelerate it by a postjunctional synergistic interaction with cholinergic muscarinic receptors.

Halothane Attenuates Endothelium-dependent Pulmonary Vasorelaxant Response to Lemakalim, an Adenosine Triphosphate (ATP)-sensitive Potassium Channel Agonist

1997 ◽  
Vol 87 (3) ◽  
pp. 625-634 ◽  
Author(s):  
Sumihiko Seki ◽  
Mayumi Horibe ◽  
Paul A. Murray
Keyword(s):  
Adenosine Triphosphate ◽  
Inhibitory Effect ◽  
Isometric Tension ◽  
Maximal Response ◽  
Response Curves ◽  
Nitric Oxide Synthase Inhibitor ◽  
Pulmonary Vasodilation ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
Channel Agonist

Background Lemakalim, an adenosine triphosphate (ATP)-sensitive potassium (K+(ATP)) channel agonist, causes profound pulmonary vasodilation in conscious dogs, which is attenuated during halothane anesthesia. The goal of the present study was to investigate the mechanism responsible for this attenuating effect of halothane. Methods Isolated canine pulmonary arterial rings were suspended for isometric tension recording in 25 ml organ baths. Rings with and without endothelium were contracted to 50% of their maximal response to phenylephrine, followed by the cumulative administration of lemakalim with or without exposure to halothane (0.5-1.5 minimum alveolar concentration [MAC] in dogs). Lemakalim dose-response curves were also generated in rings pretreated with the nitric oxide synthase inhibitor, Nw-nitro-L-arginine methyl ester (L-NAME); the cyclooxygenase inhibitor, indomethacin; or the K+(ATP) channel antagonist, glybenclamide. Results Compared with intact rings, the pulmonary vasorelaxant response to lemakalim was attenuated (P < 0.05) in endothelium-denuded rings. Halothane at 0.5 MAC had no effect on the vasorelaxant response to lemakalim. Halothane at 1 MAC attenuated (P < 0.05) the vasorelaxant response to lemakalim in intact rings, but not in endothelium-denuded rings. Halothane at 1.5 MAC attenuated (P < 0.05) the vasorelaxant response to lemakalim in both intact and endothelium-denuded rings. In endothelium-intact rings, indomethacin attenuated (P < 0.05) the vasorelaxant response to lemakalim, whereas L-NAME had no effect. Further, indomethacin, but not L-NAME, abolished the endothelium-dependent, halothane-induced attenuation of the lemakalim vasorelaxation response. Glybenclamide markedly attenuated (P < 0.05) lemakalim vasorelaxation at lemakalim doses less than 10(-6) M. Conclusions Lemakalim-induced pulmonary vasorelaxation involves an endothelium-dependent and vascular smooth muscle component. Further, halothane attenuates the endothelium-dependent pulmonary vasorelaxant response to lemakalim via an inhibitory effect on vasodilator metabolites of the cyclooxygenase pathway.

Hydrogen sulfide as a mediator of endothelium-dependent relaxation evoked by Moringa oleifera leaf extract in mesenteric arterial beds isolated from L-NAME hypertensive rats

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Direk Aekthammarat ◽  
Panot Tangsucharit ◽  
Patchareewan Pannangpetch
Keyword(s):  
Nitric Oxide ◽  
Moringa Oleifera ◽  
Channel Blocker ◽  
Resistance Arteries ◽  
Hypertensive Rats ◽  
Nitric Oxide Synthase Inhibitor ◽  
Synthase Inhibitor ◽  
Gap Junctional ◽  
Oxide Synthase ◽  
Endothelium Dependent Relaxation

AbstractObjectivesAqueous extract of Moringa oleifera leaves (MOE) is a potent inducer of endothelium-dependent relaxation of mesenteric resistance arteries of rats induced to be hypertensive using Nω-nitro-L-arginine methyl ester (L-NAME). Hydrogen sulfide (H2S) has been shown to participate in endothelium-dependent relaxation of small resistance arteries. Therefore, this study aimed to investigate whether endothelial H2S-dependent signaling plays a role in the vasorelaxation in response to MOE.MethodsMesenteric arterial beds isolated from L-NAME hypertensive rats were set up in an ex vivo perfusion system for measurement of vasoreactivity. All experiments were performed in the presence of the nitric oxide synthase inhibitor, L-NAME (100 µM) and the cyclooxygenase inhibitor, indomethacin (10 µM) to prevent the formation of nitric oxide and prostanoids, respectively.ResultsIn the presence of the nitric oxide synthase inhibitor, L-NAME and the cyclooxygenase inhibitor, indomethacin, the endothelium-dependent vasorelaxation induced by MOE (0.001–3 mg) was completely inhibited by DL-propargylglycine (100 µM), which inhibits the H2Sgenerating enzyme, cystathionine γ-lyase. This H2Sdependent response was reduced by the KATP channel blocker; glibenclamide (10 µM), the KCa channel blocker; tetraethylammonium (1 µM), and the myo-endothelial gap-junctional uncoupler; 18α-glycyrrhetinic acid (10 µM). In contrast, the muscarinic receptor antagonist, atropine (100 µM), did not affect the response to MOE.ConclusionsThe results may suggest that H2S is the likely mediator of endothelium-dependent relaxation in response to MOE in mesenteric arterial beds of L-NAME-induced hypertensive rats. MOE-induced H2S-dependent vasorelaxation involves activation of KATP and KCa channels and requires myo-endothelial gap-junctional communication.

scholarly journals Electromagnetic Fields Inhibit Endothelin-1 Production Stimulated by Thrombin in Endothelial Cells

2005 ◽  
Vol 33 (5) ◽  
pp. 545-554 ◽  
Author(s):  
S Morimoto ◽  
T Takahashi ◽  
K Shimizu ◽  
T Kanda ◽  
K Okaishi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Cell Types ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Nitric Oxide Synthase Inhibitor ◽  
Endothelin 1 ◽  
Synthase Inhibitor

Electromagnetic field (EMF) radiation has been found to induce arteriolar dilatation, but the mechanism of action remains largely unknown. This study investigated the effect of EMF radiation on the production of endothelin-1 (ET-1), a potent vasoconstrictor, by cultured endothelial cells. EMF radiation reduced ET-1 basal levels in human umbilical vein and microvascular endothelial cells, but failed to reduce ET-1 basal levels in bovine and human aortic endothelial cells. EMF radiation significantly inhibited thrombin-stimulated ET-1 production in all four endothelial cell types in a dose-dependent manner. EMF radiation significantly inhibited thrombin-induced endothelin-1 mRNA expression in all four cell types. The inhibitory effect of EMF radiation on ET-1 production was abolished by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (10−3 mol/l). These results demonstrate that EMF radiation modulates ET-1 production in cultured vascular endothelial cells and the inhibitory effect of EMF radiation is, at least partly, mediated through a nitric oxide-related pathway.

Effect of progesterone on the contractile response of isolated pulmonary artery in rabbits

2001 ◽  
Vol 79 (6) ◽  
pp. 545-550 ◽  
Author(s):  
Hong-Fang Li ◽  
Tian-Zhen Zheng ◽  
Wei Li ◽  
Song-Yi Qu ◽  
Chen-Lie Zhang
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Artery ◽  
Pulmonary Arteries ◽  
Isometric Tension ◽  
Krebs Solution ◽  
Prostaglandin Synthase ◽  
Intracellular Ca ◽  
Β Receptor ◽  
Synthase Inhibitor ◽  
Oxide Synthase

The purpose of this study was to assess the direct effect of progesterone on rabbit pulmonary arteries and to examine the mechanism of its action. Rings of pulmonary artery from male rabbits were suspended in organ baths containing Krebs solution, and isometric tension was measured. The response to progesterone was investigated in arterial rings contracted with noradrenaline (NA), KCl, and CaCl2. The effects of endothelium, nitric oxide(NO), prostaglandins, cyclic GMP(cGMP), and the adrenergic β-receptor on progesterone-induced relaxation were also assessed. Progesterone inhibited the vasocontractivity to NA, KCl, and CaCl2, and relaxed rabbit pulmonary artery. The relaxing response of progesterone in pulmonary artery was significantly reduced by removal of endothelium, inhibitors of nitric oxide synthase and guanylate cyclase, but not by prostaglandin synthase inhibitor and blockage of the adrenergic β-receptor. In Ca2+-free (0.1 mM EGTA) Krebs solution, progesterone inhibited NA-induced contraction that was intracellular Ca2+-dependent, but didn't affect the contraction of extracellular Ca2+-dependent component. Our results suggest that progesterone induces relaxation of isolated rabbit pulmonary arteries partially via NO and cGMP. Progesterone may also inhibit Ca2+ influx through potential-dependent calcium channels (PDCs) and Ca2+ release from intracellular stores.Key words: progesterone, pulmonary artery, Ca2+ channel, endothelium.

Extravascular adenosine influences endothelium-derived nitric oxide release from perfused dog semitendinosus artery

1998 ◽  
Vol 76 (2) ◽  
pp. 90-98 ◽  
Author(s):  
N Woodley ◽  
J K Barclay
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Superoxide Dismutase ◽  
Bicarbonate Buffer ◽  
Nitric Oxide Synthase Inhibitor ◽  
Nitric Oxide Release ◽  
Adenosine Receptor Antagonist ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
Endothelium Dependent Relaxation

We tested the hypothesis that extravascular adenosine induces the release of vasodilatory products from endothelial cells lining skeletal muscle vessels. Endothelium-intact (n = 35) and -denuded (n = 5) dog semitendinosus intramuscular arteries were isolated, cannulated, and placed in 100-mL baths containing Krebs-Henseleit bicarbonate buffer (Krebs) at 37°C and gassed with 95% O2- 5% CO2. Each vessel, as well as a parallel tubing segment (avascular control), was perfused at 3.5 ± 0.2 mL/min (inflow pressure 94 ± 2 mmHg; 1 mmHg = 133.3 Pa) with Krebs containing 100 µM phenylephrine, 6% dextran, and 15 units/mL superoxide dismutase. Perfusate from all segments dripped onto endothelium-denuded dog femoral artery rings. The addition of 10 µM acetylcholine to the perfusate to test the functional integrity of endothelium-intact donor segments did not alter resistance in vessel segments or change force in rings. The addition of 100 µM adenosine to the extravascular bath decreased resistance 1.5 ± 0.4 mmHg ·mL-1·min-1in vessel segments but was without effect on downstream rings. When acetylcholine was retested in the presence of extravascular adenosine, a relaxation (16 ± 6%) occurred in rings receiving perfusate from endothelium-intact segments but not endothelium-denuded or tubing segments. This relaxation was eliminated by Nomega-nitro-L-arginine (10 µM), a nitric oxide synthase inhibitor, and was attenuated to 4 ± 1% by 8-phenyltheophylline (10 µM), an adenosine receptor antagonist. Thus adenosine, in conjunction with acetylcholine, acting through a receptor-mediated event, resulted in the release of nitric oxide from the endothelium of perfused intramuscular arteries, indicating the potential for extravascular conditions to influence the release of endothelium-derived products.Key words: acetylcholine, adenosine, endothelium-dependent relaxation, nitric oxide, perfused intramuscular artery.

scholarly journals Uridine adenosine tetraphosphate-induced contraction is increased in renal but not pulmonary arteries from DOCA-salt hypertensive rats

2011 ◽  
Vol 301 (2) ◽  
pp. H409-H417 ◽  
Author(s):  
Takayuki Matsumoto ◽  
Rita C. Tostes ◽  
R. Clinton Webb
Keyword(s):  
Pulmonary Arteries ◽  
P2y Receptors ◽  
Isometric Tension ◽  
Erk Pathway ◽  
Nitric Oxide Synthase Inhibitor ◽  
Salt Hydrate ◽  
Erk Activation ◽  
Trisodium Salt ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Uridine adenosine tetraphosphate (Up4A) was reported as a novel endothelium-derived contracting factor. Up4A contains both purine and pyrimidine moieties, which activate purinergic (P2)X and P2Y receptors. However, alterations in the vasoconstrictor responses to Up4A in hypertensive states remain unclear. The present study examined the effects of Up4A on contraction of isolated renal arteries (RA) and pulmonary arteries (PA) from DOCA-salt rats using isometric tension recording. RA from DOCA-salt rats exhibited increased contraction to Up4A versus arteries from control uninephrectomized rats in the absence and presence of NG-nitro-l-arginine (nitric oxide synthase inhibitor). On the other hand, the Up4A-induced contraction in PA was similar between the two groups. Up4A-induced contraction was inhibited by suramin (nonselective P2 antagonist) but not by diinosine pentaphosphate pentasodium salt hydrate (Ip5I; P2X1 antagonist) in RA from both groups. Furthermore, 2-thiouridine 5′-triphosphate tetrasodium salt (2-ThioUTP; P2Y2 agonist)-, uridine-5′-(γ-thio)-triphosphate trisodium salt (UTPγS; P2Y2/P2Y4 agonist)-, and 5-iodouridine-5′- O-diphosphate trisodium salt (MRS 2693; P2Y6 agonist)-induced contractions were all increased in RA from DOCA-salt rats. Protein expression of P2Y2-, P2Y4-, and P2Y6 receptors in RA was similar between the two groups. In DOCA-salt RA, the enhanced Up4A-induced contraction was reduced by PD98059, an ERK pathway inhibitor, and Up4A-stimulated ERK activation was increased. These data are the first to indicate that Up4A-induced contraction is enhanced in RA from DOCA-salt rats. Enhanced P2Y receptor signaling and activation of the ERK pathway together represent a likely mechanism mediating the enhanced Up4A-induced contraction. Up4A might be of relevance in the pathophysiology of vascular tone regulation and renal dysfunction in arterial hypertension.

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