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.

Gender differences in the endothelial regulation of α2-adrenoceptor-mediated contraction in the rat aorta

1999 ◽  
Vol 97 (1) ◽  
pp. 19-25 ◽  
Author(s):  
Nuria TEJERA ◽  
Gloria BALFAGÓN ◽  
Jesús MARÍN ◽  
Mercedes FERRER
Keyword(s):  
Rank Order ◽  
Rat Aorta ◽  
Ovariectomized Rats ◽  
Maximal Response ◽  
Nitric Oxide Synthase Inhibitor ◽  
Adrenoceptor Antagonist ◽  
Α2 Adrenoceptor ◽  
No Release ◽  
Synthase Inhibitor ◽  
Oxide Synthase

The aim of this study was to determine the possible influence of sex hormones on the contractile responses induced by clonidine, an agonist of α2-adrenoceptors, as well as the endothelial modulation of these responses. For this purpose, thoracic aorta segments from male (control and castrated) and female (in oestrous phase and ovariectomized) rats were used. In intact segments from the four groups of rats, clonidine (0.01-10 µmol/l) induced concentration-dependent contractions, which were increased by the nitric oxide synthase inhibitor Nω-nitro-⌊-arginine methyl ester (0.1 mmol/l) or by endothelium removal, but were reduced by 1 µmol/l yohimbine (an α2-adrenoceptor antagonist) in all animals and by 1 µmol/l indomethacin (a cyclo-oxygenase inhibitor) in control males only. The rank order of the magnitude of the maximal response was: oestrous females > ovariectomized females > control males > castrated males, whereas the sensitivity to clonidine (EC50 value) was similar in all animals. In endothelium-denuded segments, the rank order was: oestrous females = control males > ovariectomized females = castrated males. These results suggest that: (1) the presence of oestrogen or androgen increases the contraction caused by α2-adrenoceptor activation with clonidine; (2) endothelium negatively modulates the response to this agonist in the four groups of rats, due to endothelial NO release (entirely in females and in part in males); (3) androgen also seems to modulate the response by stimulating the release of an endothelial contracting factor, probably a prostanoid; and (4) the endothelium of males has a greater capacity than that of comparable females for negative regulation of the tension generated by the underlying vascular smooth muscle.

Activation of A3Adenosine Receptors Attenuates Lung Injury after In Vivo  Reperfusion

2004 ◽  
Vol 101 (5) ◽  
pp. 1153-1159 ◽  
Author(s):  
Julia Rivo ◽  
Evelyne Zeira ◽  
Eithan Galun ◽  
Idit Matot
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Lung Injury ◽  
Adenosine Triphosphate ◽  
Blocking Agent ◽  
Benzyl Ester ◽  
Nitric Oxide Synthase Inhibitor ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Background A3 adenosine receptor (AR) activation worsens or protects against renal and cardiac ischemia-reperfusion (IR) injury, respectively. The aims of the current study were to examine in an in vivo model the effect of A3AR activation on IR lung injury and investigate the mechanism by which it exerts its effect. Methods The arterial branch of the left lower lung lobe in intact-chest, spontaneously breathing cats was occluded for 2 h and reperfused for 3 h (IR group). Animals were treated with the selective A3 receptor agonist IB-MECA (300 microg/kg intravenously) given 15 min before ischemia or with IB-MECA as described, with pretreatment 15 min earlier with the selective A3AR antagonist MRS-1191, the nonsulfonylurea adenosine triphosphate-sensitive potassium channel-blocking agent U-37883A, or the nitric oxide synthase inhibitor N-nitro-l-arginine benzyl ester. Results IB-MECA markedly (P < 0.01) reduced the percentage of injured alveoli (IR, 48 +/- 4%; IB-MECA, 18 +/- 2%), wet:dry weight ratio (IR, 8.2 +/- 0.4; IB-MECA, 4 +/- 2), and myeloperoxidase activity (IR, 0.52 +/- 0.06 U/g; IB-MECA, 0.17 +/- 0.04 U/g). This protective effect was completely blocked by pretreatment with the selective A3AR antagonist MRS-1191 and the adenosine triphosphate-sensitive potassium channel blocking agent U-37883A but not the nitric oxide synthase inhibitor N-nitro-l-arginine benzyl ester. Conclusions In the feline lung, the A3AR agonist IB-MECA confers a powerful protection against IR lung injury. This effect is mediated by a nitric oxide synthase-independent pathway and involves opening of adenosine triphosphate-sensitive potassium channels. Therefore, selective activation of A3AR may be an effective means of protecting the reperfused lung.

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.

Peristalsis regulation by tachykinin NK1 receptors in the rabbit isolated distal colon

2003 ◽  
Vol 285 (2) ◽  
pp. G325-G331 ◽  
Author(s):  
Luciano Onori ◽  
Annalisa Aggio ◽  
Gennaro Taddei ◽  
Maria F. Loreto ◽  
Rachele Ciccocioppo ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Circular Muscle ◽  
Distal Colon ◽  
Inhibitory Effect ◽  
Model System ◽  
Suitable Model ◽  
Nitric Oxide Synthase Inhibitor ◽  
Inhibitory Pathways ◽  
Synthase Inhibitor ◽  
Oxide Synthase

In the gastrointestinal tract, tachykinin NK1 receptors are widely distributed in a number of neuronal and nonneuronal cells involved in the control of gut motor activity. In particular, in the rabbit isolated distal colon, which is a suitable model system to investigate the contribution of tachykinins as noncholinergic excitatory transmitters, the influence of NK1 receptors in the regulation of peristalsis is not known. The selective NK1-receptor antagonists SR-140333 (0.3 and 1 nM) and MEN-10930 (0.3–10 nM) significantly enhanced the velocity of rabbit colonic propulsion to submaximal stimulation. The prokinetic effect of SR-140333 was prevented by Nω-nitro-l-arginine (l-NNA), a nitric oxide synthase inhibitor, indicating that NK1 receptors located on nitrergic innervation exert a functional inhibitory restraint on the circular muscle and probably on descending excitatory and inhibitory pathways during propulsion. Conversely, the selective NK1-receptor agonist septide (3–10 nM) significantly inhibited colonic propulsion. In the presence of l-NNA, the inhibitory effect of septide was reverted into a prokinetic effect, which is probably mediated by the activation of postjunctional excitatory NK1 receptors.

scholarly journals High-salt diet enhances mouse aortic relaxation through adenosine A2A receptor via CYP epoxygenases

2009 ◽  
Vol 296 (3) ◽  
pp. R567-R574 ◽  
Author(s):  
Mohammed A. Nayeem ◽  
Dovenia S. Ponnoth ◽  
Matthew A. Boegehold ◽  
Darryl C. Zeldin ◽  
John R. Falck ◽  
...  
Keyword(s):  
High Salt ◽  
Response Curves ◽  
Nitric Oxide Synthase Inhibitor ◽  
Cgs 21680 ◽  
Significant Difference ◽  
Sch 58261 ◽  
Synthase Inhibitor ◽  
Adenosine A2a ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

We hypothesize that A2A adenosine receptors (A2A AR) promote aortic relaxation in mice through cytochrome P450 (CYP)-epoxygenases and help to avoid salt sensitivity. Aortas from male mice maintained on a high-salt (HS; 7% NaCl) or normal-salt (NS; 0.45% NaCl) diet for 4–5 wks were used. Concentration-response curves (10−11–10−5 M) for 5′- N-ethylcarboxamidoadenosine (NECA; a nonselective adenosine analog) and CGS 21680 (A2A AR agonist) were obtained with different antagonists including ZM 241385 (A2A AR antagonist; 10−6 M), SCH 58261 (A2A AR antagonist; 10−6 M), Nω-nitro-l-arginine methyl ester (l-NAME; endothelial nitric oxide synthase inhibitor; 10−4 M) and inhibitors including methylsulfonyl-propargyloxyphenylhexanamide (MS-PPOH; CYP epoxygenases inhibitor; 10−5M), 14,15-epoxyeicosa-5(z)-enoic acid (14,15-EEZE; EET antagonist; 10−5M), dibromo-dodecenyl-methylsulfimide (DDMS; CYP4A inhibitor; 10−5M), and HET0016 (20-HETE inhibitor; 10−5M). At 10−7 M of NECA, significant relaxation in HS (+22.58 ± 3.12%) was observed compared with contraction in NS (−10.62 ± 6.27%, P < 0.05). ZM 241385 changed the NECA response to contraction ( P < 0.05) in HS. At 10−7 M of CGS 21680, significant relaxation in HS (+32.04 ± 3.08%) was observed compared with NS (+10.45 ± 1.34%, P < 0.05). SCH 58261, l-NAME, MS-PPOH, and 14,15-EEZE changed the CGS 21680-induced relaxation to contraction ( P < 0.05) in HS. Interestingly, DDMS and HET0016 changed CGS 21680 response to relaxation ( P < 0.05) in NS; however, there was no significant difference found between DDMS, HET0016-treated HS and NS vs. nontreated HS group ( P > 0.05). CYP2C29 protein was 55% and 74% upregulated in HS vs. NS ( P < 0.05) mice aorta and kidney, respectively. CYP4A protein was 30.30% and 35.70% upregulated in NS vs. HS ( P < 0.05) mice aorta and kidneys, respectively. A1 AR was downregulated, whereas A2A AR was upregulated in HS compared with NS. These data suggest that HS may activate CYP2C29 via A2A AR, causing relaxation, whereas NS may contribute to the upregulation of CYP4A causing contraction.

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.

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.

Glomerular and tubular interactions between renal adrenergic activity and nitric oxide

1995 ◽  
Vol 268 (6) ◽  
pp. F1004-F1008 ◽  
Author(s):  
F. B. Gabbai ◽  
S. C. Thomson ◽  
O. Peterson ◽  
L. Wead ◽  
K. Malvey ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Glomerular Filtration ◽  
Renal Nerves ◽  
Ang Ii ◽  
Nitric Oxide Synthase Inhibitor ◽  
Adrenergic Activity ◽  
Single Nephron ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Endothelium-dependent nitric oxide (EDNO) exerts control over the processes of glomerular filtration and tubular reabsorption. The importance of the renal nerves to the tonic influence of EDNO in the glomerular microcirculation and proximal tubule was tested by renal micropuncture in euvolemic adult male Munich-Wistar rats. The physical determinants of glomerular filtration and proximal reabsorption were assessed before and during administration of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), in control animals and in animals 5–9 days after either ipsilateral surgical renal denervation (DNX) or after either sham surgery (SHX). L-NMMA caused single-nephron glomerular filtration rate to decline in control and SHX animals but not in DNX rats. L-NMMA caused a reduction in proximal reabsorption in control and SHX rats, which was prevented by prior DNX. DNX did not alter urinary guanosine 3',5'-cyclic monophosphate excretion, and, although DNX upregulates glomerular angiotensin II (ANG II) receptors, prior DNX did not alter intrarenal ANG II content as evaluated by radioimmunoassay. Some component of renal adrenergic activity is required for the full expression of the glomerular and tubular effects of blockade of nitric oxide synthase.

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