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 Role of CYP epoxygenases in A2AAR-mediated relaxation using A2AAR-null and wild-type mice

2008 ◽  
Vol 295 (5) ◽  
pp. H2068-H2078 ◽  
Author(s):  
Mohammed A. Nayeem ◽  
Samuel M. Poloyac ◽  
John R. Falck ◽  
Darryl C. Zeldin ◽  
Catherine Ledent ◽  
...  
Keyword(s):  
Epoxyeicosatrienoic Acid ◽  
Wild Type ◽  
Nitric Oxide Synthase Inhibitor ◽  
Cgs 21680 ◽  
Sch 58261 ◽  
Specific Antagonist ◽  
Synthase Inhibitor ◽  
Mouse Aorta ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

We hypothesized that A2A adenosine receptor (A2AAR) activation causes vasorelaxation through cytochrome P-450 (CYP) epoxygenases and endothelium-derived hyperpolarizing factors, whereas lack of A2AAR activation promotes vasoconstriction through Cyp4a in the mouse aorta. Adenosine 5′- N-ethylcarboxamide (NECA; 10−6 M), an adenosine analog, caused relaxation in wild-type A2AAR (A2AAR+/+; +33.99 ± 4.70%, P < 0.05) versus contraction in A2AAR knockout (A2AAR−/−; −27.52 ± 4.11%) mouse aortae. An A2AAR-specific antagonist (SCH-58261; 1μM) changed the NECA (10−6 M) relaxation response to contraction (−35.82 ± 4.69%, P < 0.05) in A2AAR+/+ aortae, whereas no effect was noted in A2AAR−/− aortae. Significant contraction was seen in the absence of the endothelium in A2AAR+/+ (−2.58 ± 2.25%) aortae compared with endothelium-intact aortae. An endothelial nitric oxide synthase inhibitor ( N-nitro-l-arginine methyl ester; 100 μM) and a cyclooxygenase inhibitor (indomethacin; 10 μM) failed to block NECA-induced relaxation in A2AAR+/+ aortae. A selective inhibitor of CYP epoxygenases (methylsulfonyl-propargyloxyphenylhexanamide; 10 μM) changed NECA-mediated relaxation (−22.74 ± 5.11% at 10−6 M) and CGS-21680-mediated relaxation (−18.54 ± 6.06% at 10−6 M) to contraction in A2AAR+/+ aortae, whereas no response was noted in A2AAR−/− aortae. Furthermore, an epoxyeicosatrienoic acid (EET) antagonist [14,15-epoxyeicosa-5( Z)-enoic acid; 10 μM] was able to block NECA-induced relaxation in A2AAR+/+ aortae, whereas ω-hydroxylase inhibitors (10 μM dibromo-dodecenyl-methylsulfimide and 10 μM HET-0016) changed contraction into relaxation in A2AAR−/− aorta. Cyp2c29 protein was upregulated in A2AAR+/+ aortae, whereas Cyp4a was upregulated in A2AAR−/− aortae. Higher levels of dihydroxyeicosatrienoic acids (DHETs; 14,15-DHET, 11,12-DHET, and 8,9-DHET, P < 0.05) were found in A2AAR+/+ versus A2AAR−/− aortae. EET levels were not significantly different between A2AAR+/+ and A2AAR−/− aortae. It is concluded that CYP epoxygenases play an important role in A2AAR-mediated relaxation, and the deletion of the A2AAR leads to contraction through Cyp4a.

scholarly journals CYP-epoxygenases contribute to A2A receptor-mediated aortic relaxation via sarcolemmal KATP channels

2012 ◽  
Vol 303 (10) ◽  
pp. R1003-R1010 ◽  
Author(s):  
Dovenia S. Ponnoth ◽  
Mohammed A. Nayeem ◽  
Stephen L. Tilley ◽  
Catherine Ledent ◽  
S. Jamal Mustafa
Keyword(s):  
Nitric Oxide ◽  
Relaxation Effect ◽  
Katp Channels ◽  
Induced Response ◽  
Organ Bath ◽  
Response Curves ◽  
Nitric Oxide Synthase Inhibitor ◽  
Signaling Mechanism ◽  
Cgs 21680 ◽  
Synthase Inhibitor

Previously, we have shown that A2A adenosine receptor (A2AAR) mediates aortic relaxation via cytochrome P-450 (CYP)-epoxygenases. However, the signaling mechanism is not understood properly. We hypothesized that ATP-sensitive K+ (KATP) channels play an important role in A2AAR-mediated relaxation. Organ bath and Western blot experiments were done using isolated aorta from A2AKO and corresponding wild-type (WT) mice. Aortic rings from WT and A2A knockout (KO) mice were precontracted with submaximal dose of phenylephrine (PE, 10−6 M), and concentration-response curves for pinacidil, cromakalim (nonselective KATP openers), and diazoxide (mitochondrial KATP opener) were obtained. Diazoxide did not have any relaxation effect on PE-precontracted tissues, whereas relaxation to pinacidil (48.09 ± 5.23% in WT vs. 25.41 ± 2.73% in A2AKO; P < 0.05) and cromakalim (51.19 ± 2.05% in WT vs. 38.50 ± 2.26% in A2AKO; P < 0.05) was higher in WT than A2AKO aorta. This suggested the involvement of sarcolemmal rather than mitochondrial KATP channels. Endothelium removal, treatment with SCH 58651 (A2AAR antagonist; 10−6 M), NG-nitro-l-arginine methyl ester (l-NAME, nitric oxide synthase inhibitor) and methylsulfonyl-propargyloxyphenylhexanamide (MS-PPOH, CYP-epoxygenases inhibitor; 10−5 M) significantly reduced pinacidil-induced relaxation in WT compared with controls, whereas these treatments did not have any effect in A2AKO aorta. Glibenclamide (KATP channel inhibitor, 10−5 M) blocked 2- p-(2-carboxyethyl)phenethylamino-5′ N-ethylcarboxamido adenosine hydrochloride (CGS 21680, A2AAR agonist)-induced relaxation in WT and changed 5′- N-ethylcarboxamide (NECA) (nonselective adenosine analog)-induced response to higher contraction in WT and A2AKO. 5-Hydroxydecanoate (5-HD, mitochondrial KATP channel inhibitor, 10−4 M) had no effect on CGS 21680-mediated response in WT aorta. Our data suggest that A2AAR-mediated vasorelaxation occurs through opening of sarcolemmal KATP channels via CYP-epoxygenases and possibly, nitric oxide, contributing to pinacidil-induced responses.

An Endothelial Nitric Oxide Synthase Inhibitor Aggravates CDL-Induced Acute Pancreatitis in Rats

Pancreas ◽  
1999 ◽  
Vol 19 (4) ◽  
pp. 390-400 ◽  
Author(s):  
Takayoshi Nishino ◽  
Shin-ichiro Watanabe ◽  
Hiroyasu Oyama ◽  
Yuji Fukuya ◽  
Naoaki Hayashi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Acute Pancreatitis ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Nitric Oxide Synthase Inhibitor ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

scholarly journals Evaluation of the effects of S-methylisothiourea hemisulfate, an inducible nitric oxide synthase inhibitor, on the healing of colonic anastomosis in rats

2012 ◽  
Vol 27 (12) ◽  
pp. 892-896 ◽  
Author(s):  
Romulo Medeiros de Almeida ◽  
João Batista de Sousa ◽  
Paulo Roberto Faria Ribeiro ◽  
Silvana Marques e Silva ◽  
Marco Aurélio Pereira Firmino ◽  
...  
Keyword(s):  
Colonic Anastomosis ◽  
Breaking Strength ◽  
Control Group ◽  
Nitric Oxide Synthase Inhibitor ◽  
The Third ◽  
Significant Difference ◽  
Nitrite Nitrate ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
And Control

PURPOSE: To evaluate the effects of S-methylisothiourea hemisulfate (SMT) on the healing of colonic anastomosis in rats. METHODS: Sixty rats Wistar were distributed into two groups of 30 animals: experimental (E) and control C). The animals of experimental group received intraperitoneal SMT at 50mg/kg/dose every 12 hours for 72 hours. The control group received intraperitoneal saline at the same volume of SMT. The rats were subdivided into subgroups groups of 10 for euthanasia on the third, seventh, and 14th postoperative days (POD). We evaluated clinical and weight evolution, breaking strength and histopathology; also, a blood sample was collected for serum dosage of nitrite/nitrate. RESULTS: There was more vascular neoformation (p=0.006) and granulation (p=0.002) in the E3 group, and more mononuclear infiltrates in the C3 group (p=0.041). There was also more edema in the C14 group (p=0.008). There was no statistically significant difference in breaking strength, nitrite/nitrate dosage, and the remaining histopathological parameters. CONCLUSION: The use of S-methylisothiourea hemisulfate improved the healing of colonic anastomosis in rats on the third postoperative day by accelerating the proliferative stage of healing, but without interfering with the breaking strength of the anastomosis.

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 &lt; 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 &lt; 0.05) the vasorelaxant response to lemakalim in intact rings, but not in endothelium-denuded rings. Halothane at 1.5 MAC attenuated (P &lt; 0.05) the vasorelaxant response to lemakalim in both intact and endothelium-denuded rings. In endothelium-intact rings, indomethacin attenuated (P &lt; 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 &lt; 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.

Simulated microgravity upregulates an endothelial vasoconstrictor prostaglandin

2001 ◽  
Vol 91 (2) ◽  
pp. 789-796 ◽  
Author(s):  
Deepali S. Sangha ◽  
Sukgu Han ◽  
Ralph E. Purdy
Keyword(s):  
Nitric Oxide ◽  
Carotid Arteries ◽  
Simulated Microgravity ◽  
Cyclooxygenase Inhibitors ◽  
Nitric Oxide Synthase Inhibitor ◽  
Hindlimb Unweighting ◽  
Vascular Responsiveness ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Endothelial nitric oxide contributes to the vascular hyporesponsiveness to norepinephrine (NE) observed in carotid arteries from rats exposed to simulated microgravity. The goal of the present study was to determine whether a cyclooxygenase product of arachidonic acid also influences vascular responsiveness in this setting. Microgravity was simulated in rats by hindlimb unweighting (HU). After 20 days of HU, carotid arteries were isolated from control and HU-treated rats, and vascular rings were mounted in tissue baths for the measurement of isometric contraction. Two cyclooxygenase inhibitors, indomethacin and ibuprofen, and the selective thromboxane A2 prostanoid-receptor antagonist, SQ-29548, had no effect on the contraction to NE in control vessels but markedly reduced contraction to NE in HU vessels. When the endothelium was removed, indomethacin no longer had any effect on the NE-induced contraction in HU vessels. In endothelium-intact vessels in the presence of indomethacin, the addition of the nitric oxide synthase inhibitor, N G-l-nitro-arginine methyl ester, to the medium bathing HU vessels increased the contraction to NE to the level of that of the control vessels. These results indicate that HU treatment induced two endothelial changes in carotid artery that opposed each other. Nitric oxide activity was increased and was responsible for the vascular hyporesponsiveness to NE. The activity of a vasoconstrictor prostaglandin was also increased, and attenuated the vasodilating effect of nitric oxide.

scholarly journals Increased prostanoid dependency of arterial relaxation in Chlamydia pneumoniae-infected mice

2006 ◽  
Vol 55 (8) ◽  
pp. 1017-1021 ◽  
Author(s):  
Liisa Törmäkangas ◽  
Juha Ketonen ◽  
Maija Leinonen ◽  
Pekka Saikku ◽  
Ilari Paakkari
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Chlamydia Pneumoniae ◽  
Relaxation Response ◽  
Nitric Oxide Synthase Inhibitor ◽  
Descending Aorta ◽  
Significant Difference ◽  
Pre Treatment ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Endothelial dysfunction plays an important role in the development of atherosclerosis. Previous studies have shown that inoculation with Chlamydia pneumoniae contributes to atherosclerotic development in rabbits and hypercholesterolaemic mice and causes endothelial dysfunction in apolipoprotein E-deficient mice. The effect of acute C. pneumoniae infection on endothelial function in normocholesterolaemic C57BL/6J mice was studied by measuring the force of contraction of the descending aorta after noradrenaline stimulation and in response to methacholine-induced relaxation. In addition, the effects of the nitric oxide synthase inhibitor Nω -nitro-l-arginine methyl ester (l-NAME) and the cyclooxygenase inhibitor diclofenac on relaxation were assessed. Pre-treatment of the aortas with l-NAME decreased the relaxation response in both the infected and uninfected groups and no significant difference was detected between these groups, whereas diclofenac significantly attenuated the relaxation response only in the infected animals. In conclusion, infection shifted the balance of endothelium-derived relaxing factors from nitric oxide towards vasorelaxing prostanoids in C57BL/6J mice.

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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