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.

Evidence for microvascular dysfunction after prenatal dexamethasone at 0.7, 0.75, and 0.8 gestation in sheep

2002 ◽  
Vol 283 (3) ◽  
pp. R561-R567 ◽  
Author(s):  
Judit Molnar ◽  
Mark J. M. Nijland ◽  
David C. Howe ◽  
Peter W. Nathanielsz
Keyword(s):  
Nitric Oxide ◽  
Cardiovascular Health ◽  
Microvascular Dysfunction ◽  
Nitric Oxide Donor ◽  
Internal Diameter ◽  
Response Curves ◽  
Nitric Oxide Synthase Inhibitor ◽  
Endothelin 1 ◽  
Synthase Inhibitor ◽  
The Right

Dexamethasone (DM) was administered to pregnant ewes as three weekly courses of four injections of 2 mg at 12-h intervals. DM ( n = 7) or saline ( n= 7) was given starting at 103 days of gestation (dGA; term ∼149 days). Fetal femoral arteries (∼300-μm internal diameter) were evaluated using wire myography at 119 dGA. DM-exposed fetuses were significantly smaller than saline-exposed fetuses. DM exposure increased maximal contraction to 125 mM KCl, and maximum tension developed along with sensitivity to endothelin-1 and relaxation to bradykinin. Preincubation with the nitric oxide synthase inhibitor N G-nitro-l-arginine methyl ester shifted the dose-response curves to endothelin-1 and acetylcholine to the right in controls but not in the DM-exposed group. Relaxation to acetylcholine and to the nitric oxide donor sodium nitroprusside was similar in both groups. The combination of enhanced endothelin-induced vasoconstriction, abnormal endothelium-dependent relaxation, and normal endothelium-independent relaxation indicates microvessel dysfunction following antenatal DM administration. Because such dysfunction is associated with several forms of adult hypertension, our results indicate the potential for consequences of antenatal glucocorticoid exposure on adult cardiovascular health.

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.

Descending peristaltic reflex in the opossum esophagus

1995 ◽  
Vol 269 (2) ◽  
pp. G219-G224 ◽  
Author(s):  
W. G. Paterson ◽  
B. Indrakrishnan
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Smooth Muscle Contraction ◽  
Organ Bath ◽  
Krebs Solution ◽  
Nitric Oxide Synthase Inhibitor ◽  
Membrane Hyperpolarization ◽  
Circular Smooth Muscle ◽  
Peristaltic Reflex ◽  
Synthase Inhibitor

To test the hypothesis that the distension-induced esophageal peristaltic reflex involves a polysynaptic pathway, a triple-chamber organ bath was used to chemically isolate different regions of the opossum smooth muscle esophagus while leaving in continuity the intramural neuromuscular apparatus. Balloon distension in the oral chamber evoked membrane hyperpolarization in the aboral chamber, which was followed, on balloon deflation, by depolarization, spike burst, and circular smooth muscle contraction. This reflex was abolished by adding tetrodotoxin to any of the chambers. Addition of Ca(2+)-free 20 mM Mg2+ Krebs solution (to block synaptic transmission) to the intermediate chamber did not affect the descending peristaltic reflex. However, Ca(2+)-free 20 mM Mg2+ Krebs solution markedly attenuated the reflex when placed in either the oral or the aboral chamber. Furthermore, the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester, when placed in the aboral chamber, abolished the reflex. Other putative neurotransmitter antagonists were without effect when placed in any chamber. These studies suggest that the intramural neural pathway that mediates the descending peristaltic reflex in the opossum esophagus is not polysynaptic, but rather involves long descending neurons that depend on nitric oxide as a final mediator.

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.

scholarly journals Selective estrogen receptor-α and estrogen receptor-β agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide-dependent mechanism

2008 ◽  
Vol 295 (5) ◽  
pp. R1486-R1493 ◽  
Author(s):  
Tim Lahm ◽  
Paul R. Crisostomo ◽  
Troy A. Markel ◽  
Meijing Wang ◽  
Yue Wang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Estrogen Receptor ◽  
Pulmonary Artery ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Organ Bath ◽  
Sprague Dawley ◽  
Response Curves ◽  
Vascular Effects ◽  
M 10 ◽  
Dependent Mechanism

Both endogenous and exogenous estrogen decrease pulmonary artery (PA) vasoconstriction. Whether these effects are mediated via estrogen receptor (ER)-α or ER-β, and whether the contribution of ERs is stimulus-dependent, remains unknown. We hypothesized that administration of the selective ER-α agonist propylpyrazole triol (PPT) and/or the selective ER-β agonist diarylpropiolnitrile (DPN) rapidly decreases PA vasoconstriction induced by pharmacologic and hypoxic stimuli via a nitric oxide (NO)-dependent mechanism. PA rings ( n = 3–10/group) from adult male Sprague-Dawley rats were suspended in physiologic organ baths. Force displacement was measured. Vasoconstrictor responses to phenylephrine (10−8M − 10−5M) and hypoxia (Po2 35–45 mmHg) were determined. Endothelium-dependent and -independent vasorelaxation were measured by generating dose-response curves to acetylcholine (10−8M − 10−4M) and sodium nitroprusside (10−9M − 10−5M). PPT or DPN (10−9M − 5 × 10−5M) were added to the organ bath in the presence and absence of the NO-synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) (10−4M). Selective ER-α activation (PPT, 5 × 10−5M) rapidly (<20 min) decreased phenylephrine-induced vasoconstriction. This effect, as well as PPT's effects on endothelium-dependent vasorelaxation, were neutralized by l-NAME. In contrast, selective ER-β activation (DPN, 5 × 10−5M) rapidly decreased phase II of hypoxic pulmonary vasoconstriction (HPV). l-NAME eliminated this phenomenon. Lower PPT or DPN concentrations were less effective. We conclude that both ER-α and ER-β decrease PA vasoconstriction. The immediate onset of effect suggests a nongenomic mechanism. The contribution of specific ERs appears to be stimulus specific, with ER-α primarily modulating phenylephrine-induced vasoconstriction, and ER-β inhibiting HPV. NO inhibition eliminates these effects, suggesting a central role for NO in mediating the pulmonary vascular effects of both ER-α and ER-β.

Effects of Early Neuronal and Delayed Inducible Nitric Oxide Synthase Blockade on Cardiovascular, Renal, and Hepatic Function in Ovine Sepsis

2010 ◽  
Vol 113 (6) ◽  
pp. 1376-1384 ◽  
Author(s):  
Matthias Lange ◽  
Atsumori Hamahata ◽  
Daniel L. Traber ◽  
Yoshimitsu Nakano ◽  
Aimalohi Esechie ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Nitric Oxide Synthase Inhibitor ◽  
Nitrite Nitrate ◽  
Synthase Inhibitor ◽  
Plasma Nitrite ◽  
Oxide Synthase ◽  
Organ Dysfunctions ◽  
Inducible Nitric Oxide

Background Recent evidence suggests that nitric oxide produced via the neuronal nitric oxide synthase is involved mainly in the early response to sepsis, whereas nitric oxide derived from the inducible nitric oxide synthase is responsible during the later phase. We hypothesized that early neuronal and delayed inducible nitric oxide synthase blockade attenuates multiple organ dysfunctions during sepsis. Methods Sheep were randomly allocated to sham-injured, nontreated animals (n = 6); injured (48 breaths of cotton smoke and instillation of Pseudomonas aeruginosa into the lungs), nontreated animals (n = 7); and injured animals treated with a neuronal nitric oxide synthase inhibitor from 1 to 12 h and an inducible nitric oxide synthase inhibitor from 12 to 24 h postinjury (n = 6). Results The injury induced arterial hypotension, vascular leakage, myocardial depression, and signs of renal and hepatic dysfunctions. The treatment significantly attenuated, but did not fully prevent, the decreases in mean arterial pressure and left ventricular stroke work index. Although the elevation of creatinine levels was partially prevented, the decreases in urine output and creatinine clearance were not affected. The injury-related increases in bilirubin levels, international normalized ratio, and lipid peroxidation in liver tissue were significantly attenuated. Although plasma nitrite/nitrate levels were significantly increased versus baseline from 12-24 h in controls, plasma nitrite/nitrate levels were not increased in treated animals. Conclusions The combination treatment shows potential benefit on sepsis-related arterial hypotension and surrogate parameters of organ dysfunctions in sheep. It may be crucial to identify the time course of expression and activation of different nitric oxide synthase isoforms in future investigations.

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