Adenosine is not responsible for local metabolic control  of coronary blood flow in dogs during exercise

Tune, Johnathan D.; Richmond, Keith Neu; Gorman, Mark W.; Olsson, Ray A.; Feigl, Eric O.

doi:10.1152/ajpheart.2000.278.1.h74

Cited by 78 publications

(101 citation statements)

References 33 publications

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“…Glibenclamide treatment significantly decreased the slope of this relationship (P ϭ 0.03), indicating that K ATP channels are important to functional exercise coronary hyperemia in alloxaninduced diabetes. Because of the normally high oxygen extraction by the left ventricle (8,22,24), the data points and regression lines lie extremely close to the line of 100% oxygen extraction (oxygen consumed ϭ oxygen delivery) illustrated in Fig. 2.…”

Section: Resultssupporting

confidence: 62%

“…A more sensitive index of the relationship between coronary blood flow and myocardial metabolism is shown in the plot of coronary venous PO 2 versus MVO 2 (Fig. 4) (4,5,8,20,22,24). K ATP channel blockade with glibenclamide made the slope of this relationship more negative (P ϭ 0.01), indicating that K ATP channels contribute to local metabolic coronary vasodilation in experimental diabetes.…”

Section: Resultsmentioning

confidence: 99%

“…Using sterile technique, a left lateral thoracotomy was performed in the fifth intercostal space. A custom-made, coextruded polyurethane catheter (Putnam Plastics, Dayville, CT) was implanted in the descending thoracic aorta to measure aortic blood pressure and obtain arterial blood samples (8,22). A second polyurethane catheter was placed in the coronary sinus via a purse-string suture in the right atrial appendage for coronary venous blood sampling.…”

mentioning

confidence: 99%

“…Importantly, by plotting coronary response variables as a function of MVO 2 , these plots account for any drug-induced changes in heart rate, blood pressure, or contractility that may significantly affect myocardial oxygen demand. Many studies have used this approach to analyze mechanisms of coronary blood flow control (3)(4)(5)8,20,22,24). Statistical analyses.…”

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confidence: 99%

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ATP-Dependent K+ Channels Contribute to Local Metabolic Coronary Vasodilation in Experimental Diabetes

et al. 2002

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This study tested whether ATP-dependent K ؉ channels (K ATP channels) are an important mechanism of functional coronary hyperemia in conscious, instrumentimplanted diabetic dogs. Data were collected at rest and during exercise before and after induction of diabetes with alloxan monohydrate (40 -60 mg/kg intravenously). K ATP channels were inhibited with glibenclamide (1 mg/kg intravenously). In nondiabetic dogs, arterial plasma glucose concentration increased from 4.8 ؎ 0.3 to 21.5 ؎ 2.2 mmol/l 1 week after alloxan injection. In nondiabetic dogs, exercise increased myocardial oxygen consumption (MVO 2 ) 3.4-fold, myocardial O 2 delivery 3.0-fold, and heart rate 2. N umerous investigations have focused on the role of ATP-dependent K ϩ (K ATP ) channels in coronary blood flow regulation (1-14). These studies indicate that K ATP channels are important in regulating coronary vascular resistance under baseline conditions (3-10), during hypoxic coronary vasodilation (11,12), and during reactive coronary hyperemia (1,4,13). However, it does not appear that K ATP channels are required to increase coronary blood flow when myocardial metabolism is increased (3)(4)(5)7,8).Recently, Kersten et al. (14) found that diabetes enhanced K ATP channel-mediated coronary vasodilation of coronary arterioles, suggesting that K ATP channels are important in local metabolic coronary vasodilation in diabetes. Supporting this notion are the results of Shimoni et al. (15) showing that the half-maximal inhibitory concentration (IC 50 ) for ATP-dependent inhibition of K ATP channels was approximately twofold higher for channels from diabetic rat hearts. If there is an increase of K ATP channel activity in diabetes, then oral hypoglycemic agents such as glibenclamide (Glyburide or Diabeta), which are K ATP channel antagonists, could seriously impair control of coronary blood flow, especially when myocardial oxygen demand is elevated. Despite this fact, no study has examined whether K ATP channels contribute to metabolic coronary vasodilation in an intact diabetic model. Furthermore, characterizing mechanisms that regulate coronary vascular tone is particularly important since coronary flow reserve (16 -19), functional coronary hyperemia (18), and the balance between coronary blood flow and myocardial metabolism (20) are impaired in diabetic subjects. Accordingly, this study was designed to determine whether K ATP channels contribute to local metabolic coronary vasodilation in diabetic subjects. Experiments were conducted at rest and during graded treadmill exercise, with and without K ATP channel blockade (glibenclamide, 1 mg/kg i.v.) (7,8), in chronically instrument-implanted dogs before and after induction of diabetes with alloxan monohydrate (40 -60 mg/kg i.v.) (21). RESEARCH DESIGN AND METHODSSurgical preparation. This investigation was approved by the Institutional Animal Care and Use Committee and was conducted in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health publ. no. 85-23, revise...

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Section: Resultssupporting

confidence: 62%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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ATP-Dependent K+ Channels Contribute to Local Metabolic Coronary Vasodilation in Experimental Diabetes

et al. 2002

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“…We [20,44] and others [10,11,45] previously demonstrated that adenosine also plays a physiological role in regulating coronary resting flow in human [11], swine [10], dogs [45], guinea pigs [46], and mice [20,44], while some other groups failed to observe an endogenous role of adenosine [3,47,48], which leaves this scientific topic controversial. This discrepancy may be due to different animal models, differences in species, and/or different agonists and antagonists applied in these studies [19].…”

Section: Adenosine-induced Increase In Coronary Flow Is Mediated In Pmentioning

confidence: 99%

Involvement of NADPH oxidase in A2A adenosine receptor-mediated increase in coronary flow in isolated mouse hearts

Zhou

Rajamani

Labazi

et al. 2015

Purinergic Signalling

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Adenosine increases coronary flow mainly through the activation of A 2A and A 2B adenosine receptors (ARs). However, the mechanisms for the regulation of coronary flow are not fully understood. We previously demonstrated that adenosine-induced increase in coronary flow is in part through NADPH oxidase (Nox) activation, which is independent of activation of either A 1 or A 3 ARs. In this study, we hypothesize that adenosine-mediated increase in coronary flow through Nox activation depends on A 2A but not A 2B ARs. Functional studies were conducted using isolated Langendorff-perfused mouse hearts. Hydrogen peroxide (H 2 O 2 ) production was measured in isolated coronary arteries from WT, A 2A AR k n o c k o u t ( K O ) , a n d A 2 B A R K O m i c e u s i n g dichlorofluorescein immunofluorescence. Adenosineinduced concentration-dependent increase in coronary flow was attenuated by the specific Nox2 inhibitor gp91 ds-tat or reactive oxygen species (ROS) scavenger EUK134 in both WT and A 2B but not A 2A AR KO isolated hearts. Similarly, the A 2A AR selective agonist CGS-21680-induced increase in coronary flow was significantly blunted by Nox2 inhibition in both WT and A 2B AR KO, while the A 2B AR selective agonist BAY 60-6583-induced increase in coronary flow was not affected by Nox2 inhibition in WT. In intact isolated coronary arteries, adenosine-induced (10 μM) increase in H 2 O 2 formation in both WT and A 2B AR KO mice was attenuated by Nox2 inhibition, whereas adenosine failed to increase H 2 O 2 production in A 2A AR KO mice. In conclusion, adenosine-induced increase in coronary flow is partially mediated by Nox2-derived H 2 O 2 , which critically depends upon the presence of A 2A AR.

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Measurement of adenine nucleotides in plasma

et al. 2003

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The goal of this study was to identify the most important variables affecting bioluminescent ATP, ADP and AMP measurements in plasma and to develop an assay that takes these variables into account. Blood samples were drawn from conscious dogs. A 'stop solution' containing EDTA was prepared, which greatly retarded plasma ATP degradation by chelating Mg(+2) and Ca(+2) that are co-factors for many ATPases. Stop solution and blood were mixed using a two-syringe withdrawal system. Samples were centrifuged twice in order to remove red blood cells, and ATP was measured in the supernatant using the firefly luciferase assay. Sample pH was adjusted to the optimal range (7.75-7.95) and Mg(2+) (necessary for the luciferase reaction) was added back to the sample within the luminometer 2 s prior to luciferase addition. Four assay tubes were prepared for each plasma sample, containing standard additions of 0-15 pmol added ATP, in order to quantify native plasma ATP content. In separate plasma/stop solution samples ADP + ATP was measured after converting ADP to ATP via the pyruvate kinase reaction, and AMP + ADP + ATP was measured after addition of both myokinase and pyruvate kinase. Addition of forskolin and isobutylmethylxanthine (IBMX) to the stop solution to inhibit platelets resulted in lower ATP concentrations. Measurement of ATP and haemoglobin from lysed erythrocytes revealed that haemolysis exerts a strong influence on plasma ATP concentration that must be taken into account.

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Adenosine is not responsible for local metabolic control of coronary blood flow in dogs during exercise

Cited by 78 publications

References 33 publications

ATP-Dependent K+ Channels Contribute to Local Metabolic Coronary Vasodilation in Experimental Diabetes

ATP-Dependent K+ Channels Contribute to Local Metabolic Coronary Vasodilation in Experimental Diabetes

Involvement of NADPH oxidase in A2A adenosine receptor-mediated increase in coronary flow in isolated mouse hearts

Measurement of adenine nucleotides in plasma

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