Effect of adenosine receptor blockade: preventing protective preconditioning depends on time of initiation

1993 ◽  
Vol 265 (2) ◽  
pp. H504-H508 ◽  
Author(s):  
J. D. Thornton ◽  
C. S. Thornton ◽  
J. M. Downey
Keyword(s):  
Protective Effect ◽  
Ischemic Preconditioning ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Receptor Blockade ◽  
Risk Zone ◽  
Time Points ◽  
Adenosine Receptor Antagonist ◽  
Rabbit Myocardium ◽  
Ischemic Period

Ischemic preconditioning protects the rabbit myocardium from infarction from a subsequent ischemia, and adenosine receptors appear to be involved in this protection. The present study attempts to determine when adenosine receptors must be occupied to achieve protection by infusing the adenosine receptor antagonist PD-115,199 at various time points during the study. Open-chest rabbits were subjected to 30 min of regional ischemia followed by 3 h of reperfusion and had 38 +/- 4% infarction of the risk zone. When hearts were preconditioned by 5 min of ischemia and 10 min reperfusion before the 30-min period of ischemia, only 9 +/- 2% infarction occurred. PD-115,199 given 5 min before the ischemic preconditioning episode blocked the protective effect of preconditioning (39 +/- 5% infarction). PD-115,199 also blocked the protection when given between the ischemic preconditioning episode and the 30-min period of ischemia (30 +/- 4% infarction). PD-115,199 given at the end of 30 min of ischemia did not block protection in preconditioned (PC) hearts (17 +/- 5% infarction) and had no effect on non-PC hearts (44 +/- 6% infarction). In prior studies we found that exogenous adenosine could substitute for ischemia to precondition the heart, indicating that adenosine is an initiator of preconditioning. These results, however, indicate that adenosine receptors must also be occupied during the long ischemic period for preconditioning to be protective and suggest that adenosine is a mediator of preconditioning as well.

scholarly journals Caffeine accelerates recovery from general anesthesia via multiple pathways

2017 ◽  
Vol 118 (3) ◽  
pp. 1591-1597 ◽  
Author(s):  
Robert Fong ◽  
Suhail Khokhar ◽  
Atif N. Chowdhury ◽  
Kelvin G Xie ◽  
Josiah Hiu-Yuen Wong ◽  
...  
Keyword(s):  
General Anesthesia ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Intracellular Camp ◽  
Receptor Blockade ◽  
Adult Rats ◽  
Adenosine Receptor Antagonist ◽  
Recovery From Anesthesia ◽  
High Level ◽  
Camp Levels

Various studies have explored different ways to speed emergence from anesthesia. Previously, we have shown that three drugs that elevate intracellular cAMP (forskolin, theophylline, and caffeine) accelerate emergence from anesthesia in rats. However, our earlier studies left two main questions unanswered. First, were cAMP-elevating drugs effective at all anesthetic concentrations? Second, given that caffeine was the most effective of the drugs tested, why was caffeine more effective than forskolin since both drugs elevate cAMP? In our current study, emergence time from anesthesia was measured in adult rats exposed to 3% isoflurane for 60 min. Caffeine dramatically accelerated emergence from anesthesia, even at the high level of anesthetic employed. Caffeine has multiple actions including blockade of adenosine receptors. We show that the selective A2a adenosine receptor antagonist preladenant or the intracellular cAMP ([cAMP]i)-elevating drug forskolin, accelerated recovery from anesthesia. When preladenant and forskolin were tested together, the effect on anesthesia recovery time was additive indicating that these drugs operate via different pathways. Furthermore, the combination of preladenant and forskolin was about as effective as caffeine suggesting that both A2A receptor blockade and [cAMP]i elevation play a role in caffeine’s ability to accelerate emergence from anesthesia. Because anesthesia in rodents is thought to be similar to that in humans, these results suggest that caffeine might allow for rapid and uniform emergence from general anesthesia in humans at all anesthetic concentrations and that both the elevation of [cAMP]i and adenosine receptor blockade play a role in this response. NEW & NOTEWORTHY Currently, there is no method to accelerate emergence from anesthesia. Patients “wake” when they clear the anesthetic from their systems. Previously, we have shown that caffeine can accelerate emergence from anesthesia. In this study, we show that caffeine is effective even at high levels of anesthetic. We also show that caffeine operates by both elevating intracellular cAMP levels and by blocking adenosine receptors. This complicated pharmacology makes caffeine especially effective in accelerating emergence from anesthesia.

Endogenous myocardial norepinephrine is not essential for ischemic preconditioning in rabbit heart

1996 ◽  
Vol 270 (3) ◽  
pp. H1078-H1084 ◽  
Author(s):  
J. L. Ardell ◽  
X. M. Yang ◽  
B. A. Barron ◽  
J. M. Downey ◽  
M. V. Cohen
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Rabbit Heart ◽  
Chemical Sympathectomy ◽  
Single Cycle ◽  
Risk Zone ◽  
Regional Ischemia ◽  
Norepinephrine Content ◽  
Ischemic Period

To determine whether endogenous cardiac catecholamines mediate ischemic preconditioning (PC) in the rabbit heart, myocardial catecholamines were depleted by reserpine (5 mg/kg, 18-24 h pre-PC) or surgical sympathectomy (2 wk pre-PC). In vivo hearts were subjected to 30 min of regional ischemia and 3 h of reperfusion. PC involved either one or four cycles of 5-min ischemia and 10-min reperfusion before the 30-min ischemic period. Right ventricular norepinephrine content (pmol/mg protein), 51.4 +/- 11.1 in untreated rabbits, was reduced to 0.6 +/- 0.2 and 1.8 +/- 0.5 by surgical sympathectomy and reserpine, respectively. Infarct size (IS) was measured by tetrazolium and expressed as percentage of the risk zone. In untreated animals exposed solely to 30 min of regional ischemia IS was 35.5 +/- 1.6% and was unchanged by reserpine (43.3 +/- 5.4%) or surgical sympathectomy (33.4 +/- 3.5%). compared with infarction in the respective non-PC controls, IS in untreated (7.4 +/- 1.5%, P < 0.0001) and surgically sympathectomized (11.2 +/- 1.5%, P < 0.0001) animals was significantly diminished by a single cycle of PC, but the latter exerted less protection in reserpinized animals (27.6 +/- 3.5%, P < 0.0025). Four cycles of PC, however, reduced IS to 10.3 +/- 1.2% in reserpinized animals. Therefore, despite comparable depression of myocardial norepinephrine content, surgical and chemical sympathectomy had different effects on the level of protection afforded by ischemic PC. These data demonstrate that endogenous myocardial catecholamines are not essential for protection from PC in the rabbit.

scholarly journals Effects of an adenosine-receptor antagonist on insulin-resistance in soleus muscle from obese Zucker rats

1984 ◽  
Vol 221 (3) ◽  
pp. 915-917 ◽  
Author(s):  
R A Challis ◽  
L Budohoski ◽  
B McManus ◽  
E A Newsholme
Keyword(s):  
Insulin Resistance ◽  
Receptor Antagonist ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Glucose Utilization ◽  
Glycogen Synthesis ◽  
Zucker Rats ◽  
Adenosine Receptor Antagonist ◽  
Obese Rats ◽  
Obese Zucker Rats

The decreased sensitivity of glycolysis to insulin seen in isolated soleus muscles from genetically obese Zucker rats was abolished by addition of the adenosine-receptor antagonist 8-phenyltheophylline to the incubation medium; 8-phenyltheophylline had no effect on the sensitivity of glycogen synthesis to insulin. These findings suggest that changes in the sensitivity of glucose utilization by muscles of genetically obese rats may be explained, in part, by a modification in either the concentration of adenosine or the affinity of adenosine receptors in skeletal muscle.

Adenosine-enhanced ischemic preconditioning: adenosine receptor involvement during ischemia and reperfusion

2001 ◽  
Vol 280 (2) ◽  
pp. H591-H602 ◽  
Author(s):  
James D. McCully ◽  
Yoshiya Toyoda ◽  
Masahisa Uematsu ◽  
Robert D. Stewart ◽  
Sidney Levitsky
Keyword(s):  
Infarct Size ◽  
Functional Recovery ◽  
Ischemic Preconditioning ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Ischemia And Reperfusion ◽  
Infarct Size Reduction

Adenosine-enhanced ischemic preconditioning (APC) extends the cardioprotection of ischemic preconditioning (IPC) by both significantly decreasing myocardial infarct size and significantly enhancing postischemic functional recovery. In this study, the role of adenosine receptors during ischemia-reperfusion was determined. Rabbit hearts ( n = 92) were used for Langendorff perfusion. Control hearts were perfused for 180 min, global ischemia hearts received 30-min ischemia and 120-min reperfusion, and IPC hearts received 5-min ischemia and 5-min reperfusion before ischemia. APC hearts received a bolus injection of adenosine coincident with IPC. Adenosine receptor (A1, A2, and A3) antagonists were used with APC before ischemia and/or during reperfusion. GR-69019X (A1/A3) and MRS-1191/MRS-1220 (A3) significantly increased infarct size in APC hearts when administered before ischemia and significantly decreased functional recovery when administered during both ischemia and reperfusion ( P < 0.05 vs. APC). DPCPX (A1) administered either before ischemia and/or during reperfusion had no effect on APC cardioprotection. APC-enhanced infarct size reduction is modulated by adenosine receptors primarily during ischemia, whereas APC-enhanced postischemic functional recovery is modulated by adenosine receptors during both ischemia and reperfusion.

scholarly journals Ticagrelor alleviates sepsis-induced myocardial injury via an adenosine-dependent pathway in a mouse sepsis model

2020 ◽  
Vol 43 (4) ◽  
pp. E44-55
Author(s):  
Shengxing Tang ◽  
Cong Fu ◽  
Qiancheng Xu ◽  
Wenjun Guo ◽  
Yuhan Cao
Keyword(s):  
Western Blot ◽  
Protective Effect ◽  
Receptor Antagonist ◽  
Adenosine Receptor ◽  
Myocardial Injury ◽  
Cardiomyocyte Apoptosis ◽  
Tunel Staining ◽  
Myocardial Tissue ◽  
Adenosine Receptor Antagonist ◽  
Tnf Α

Purpose: The purpose of this study was to determine whether ticagrelor, a classic anti-platelet drug, has a therapeutic effect on sepsis-induced myocardial injury. Methods: The C57BL6J mice received oral ticagrelor (10, 25 and 50 mg/kg) for seven days after which cecum ligation and puncture (CLP) were performed. An adenosine-receptor antagonist (CGS15943) was administered two hours before CLP. After 24 h, cardiac function was measured using cardiac echocardiography, then the heart and blood were collected. Hematoxylin and eosin (HE) staining and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL staining) were used to observe pathological changes and cardiomyocyte apoptosis. Plasma concentration of TNF-α, IL-6 and adenosine and myocardial tissue levels of TNF-α and IL-6 were determined. Survival analysis was performed. Western blot was used to determine the expression of a signalling protein in the myocardial tissue. Results: The HE and TUNEL staining showed less inflammatory cell infiltration and less cardiomyocyte apoptosis in the ticagrelor group. Cardiac echocardiography showed preserved heart function in the ticagrelor group. Plasma TNF-α, IL-6 and relative expression of TNF-α and IL-6 in myocardial tissue were significantly lower in the ticagrelor group. Plasma adenosine levels were significantly higher in the ticagrelor group. Adenosine-receptor antagonists significantly blocked the protective effect of ticagrelor. Ticagrelor reduced the mortality of sepsis mice, and this reduction was blocked by the adenosine-receptor antagonist. Western blot showed that ticagrelor activated the phosphorylation of AKT and mTOR. Adenosine-receptor antagonists inhibited the activation of AKT and mTOR. Conclusion: The protective effect of ticagrelor was dependent on adenosine-receptor activation, with downstream upregulation of phosphorylation of AKT and mTOR.

Interactions between alpha-adrenoceptors and adenosine receptors on microvascular smooth muscle

1991 ◽  
Vol 260 (5) ◽  
pp. H1655-H1666 ◽  
Author(s):  
K. Nishigaki ◽  
J. E. Faber ◽  
M. Ohyanagi
Keyword(s):  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Receptor Stimulation ◽  
Alpha Adrenoceptors ◽  
Adenosine Receptor Antagonist ◽  
Adenosine Receptor Agonist ◽  
Muscle Concentration ◽  
Tissue Acidosis

alpha 2-Adrenoceptor but not alpha 1-adrenoceptor constriction of arterioles is selectively inhibited by tissue acidosis, ischemia, and increased metabolic rate. To further examine neural-local interactions, we studied the effect of adenosine receptor stimulation on alpha 1- or alpha 2-adrenoceptor constriction. Intravital microscopy was used to study large arterioles (133 +/- 3 microns diam; mean +/- SE), small arterioles (16 +/- 1 microns), and large venules (178 +/- 3 microns) of rat cremaster skeletal muscle. Concentration-response (diameter change) curves were obtained for bath-added norepinephrine in the presence of either rauwolscine or prazosin to provide selective alpha 1- and alpha 2-constriction, respectively. The adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (2.24 x 10(-8) M) significantly attenuated both alpha 1- and alpha 2-constriction by 5- to 20-fold; alpha 1-constriction was three- to fourfold more sensitive than alpha 2-constriction. Similar inhibitory effects were obtained with adenosine (2.24 x 10(-6) M). The adenosine receptor antagonist 8-[4-[N(2-aminoethyl)carbamoylmethoxy]phenyl]-1,3-dipropylxanthine (0.7 microM) reversed the inhibitory effect of adenosine, which implicates extracellular A2 adenosine receptors. Intrinsic tone in large vessels was unaffected by adenosine receptor stimulation but was completely inhibited in small arterioles. These findings suggest that both alpha 2- and especially alpha 1-adrenoceptor constriction and intrinsic tone (of small but not large arterioles) are inhibited by physiologically relevant concentrations of adenosine.

scholarly journals Increases in Interstitial Adenosine and Cerebral Blood Flow with Inhibition of Adenosine Kinase and Adenosine Deaminase

1993 ◽  
Vol 13 (2) ◽  
pp. 201-207 ◽  
Author(s):  
Veronica M. Sciotti ◽  
David G. L. Van Wylen
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Adenosine Deaminase ◽  
Adenosine Receptor ◽  
Kinase Inhibitor ◽  
Adenosine Kinase ◽  
The Other ◽  
Brain Microdialysis ◽  
Receptor Blockade ◽  
Adenosine Receptor Antagonist

The purpose of this study was to determine the changes in interstitial fluid (ISF) adenosine and cerebral blood flow (CBF) during inhibition of adenosine kinase or adenosine deaminase. Brain microdialysis was used to (a) measure CBF (H2 clearance), (b) sample cerebral ISF, and (c) deliver drugs locally to the brain. Microdialysis probes were implanted bilaterally in the caudate nucleus of halothane-anesthetized rats ( n = 11). One probe was perfused with artificial cerebrospinal fluid (CSF) containing iodotubercidin (IODO), an adenosine kinase inhibitor, while the other probe was perfused with erythro-2-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase inhibitor. Both probes were subsequently perfused with EHNA + IODO. Finally, 8-( p-sulfophenyl)theophylline (SPT), an adenosine receptor antagonist, was added to EHNA + IODO in one probe, while the other probe continued to receive only EHNA + IODO. CBF and dialysate adenosine levels increased with either EHNA or IODO; however, the increases were greater with IODO. EHNA + IODO further increased CBF and dialysate adenosine. The hyperemia observed with EHNA + IODO was abolished by adenosine receptor blockade. These data suggest that basal adenosine levels are influenced to a greater extent by adenosine kinase than by adenosine deaminase. In addition, the increased CBF observed with inhibition of adenosine metabolism and the attenuation of this vasodilatory response with adenosine receptor blockade support a role for adenosine in CBF regulation.

scholarly journals Adenosine kinase inhibition protects against cisplatin-induced nephrotoxicity

2019 ◽  
Vol 317 (1) ◽  
pp. F107-F115 ◽  
Author(s):  
Wei Cao ◽  
Yanggang Yuan ◽  
Xi Liu ◽  
Qing Li ◽  
Xiaofei An ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Receptor Antagonist ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion ◽  
Adenosine Kinase ◽  
Extracellular Adenosine ◽  
Adenosine Receptor Antagonist ◽  
Cardiovascular Side Effects

Numerous studies have demonstrated that several mechanisms, including oxidative stress, DNA damage, and inflammatory responses, are closely linked to cisplatin-induced nephrotoxicity. Adenosine, emerging as a key regulatory molecule, is mostly protective in the pathophysiology of inflammatory diseases. A previous study showed that some of the adenosine receptors led to renal protection against ischemia-reperfusion injury. However, these adenosine receptor agonists lack a useful therapeutic index due to cardiovascular side effects. We hypothesized that inhibition of adenosine kinase (ADK) might exacerbate extracellular adenosine levels to reduce cisplatin-induced renal injury. In the present study, pretreatment with the ADK inhibitor ABT-702 could markedly attenuate cisplatin-induced acute kidney injury, tubular cell apoptosis, oxidative stress, and inflammation in the kidneys. Consistent with in vivo results, inhibition of ADK suppressed cisplatin-induced apoptosis, reactive oxygen species production, and inflammation in HK2 cells. Additionally, the protective effect of ADK inhibition was abolished by A1 or A2B adenosine receptor antagonist and enhanced by A2A or A3 adenosine receptor antagonist. Collectively, the results suggest that inhibition of ADK might increase extracellular adenosine levels, which inhibited cisplatin-induced oxidative stress and inflammation via A1 and A2B adenosine receptors, finally suppressing cisplatin-induced cell apoptosis. Pharmacological therapies based on ADK will be of potential use in therapy of cisplatin-induced nephrotoxicity.

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