Single or multiple brief periods of ischemia (preconditioning) have been shown to protect the myocardium from infarction after a subsequent more prolonged ischemic insult. To test hypothesis that preconditioning is result opening ATP-sensitive potassium (KATP) channels, selective KATP channel antagonist, glibenclamide, was administered before immediately in barbital-anesthetized open-chest dogs subjected 60 minutes left circumflex coronary artery (LCX) occlusion followed by 5 hours...

The plant-derived cannabinoids Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD) both have immunosuppressive effects; although some effects of THC are mediated by the CB 2 receptor, binds CBD weakly. In examining on microglial proliferation, we found that these compounds potently inhibit [ 3 H]thymidine incorporation into a murine cell line with no effect cycle. Treatment decreased uptake microglia, IC 50 values match inhibition DNA. and, less potently, H]adenosine to similar extent as...

The objective of the present study was to characterize role adenosine in myocardial ischemic preconditioning canine heart. Preconditioning with 5 min ischemia resulted a marked reduction infarct size after 60 left circumflex coronary artery occlusion and h reperfusion barbital-anesthetized dogs compared that were not preconditioned (4.8 +/- 1.9 vs. 27.9 4.5%; P < 0.05). Pretreatment either nonselective receptor antagonist PD 115199 or selective A1 8-cyclopentyl-1,3-dipropylxanthine...

Journal Article Blockade of ischaemic preconditioning in dogs by the novel ATP dependent potassium channel antagonist sodium 5-hydroxydecanoate Get access John A Auchampach, Auchampach Department Pharmacology and Toxicology, Medical College Wisconsin, 8701 Waterdown Plank Road, Milwaukee, WI 53226, USA: J G Gross; Bristol-Myers Squibb, Princeton, New Jersey, Grover. Correspondence to Dr Gross. Search for other works this author on: Oxford Academic PubMed Google Scholar Gary Grover, Grover...

Using conscious rabbits, we examined the effect of ischemic preconditioning (PC) on p44 and p42 mitogen-activated protein kinases (MAPKs). We found that both isoforms contribute significantly to total MAPK activity in heart (in-gel kinase assay: p44, 59 ± 1%; p42, 41 1%). Ischemic PC (6 cycles 4-min occlusion/4-min reperfusion) elicited a pronounced increase cellular (+89%). This increase, which occurred exclusively nuclear fraction, was contributed by +97%; +210%) accompanied migration two...

We cloned and characterized the canine A₃ adenosine receptor (AR) examined AR-induced degranulation of BR line mastocytoma cells. Canine A₃AR transcript is found predominantly in spleen, lung, liver, testes encodes a 314-amino acid heptahelical receptor.¹²⁵I-<i>N</i>⁶-Aminobenzyladenosine binds to two affinity states with<i>K</i>_<i>D</i> values 0.7 ± 0.1 16 0.8 nm, reflecting G protein-coupled -uncoupled receptors, respectively. Xanthine...

Adenosine is elaborated in injured tissues where it suppresses inflammatory responses of essentially all immune cells, including production proinflammatory cytokines such as tumor necrosis factor-α (TNF-α). Most the anti-inflammatory actions adenosine have been attributed to signaling through A_2A receptor (A_2AAR). Previously, however, has shown that A₃AR agonist <i>N</i>⁶-(3-iodobenzyl)adenosine-5′-<i>N</i>-methylcarboxamide (IB-MECA) potently...

BACKGROUND Several recent studies suggest that activation of ATP-dependent potassium (K(ATP)) channels in the myocardium plays an important cardioprotective role during ischemia. The present study was undertaken to examine further this ion channel vivo a model "stunned" myocardium. METHODS AND RESULTS Barbital-anesthetized dogs were subjected 15 minutes left anterior descending (LAD) coronary artery occlusion followed by 3 hours reperfusion. Regional myocardial blood flow measured...

Abstract To examine the cardioprotective role of A 3 adenosine receptors during myocardial ischemia/reperfusion injury, we tested effect N 6 -(3-iodobenzyl)adenosine-5′- -methyluronamide (IB-MECA), a potent and selective receptor agonist, in models stunning infarction chronically instrumented conscious rabbits. In phase I (studies stunning), rabbits were subjected to six 4-minute coronary occlusions, each separated by reperfusion periods, after which recovery systolic wall thickening was...

purpose. Cannabidiol (CBD), a nonpsychotropic, nontoxic compound has been shown to block diabetes- and endotoxin-induced retinal damage. However, the protective mechanism of this anti-inflammatory cannabinoid is not completely understood. The goal study determine role adenosine signaling in inflammation its potential modulation by CBD. methods. receptor (AR) subtypes expressed rat microglial cells were assessed quantitative real-time RT-PCR. AR function was determined via vitro vivo...

Inhibition of adenosine receptors could reduce metastasis by enhancing prenylation-dependent signaling that promotes cell-cell adhesion.

(N)-Methanocarba adenosine 5'-methyluronamides containing known A(3) AR (adenosine receptor)-enhancing modifications, i.e., 2-(arylethynyl)adenine and N(6)-methyl or N(6)-(3-substituted-benzyl), were nanomolar full agonists of human (h) A(3)AR highly selective (K(i) ∼0.6 nM, 2-(halophenylethynyl) analogues 13 14). Combined 2-arylethynyl-N(6)-3-chlorobenzyl substitutions preserved affinity/selectivity in the (N)-methanocarba series (e.g., 3,4-difluoro agonist MRS5698 31, K(i) 3 mouse A(3))...

Abstract —We investigated whether activation of A 1 or 3 adenosine receptors (ARs) induces late preconditioning (PC) against infarction in conscious rabbits using the selective AR agonists 2-chloro- N 6 -cyclopentyladenosine (CCPA) and -3-iodobenzyladenosine-5′- -methylcarboxamide (IB-MECA). In vitro radioligand binding cAMP assays demonstrated CCPA to be ≈200- 400-fold for rabbit IB-MECA ≈20-fold AR. We observed that (1) pretreatment 24 hours earlier with (100 μg/kg IV bolus) 300 μg/kg)...

The objective of the present study was to determine effect a novel K+ channel opener, Aprikalim (RP 52891; [trans-(-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothio-pyran carbothiamide-1-oxide]), on myocardial infarct size in barbital-anesthetized dogs subjected 90 min left circumflex coronary artery occlusion followed by 5 hr reperfusion. To if RP 52891 is mediating its effects opening adenosine triphosphate regulated potassium channels (KATP), glibenclamide, KATP antagonist used. Dogs were...

The objective of this study was to determine whether ATP-dependent potassium channel activation is involved in the mechanism by which nicorandil reduces postischemic contractile dysfunction produced a brief period ischemia (myocardial stunning). Barbital-anesthetized dogs were subjected 15-min left anterior descending (LAD) coronary artery occlusion followed 3-h reperfusion. Saline or (100 micrograms/kg + 25 micrograms/kg/min) infused 15 min before and throughout with without addition KATP...

We used pharmacological agents and genetic methods to determine whether the potent A₃ adenosine receptor (AR) agonist 2-chloro-<i>N</i>⁶-(3-iodobenzyl)adenosine-5′-<i>N</i>-methylcarboxamide (Cl-IB-MECA) protects against myocardial ischemia/reperfusion injury in mice via A₃AR or interactions with other AR subtypes. Pretreating wild-type (WT) Cl-IB-MECA reduced infarct size induced by 30 min of coronary occlusion 24 h reperfusion at doses (30 100 μg/kg) that...

The role of endothelial nitric oxide synthase (eNOS) in isoflurane postconditioning (IsoPC)-elicited cardioprotection is poorly understood. authors addressed this issue using eNOS mice.In vivo or Langendorff-perfused mouse hearts underwent 30 min ischemia followed by 2 h reperfusion the presence and absence produced with 5 before 3 after reperfusion. Ca+-induced mitochondrial permeability transition (MPT) pore opening was assessed isolated mitochondria. Echocardiography used to evaluate...

We examined the cardioprotective profile of new A₃ adenosine receptor (AR) agonist CP-532,903 [<i>N</i>⁶-(2,5-dichlorobenzyl)-3′-aminoadenosine-5′-<i>N</i>-methylcarboxamide] in an vivo mouse model infarction and isolated heart global ischemia/reperfusion injury. In radioligand binding cAMP accumulation assays using human embryonic kidney 293 cells expressing recombinant ARs, was found to bind with high affinity A₃ARs (<i>K</i>_i = 9.0 ± 2.5 nM)...

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This study describes the localization and computational prediction of a binding site for A₃ adenosine receptor (A₃AR) positive allosteric modulator 2-cyclohexyl-1<i>H</i>-imidazo[4,5-c]quinolin-4-(3,4-dichlorophenyl)amine (LUF6000). The work reveals an extrahelical lipid-facing pocket disparate from orthosteric that encompasses transmembrane domain (TMD) 1, TMD7, Helix (H) 8, which was predicted by molecular modeling validated mutagenesis. According to model, nearly...

The effects of nicorandil, a nicotinamide nitrate with K+-channel-opening activity, was investigated in several models ischemia-reperfusion injury conscious and anesthetized dogs or isolated buffer-perfused rat hearts. In reversible ischemic (stunned myocardium) dogs, nicorandil resulted an enhanced recovery regional systolic shortening during reperfusion after single episode coronary artery occlusion (10–15 min). These beneficial actions were not shared by the nitrovasodilator sodium...