• Biomolecules & Therapeutics
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• v.13 no.3
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• pp.138-142
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• 2005

Adenosine and GABA are known to be major inhitory neurotransmitters in the central nervous system and its receptors mediate various neurophamacological effects including cardiovascular modulatory effects. Inhibitory cardiovascular effects induced by intrathecal (i.t.) administration of adenosine $A_1$ receptor agonist and its modulation by cyclic AMP was suggested by our previous report. In this experiment, we examined the modulation of cardiovascular effects of adenosine $A_1$ receptor and adenosine $A_2$ receptor by $GABA_B$ receptors antagonist in the spinal cord. I.t. administration of 10 nmol of $N^6$-cyclohexyladenosine (CHA, an adenosine $A_1$ receptor agonist), I.t. administration of 2 nmol of 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA, an adenosine $A_2$ receptor agonist), pretreatment with 5-aminovaleric acid (a $GABA_B$ receptor antagonist, 50 nmol, i.t.) prior to administration of CHA and pretreatment with 5-aminovaleric acid (a $GABA_B$ receptor antagonist, 50 nmol, i.t.) prior to administration of CPCA were performed in anesthetized, artificially ventilated Sprague-Dawley rats. I.t. administration of 50 nmol of 5-aminovaleric acid significantly attenuated the inhibitory cardiovascular effects of CHA but did not attenuated the inhibitory cardiovascular effects of CPCA. It is suggested that cardiovascular responses of adenosine $A_1$ receptor is modulated by $GABA_B$ receptor and adenosine $A_2$ receptor is not modulated by $GABA_B$ receptor in the spinal cord.

• The Korean Journal of Pharmacology
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• v.30 no.2
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• pp.181-190
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• 1994

In rat atrium the characteristics of purinergic receptors were investigated by observing the effects of some purinergic receptor agonists and antagonists on action potential and contractile force. The statistically significant effects of $ATP(10^{-6}{\sim}10^{-3}M)$ and adenosine $(10^{-6}{\sim}10^{-3}M)$ on normal action potential characteristics were a dose-dependent shortening of action potential duration $(APD_{90})$ by both agents and hyperpolarization by $ATP(10^{-4},10^{-3}M)$. $CAP(10^{-8}{\sim}10^{-4}M)$, an $A_1$ adenosine receptor agonist, shortened $(APD_{90})$ markedly in a dose-dependent manner and these effects were almost abolished by $DPCPX\;(10^{-6}\;M), an $A_1$, adenosine receptor antagonist, but not affected by $DMPX(2{\times}10^{-6}\;M)$, an $A_2$ adenosine receptor agonist. On the other hand, CGS $21680(10^{-7}{\sim}10^{-4}M)$, an $A_2$ adenosine receptor agonist, elicited a slight shortening of $(APD_{90})$ and these effects were inhibited by DPCPX but persisted in the presence of DPMX. Adenosine $(10^{-6}{\sim}10{\-4}\;M)$ decreased the basal contraction of atrial muscle in a dose-dependent manner and these effects were not inhibited by DMPX but by DPCPX. These results suggests that purinergic receptor agonists depress the cardiac activity by a short ening of action potential duration and this effect is mostly mediated by $A_1$ adenosine receptors in rat atrium.

• Biomolecules & Therapeutics
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• v.12 no.2
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• pp.68-73
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• 2004

This study was performed to investigate the regulatory mechanism of cerebral blood How of adenosine $A_2$ receptor agonist in the rats, and to define whether its mechanism is mediated by nitric oxide (NO), adenylate cyclase and guanylate cyclase. In pentobarbital-anesthetized, pancuronium-paralyzed and artificially ventilated male Sprague-Dawley rats, all drugs were applied topically to the cerebral cortex. Blood flow from cerebal cortex was measured using laser-Doppler flowmetry. Topical application of an adenosine $A_2$ receptor agonist [5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA; 4 umol/l)] increased cerebral blood flow. This effect of CPCA (4 umol/l) was blocked by pretreatment with NO synthase inhibitor [$N^G$-nitro-L-argine methylester (L-NAME; 140 umol/l)] and adenylate cyclase inhibitor [MDL-12,330 (20 umol/l)]. But the effect of CPCA (4 umol/l) was not blocked by pretreatment with guanylate cyclase inhibitor [LY-83,583 (10 umol/l)]. These results suggest that adenosine $A_2$ receptor increases cerebral blood How. It seems that this action of adenosine $A_2$ receptor is mediated via the NO and the activation of adenylate cyclase in the cerebral cortex of the rats.

• Biomolecules & Therapeutics
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• v.12 no.2
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• pp.108-113
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• 2004

This study was performed to investigate the regulatory mechanism of cerebral blood flow of adenosine $A_{2B}$ receptor agonist in the rats, and to define whether its mechanism is mediated by adenylate cyclase and guanylate cyclase. in pentobarbital-anesthetized, pentobrabital-paralyzed and artificially ventilated male Sprague-Dawley rats, all drugs were applied topically to the cerebral cortex. Blood How from cerebral cortex was measured using laser-Doppler flowmetry. Topical application of an adenosine $A_{2B}$ receptor agonist, 5'-N-ethylcar-boxamidoadenosine (NECA; 4 umol/l) increased cerebral blood flow. This effect of NECA (4 umol/l) was not blocked by pretreatment with adenylate cyclase inhibitor, MDL-12330 (20 umol/l). But effect of NECA (4 umol/l) was blocked by pretreatment with guanylate cyclase inhibitor, LY-83383 (10 umol/l). These results suggest that adenosine $A_{2B}$ receptor increases cerebral blood flow. It seems that this action of adenosine $A_{2B}$ receptor is mediated via the activation of guanylate cyclase in the cerebral cortex of the rats.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.1
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• pp.31-39
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• 1998

As it has been reported that the depolarization induced acetylcholine (ACh) release is modulated by activation of presynaptic $A_1$ adenosine heteroreceptor and various lines of evidence suggest the $A_2$ adenosine receptor is present in the hippocampus. The present study was undertaken to delineate the role of adenosine receptors on the hippocampal ACh release. Slices from the rat hippocampus were equilibrated with $[^3H]choline$ and then the release amount of the labelled product, $[^3H]ACh$, which was evoked by electrical stimulation (rectangular pulses, 3 Hz, 2 ms, 24 mA, $5\;V/cm^{-1}$, 2 min), was measured, and the influence of various adenosine receptor-related agents on the evoked tritium outflow was investigated. And also, the drug-receptor binding assay was performed in order to confirm the presence of $A_1$ and $A_2$ adenosine receptors in the rat hippocampus. N-ethylcarboxamidoadenosine (NECA), a potent adenosine receptor agonist with nearly equal affinity at $A_1$ and $A_2$ adenosine receptors, in concentrations ranging from $1{\sim}30\;{\mu}M$, decreased the electrically-evoked $[^3H]ACh$ release in a concentration-dependent manner without affecting the basal rate of release. And the effect of NECA was significantly inhibited by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 2 ${\mu}M$), a selective $A_1$ adenosine receptor antagonist, but was not influenced by 3,7-dimethyl-1-propargylxanthine (DMPX, 5 ${\mu}M$), a specific $A_2$ adenosine receptor antagonist. $N^6-cyclopentyladenosine$ (CPA), a selective $A_1$ adenosine receptor agonist, in doses ranging from 0.1 to 10 ${\mu}M$, reduced evoked $[^3H]ACh$ release in a dose-dependent manner without the change of the basal release. And the effect of CPA was significantly inhibited by 2 ${\mu}M$ DPCPX treatment. 2-P-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680C), a potent $A_2$ adenosine receptor agonist, in concentrations ranging from 0.1 to 10 ${\mu}M$, did not alter the evoked ACh release. In the drug-receptor binding assay, the binding of $[^3H]2-chloro-N^6-cyclopentyladenosine$ ($[^3H]$CCPA) to the $A_1$ adenosine receptor of rat hippocampal membranes was inhibited by CPA ($K_i$ = 1.22 nM), NECA ($K_i=10.17 nM$) and DPCPX ($K_i=161.86 nM$), but not by CGS-21680C ($K_i=2,380 nM$) and DMPX ($K_i=22,367 nM$). However, the specific binding of $[^3H]CGS-21680C$ to the $A_2$ adenosine receptor was not observed. These results suggest that the $A_1$ adenosine heteroreceptor play an important role in evoked ACh release, but the presence of $A_2$ adenosine receptor is not confirmed in this study.

• Biomolecules & Therapeutics
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• v.13 no.1
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• pp.35-40
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• 2005

This study was performed to investigate the regulatory mechanism of cerebral blood flow of adenosine A$_{2B}$ receptor agonist in the rats, and to define whether its mechanism is mediated by adenylate cyclase, guanylate cyclase and potassium channel. In pentobarbital-anesthetized, pancuronium-paralyzed and artificially ventilated male Sprague-Dawley rats, all drugs were applied topically to the cerebral cortex. Blood flow from cerebral cortex was measured using laser-Doppler flowmetry. Topical application of an adenosine A$_{2B}$ receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA; 4 umol/I) increased cerebral blood flow. This effect of NECA (4 umol/I) was not blocked by pretreatment with adenylate cyclase inhibitor, MDL-12,330 (20 umol/I). But effect of NECA (4 umol/I) was blocked by pretreatment with guanylate cyclase inhibitor, LY-83,583 (10 umol/I) and pretreatment with ATP-sensitive potassium channel inhibitor, glipizide (5 umol/I). These results suggest that adenosine A$_{2B}$ receptor increases cerebral blood flow. It seems that this action of adenosine A$_{2B}$ receptor is mediated via the activation of guanylate cyclase and ATP-sensitive potassium channel in the cerebral cortex of the rats.

• The Korean Journal of Physiology
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• v.30 no.1
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• pp.85-96
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• 1996

Adenosine and its analogues are known to possess analgesic effects and to be involved in the opiate-induced antinociception as well. This study was designed to investigate the effects of three adenosine agonists, 5'- (N-cyclopropyl) -carboxamidoadenosine(CPCA), 5'-N-ethylcarboxamidoadeno-sine (NECA) and $N^6-cyclohexyladenosine$ (CHA) on the signal transmission in the spinal cord and also to elucidate mechanisms of their actions in the anesthetized cat. All the tested adenosine agonists(i.v,) exerted inhibitory effects on the responsiveness of the wide dynamic range (WDR) cells, the inhibitory action of CHA, an adenosine $A_1$ receptor agonist, $(80{\mu}g/Kg)$ being most weak. The intravenous CPCA, an adenosine $A_2$ receptor agonist, $(20{\mu}g\;/Kg)$ and NECA, nonspecific adenosine receptor agonist, $(20{\mu}g\;/Kg)$ inhibited the responses of WDR cells to pinch and C fiber stimulation more strongly than those to brush and A fiber stimulation. CPCA (i.v.) also suppressed the responses of WDR cells to thermal stimulus. And all the CPCA-induced inhibitions were caffeine-reversible. When CPCA was directly applied onto the spinal cord or intravenously administered into the spinal cat, on average, about three quarters of the CPCA-induced inhibitory effect was abolished. On the other hand, in the animal with spinal lesions in the ipsilateral dorsolateral area, the CPCA-induced inhibition was comparable to that observed in the spinal cats. In conclusion, this study shows that adenosine agonists strongly suppress the responses of WDR cells to pinch, C fiber stimulation and thermal stimuli mainly through the supraspinal adenosine $A_2-receptors$.

• Biomolecules & Therapeutics
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• v.16 no.4
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• pp.320-327
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• 2008

Several lines of evidence indicate that adenosine $A_{2A}$ agonist disrupts spatial working memory. However, it is unclear which stages of learning and memory are affected by the stimulation of adenosine $A_{2A}$ receptor. To clarify these points, we employed CV-1808 as adenosine $A_{2A}$ agonist and investigated its effects on acquisition, consolidation, and retrieval phases of learning and memory using passive avoidance and the Morris water maze tasks. During the acquisition phase, CV-1808 (2-phenylaminoadenosine, 1 and 2 mg/kg, i.p.) decreased the latency time in passive avoidance task and the mean savings in the Morris water maze task, respectively. During the consolidation and retrieval phase tests, CV-1808 did not exhibited any effects on latency time in passive avoidance task and the mean savings in the Morris water maze task. These results suggest that CV-1808 as an adenosine $A_{2A}$ agonist impairs memory acquisition but not consolidation or retrieval.

• Biomolecules & Therapeutics
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• v.14 no.2
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• pp.119-124
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• 2006

This study was performed to investigate the influence of the spinal adenosine $A_1$ receptors on the central regulation of blood pressure (BP) and heart rate (HR), and to define whether its mechanism is mediated by cyclic AMP (cAMP), cyclic GMP (cGMP) or potassium channel. Intrathecal (i.t.) administration of drugs at the thoracic level were performed in anesthetized, artificially ventilated male Sprague-Dawley rats. I.t. injection of adenosine $A_1$ receptor agonist, $N^6$-cyclohexyladenosine (CHA; 1, 5 and 10 nmol) produced dose dependent decrease of BP and HR and it was attenuated by pretreatment of 50 nmol of 8-cyclopentyl-1,3-dimethylxanthine, a specific adenosine $A_1$ receptor antagonist. Pretreatment with a cAMP analogue, 8-bromo-cAMP, also attenuated the depressor and bradycardiac effects of CHA (10 nmol), but not with cGMP analogue, 8-bromo-cGMP. Pretreatment with a ATP-sensitive potassium channel blocker, glipizide (20 nmol) also attenuated the depressor and bradycardiac effects of CHA (10 nmol). These results suggest that adenosine $A_1$ receptor in the spinal cord plays an inhibitory role in the central cardiovascular regulation and that this depressor and bradycardiac actions are mediated by cAMP and potassium channel.

• Biomolecules & Therapeutics
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• v.13 no.2
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• pp.95-100
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• 2005

This study was performed to investigate the mechanism of cerebral blood flow of adenosine $A_{2B}$ receptor agonist in the rats, and to define whether its mechanism is mediated by nitric oxide (NO) and guanylate cyclase. In pentobarbital-anesthetized, pancuronium-paralyzed and artificially ventilated male Sprague-Dawley rats, all drugs were applied topically to the cerebral cortex. Blood flow from cerebral cortex was measured using laser-doppler flowmetry. Topical application of an adenosine $A_{2B}$ receptor agonist, 5'-N-ethylcar-boxamidoadenosine (NECA; $4{\mu}mol/l$) increased cerebral blood flow. This effect of NECA ($4{\mu}mol/l$) was blocked by pretreatment with NO synthase inhibitor, $N^G$-nitro-L-argine methvlester (L-NAME; $40{\mu}mol/l$) and guanylate cyclase inhibitor, LY-83,583 ($10{\mu}mol/l$). These results suggest that adenosine $A_{2B}$ receptor increases cerebral blood flow. It seems that this action of adenosine $A_{2B}$ receptor is mediated via the NO and the activation of guanylate cyclase in the cerebral cortex of the rats.