• Biomolecules & Therapeutics
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• 제13권3호
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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 Physiology
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• 제23권2호
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• pp.377-391
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• 1989

Recently it was suggested that the endogenous adenosine might be the mediator for the intercellular communication in the regulation of tubuloglomerular feedback control and renin release. Even though the previous data showed more important regulatory roles in the renal hemodynamics and renin release for the A1 adenosine receptor, it has not yet been settled down about the functional subclassification of renal adenosine receptors. The purpose of the present experiment was to clarify the importance of the renal adenosine receptors for the regulations of the hemodynamic, excretory and secretory functions. Experiments have been done in unanesthetized rabbits. Intrarenal arterial infusion of A1 adenosine antagonist, 8-phenyltheophylline, $3{\sim}30\;nmole/min$, increased urine flow, renal hemodynamics and urinary excretion of sodium. Intrarenal arterial infusion of Al antagonist, 1-3-diethyl-8-phenylxanthine (DPX), $10{\sim}100\;nmole/min$, increased renal hemodynamics and excretory functions. Non-specific adenosine antagonist, theophylline, $30{\sim}300\;nmole/min$, resulted in dose dependent increases in renal hemodynamics and excretory function. All of the three adenosine antagonists for the increases in renal hemodynamics, excretory and secretory functions was 8-phenyltheophylline > DPX > theophylline. These results suggest that the endogenous adenosine is important for the intrinsic regulatory roles for the renal functions through the adenosine receptors, and that the A1 adenosine receptor is more important than the A2 receptor in the regulation of renal hemodynamics, excretory and renin secretory functions.

• The Korean Journal of Physiology and Pharmacology
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• 제1권6호
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• pp.657-664
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• 1997

The effects of adenosine, adenosine A1 receptor antagonist (DPCPX), or NMDA receptor antagonist (APV) on the spontaneous release of $[^3H]-5-hydroxytryptamine$ ($[^3H]-5-HT$) during normoxic/normoglycemic or hypoxic/hypoglycemic period were studied in the rat hippocampal slices. The hippocampus was obtained from the rat brain and sliced $400\;{\mu}m$ thickness with the tissue slicer. After 30 min's preincubation in the normal buffer, the slices were incubated for 30 min in a buffer containing $[^3H]-5-HT$ ($0.1\;{\mu}M,\;74{\mu}Ci/8\;ml$) for uptake, and washed. To measure the release of $[^3H]-5-HT$ into the buffer, the incubation medium was drained off and refilled every ten minutes through sequence of 14 tubes. Induction of glucose/oxygen deprivation (GOD; medium depleting glucose and gassed with 95% $N_2/5%\;CO_2$) was done in 6th and 7th tube. The radioactivities in each buffer and the tissue were counted using liquid scintillation counter and the results were expressed as a percentage of the total radioactivities. When slices were exposed to GOD for 20 mins, the spontaneous release of $[^3H]-5-HT$ was markedly increased and this increase of $[^3H]-5-HT$ release was blocked by adenosine ($10\;{\mu}M$) or DL-2-amino-5-phosphonovaleric acid (APV; $30\;{\mu}M$). Adenosine $A_1$ receptor specific antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) exacerbate GOD-induced increase of spontaneous release of $[^3H]-5-HT$. These results suggest that Adenosine may play a role in the GOD-induced spontaneous release of $[^3H]-5-HT$ through adenosine $A_1$ receptor activity.

• The Korean Journal of Physiology
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• 제24권2호
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• pp.269-280
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• 1990

The purpose of the present experiment was to determine the functional subclassification of renal adenosine receptor fer the hemdynamic, excretory and secretory functions in unanesthetized rabbits. Adenosine antagonist, 8-phenyltheophylline (8-PT) or theophylline, was infused into the left renal artery followed by an infusion of adenosine agonist, cyclohexyladenosine (CHA) or 5'-N-ethylcarboxamidoadenosine (NECA). Intrarenal arterial infusion of CHA or NECA caused decreases in urine volume, glomerular filtration rate, renal plasma flow and excreted amount of electrolytes and renin release in a dose-dependent manner. Dose-response curves in renal function by CHA or NECA was similar and shifted to the right with pretreatment of 8-PT or theophylline. No significant differences in renal response to CHA and NECA in antagonist-treated rabbits were observed. However, the decrease in renin secretion rate was not affected by the adminstration of adenosine antagonists. These results suggest that the renal effect of adenosine receptor agonists appears by way of specific adenosine receptor, but which is not functionally subclassified in the rabbit.

• The Korean Journal of Physiology and Pharmacology
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• 제2권6호
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• pp.753-761
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• 1998

Preconditioning of a heart with small doses of catecholamines induces a tolerance against the subsequent lethal ischemia. The present study was performed to find a specific receptor pathway involved with the catecholamine preconditioning and to test if adenosine plays a role in this cardioprotective effect. Isolated rat hearts, pretreated with small doses of ${\alpha}-\;or\;{\beta}-adrenergic$ agonists/antagonists, were subjected to 20 minutes ischemia and 20 minutes reperfusion by Langendorff perfusion method. Cardiac mechanical functions, lactate dehydrogenase and adenosine release from the hearts were measured before and after the drug treatments and ischemia. In another series of experiments, adenosine $A_1\;or\;A_2$ receptor blockers were treated prior to administration of adrenergic agonists. Pretreatments of a ${\beta}-agonist,\;isoproterenol(10^{-9}{\sim}10^{-7}\;M)$ markedly improved the post-ischemic mechanical function and reduced the lactate dehydrogenase release. Similar cardioprotective effect was observed with an ?-agonist, phenylephrine pretreatment, but much higher $concentration(10^{-4}\;M)$ was needed to achieve the same degree of cardioprotection. The cardioprotective effects of isoproterenol and phenylephrine pretreatments were blocked by a ${\beta}_1-adrenergic$ receptor antagonist, atenolol, but not by an ${\alpha}_1-antagonist,$ prazosin. Adenosine release from the heart was increased by isoproterenol, and the increase was also blocked by atenolol, but not by prazosin. A selective $A_1-adenosine$ receptor antagonist, 1,3-dipropyl-8-cyclopentyl xanthine (DPCPX) blocked the cardioprotection by isoproterenol pretreatment. These results suggest that catecholamine pretreatment protects rat myocardium against ischemia and reperfusion injury by mediation of ${\beta}_1-adrenergic$ receptor pathway, and that adenosine is involved in this cardioprotective effect.

• Biomolecules & Therapeutics
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• 제27권6호
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• pp.584-590
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• 2019

Luteolin, a widespread flavonoid, has been known to have neuroprotective activity against various neurologic diseases such as epilepsy, and Alzheimer's disease. However, little information is available regarding the hypnotic effect of luteolin. In this study, we evaluated the hypnotic effect of luteolin and its underlying mechanism. In pentobarbital-induced sleeping mice model, luteolin (1, and 3 mg/kg, p.o.) decreased sleep latency and increased the total sleep time. Through electroencephalogram (EEG) and electromyogram (EMG) recording, we demonstrated that luteolin increased non-rapid eye movement (NREM) sleep time and decreased wake time. To evaluate the underlying mechanism, we examined the effects of various pharmacological antagonists on the hypnotic effect of luteolin. The hypnotic effect of 3 mg/kg of luteolin was not affected by flumazenil, a GABAA receptorbenzodiazepine (GABAAR-BDZ) binding site antagonist, and bicuculine, a GABAAR-GABA binding site antagonist. On the other hand, the hypnotic effect of 3 mg/kg of luteolin was almost completely blocked by caffeine, an antagonist for both adenosine A1 and A2A receptor (A1R and A2AR), 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1R antagonist, and SCH-58261, an A2AR antagonist. From the binding affinity assay, we have found that luteolin significantly binds to not only A1R but also A2AR with $IC_{50}$ of 1.19, $0.84{\mu}g/kg$, respectively. However, luteolin did not bind to either BDZ-receptor or GABAAR. From these results, it has been suggested that luteolin has hypnotic efficacy through A1R and A2AR binding.

• 대한약리학회지
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• 제30권2호
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• pp.145-152
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• 1994

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 indicate the $A_2-receptor$ is present In hippocampus, this study was undertaken to delineate the role of adenosine receptors on hippocampal ACh release. Slices from the rat hippocampus were equilibrated with $[^3H]-choline$ and the release of the labelled product, $[^3H]-ACh$, which evoked by electrical stimulation(3 Hz, $5\;Vcm^{-1}$, 2 ms, rectangular pulses) was measured, and the influence of various agents on the evoked tritium outflow was Investigated. Adenosine$(0.3{\sim}100\;{\mu}M)$ and CPA$(0.1{\sim}30\;{\mu}M)$ decreased the $[^3H]-ACh$ release in a dose-dependent manner without changing the basal rate of release. DPCPX$(1{\sim}10\;{\mu}M)$, a selective $A_1-receptor$, antagonist, increased the $[^3H]-ACh$ release in a dose related fashion with slight increase of basal tritium release. And the effects of adenosine and CPA were significantly inhibited by $DPCPX(2\;{\mu}M)$ treatment. CPCA, a specific $A_2-agonist$, in concentration ranging from 0.3 to 30 ${\mu}M$, decreased the evoked tritium outflow, and these effects were also abolished by $DPCPX(2\;{\mu}M)$ treatment. But the CPCA effects were not affected by $DMPX(2\;{\mu}M)$, a specific Aa-antagonist, treatment. However, CGS 21680c, a recently introduced potent $A_2-agonist$, in concentration ranging from 0.1 to $10{\mu}M$, did not alter the evoked tritium outflow. These results indicate that the decrement of the evoked ACh release by adenosine is mediated by $A_1-heteroreceptor$, but $A_2-adenosine$ receptor is not involved in ACh release in the rat hippocampus.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1994년도 춘계학술대회 and 제3회 신약개발 연구발표회
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• pp.294-294
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• 1994

To investigate analgesic mechanism of capsaicin and its analogues (capsaicinoids), release of adenosine was measured by high performance liquid chromatography from dorsal spinal cord synaptosomes, Exposure of synaptosomes to K$\^$+/ and morphine produced a dose dependent release of adenosine in the presence of Ca$\^$++/. Capsaicin (0.1, 1, 10 M), and its analogues 6-paradol (1, 10 M), NE-19550 (1, 10, 100 M), DMNE (1, 10, 100 M) and KR 25018 (0.1, 1, 10 M) produced a dose dependent release of adenosine in the presence of Ca$\^$++/. Nifedipine, L-type voltage sensitive calcium channel blocker, inhibited K$\^$+/ (6, 12 mM)- and morphine (10 M)-evoked release of adenosine completely, but inhibited capsaicin, and capsaicinoids-evoked release of adenosine partially. Capsazepine, a novel capsaicin select ive antagonist, blocked only capsaicin and capsaicinoids induced release of adenosine. Therefore, the adenosine release by capsaicin and capsaicinoids having antinociceptive effects involve activation of capsaicin specific receptor and capsaicin sensitive Ca$\^$++/ channel.

• 약학회지
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• 제43권1호
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• pp.55-60
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• 1999

To investigate analgesic mechanism of capsaicin and its analogues (capaicinoids) adenosine release was measured by high performance liquid chromatography from rat spinal cord synaptosomes. Exposure of synaptosomes to $K^+$ and morphine produced a dose dependent release of adenosine in the presence of $Ca^{++}$. Capsaicin (0.1, 1, $10{\;}{\mu}M$), and its analogues: NE-19550 (1, 10, $100{\;}{\mu}M$), DMNE (1, 10, $100{\;}{\mu}M$) and KR 25018 (0.1, 1, $10{\;}{\mu}M$) produced a concentration dependent release of adenosine in the presence of $Ca^{++}$. Nifedifine, L-type voltage sensitive calcium channel blocker, inhibited $K^+$ (6, 12 mM)-and morphine ($10{\;}{\mu}M$)-evoked release of adenosine partially. Capsazepine, a novel capsaicin selective antagonist, blocked only capsaicin and capsaicinoids induced release of adenoside. Therefore, it is suggested that the adenosine release by capsaicin and capsaicinoids having antinociceptive effects involves actvation of capsaicin specific receptor and capsaicin sensitive $Ca^{++}$. channel.

• The Korean Journal of Physiology and Pharmacology
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• 제2권1호
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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.