Activation of adenosine A_1 receptor inhibits glucose-induced cardiomyocyte hypertrophy / 中国药理学通报

Aim To demonstrate the effects and mechanism of adenosine A1 receptor agonist R(-)-N6-(2-phenylisopropyl) adenosine(R-PIA) on high glucose(HG)-induced myocardial hypertrophy by in vitro cultured myocardial cells from neonatal rats.Methods The protein content was assayed by the method of Lowry. The expression of p-ERK1/2 and ERK1/2 was determined by Western blot.The [Ca~(2+)]I transient changes of cell loaded Fura-2/AM were measured by Till image system.Results 1 μmol·L~(-1) R-PIA and U0126 inhibited similarly HG-induced increase of the protein content and [Ca~(2+)]I transient along with the relative expression of p-ERK1/2.These responses were completely abolished by adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine(CPDPX).Conclusion Adenosine A1 receptor stimulation significantly inhibits HG-induced myocardial hypertrophy by mediating ERK1/2 pathway and Ca~(2+).

Effects and Mechanism of Adenosine A_1 Receptor Agonist on Isoproterenol Induced Hypertrophy in Cultured Neonatal Rats Myocardial Cells / 中华高血压杂志

Objective To demonstrate the inhibitory effect of adenosine A_1 receptor agonist R(-)-N6-(2-phe- nylisopropyl) adenosine (R-HA) and cross-talk between adenosine A_1 receptor and CaMKII on Isoproterenol (Iso)- induced hypertrophy in cultured myocardial cells in neonatal rats.Methods The protein synthesis was determined by incorporation of [~3H]-leucine into myocyte protein.The expression of CaMK Ⅱ ? B was determined by Western- blot.The [Ca~(2+)]i transient was measured in myocytes loaded with fura-2 by the spectrofluorometric method. Results R-PIA (1?mol/L) inhibited Iso(10 ?mol/L)-induced increase of [~3 H-]-leucine incorporation [(R-PIA: 974.8?58.6) vs (Iso:1220.8?240.5) count per min per well,P

The Effects of Intrathecal Adenosine A1 Receptor Agonists (R-PIA) on the Morphine Tolerance in a Rat Model of Postoperative Pain / 대한마취과학회지

BACKGROUND: Analgesic tolerance to opioids has been described in both experimental and clinical conditions, which may limit their clinical utility. This study investigated the effects of intrathecal adenosine A1 receptor agonist (R-PIA) on spinal morphine tolerance. METHODS: SD rats were given intrathecal injections of saline 10microliter, R-PIA 10microgram, morphine 10microgram, or R-PIA plus morphine combinations for 7 days (R-PIA given for days 1-7; days 1-3; or days 5-7). Antiallodynic testing using von Frey filaments was carried out before and 30 minutes after the drug injection. On day 8, an antiallodynic dose-response curve was constructed and the 50% effective dose (ED(50)) for morphine (given alone) was calculated for each study group. RESULTS: The coinjection group of R-PIA with morphine blocked the development of tolerance, as shown by the preservation of morphine antiallodynia over 7 days the concomitant decrease in the ED(50) values on day 8, compared with the morphine-alone group. Although additive analgesia over days 1-7 cannot be ruled out, the reductions of the ED(50) in the R-PIA and morphine combination group suggest some suppression of tolerance. CONCLUSIONS: These results suggest that intrathecal R-PIA prevents the development of spinal opioid tolerance. Future studies will be needed to examine the respective roles of supraspinal and peripheral sites of R-PIA and morphine interaction, and to investigate the mechanisms underlying the action of R-PIA on opioid tolerance.

The Effect of ATP-sensitive Potassium Channel on R-PIA Induced Mechanical Antiallodynia in a Peripheral Neuropathic Rat / 대한통증학회지

BACKGROUND: Nerve ligation injury may produce mechanical allodynia, but this can be reversed after an intrathecal administration of adenosine analogues. In many animal and human studies, ATP-sensitive potassium channel blockers have been known to reverse the antinociceptive effect of various drugs. This study was performed to evaluate the mechanical antiallodynic effects of spinal R-PIA (Adenosine A1 receptor agonist) and the reversal of these effects due to pretreatment with glibenclamide (ATP-sensitive potassium channel blocker). Thus, the relationship between the antiallodynic effects of R-PIA and ATP-sensitive potassium channel were investigated in a neuropathic model. METHODS: Male Sprague Dawley rats were prepared by tightly ligating the left lumbar 5th and 6th spinal nerves and implantation of a chronic lumbar intrathecal catheter for drug administration. The mechanical allodynia was measured by applying von Frey filaments ipsilateral to the lesioned hind paw. And the thresholds for paw withdrawal assessed. In study 1, either R-PIA (0.5, 1 and 2microgram) or saline were administered intrathecally for the examination of the antiallodynic effect of R-PIA. In study 2, glibenclamide (2, 5, 10 and 20 nM) was administered intrathecally 5 min prior to an R-PIA injection for investigation of the reversal of the antiallodynic effects of R-PIA. RESULTS: The antiallodynic effect of R-PIA was produced in a dose dependent manner. In study 1, the paw withdrawal threshold was significantly increased with 2microgram R-PIA (P < 0.05). In study 2, the paw withdrawal threshold with 2microgram R-PIA was significantly decreased almost dose dependently by intrathecal pretreatment of 5, 10 and 20 nM glibenclamide (P < 0.05). CONCLUSIONS: These results demonstrated that an intrathecal injection of ATP-sensitive potassium channel blockers prior to an intrathecal injection of adenosine A1 receptors agonist had an antagonistic effect on R-PIA induced antiallodynia. The results suggest that the mechanism of mechanical antiallodynia, as induced by an intrathecal injection of R-PIA, may involve the ATP-sensitive potassium channel at both the spinal and supraspinal level in a rat nerve ligation injury model.

The Mechanical Antiallodynic Effect of intrathecal Morphine and R-Phenylisopropyl-Adenosine in Rats with Spinal Nerve Ligation / 대한마취과학회지

BACKGORUND: A nerve ligation injury may produce a pain syndrome including mechanical allodynia. Usually the antiallodynic effect of morphine is diminished in a neuropathic rat model. However, in a previous study, spinal morphine was found to have an antiallodynic effect in a neuropathic rat model. Therefore, the present study was performed to observe the mechanical antiallodynic effects of spinal morphine and R-PiA, and to investigate the relationship between the two. METHODS: Male SD rats were prepared by tightly ligating the left L5 and L6 spinal nerve and by implanting a lumbar intrathecal catheter. in study 1, each of the 5 groups (morphine at 3 or 10mug, adenosine A1 receptor agonist (R-PiA) at 3 or 10mug, or saline) were administered intrathecally to examine changes in the mechanical allodynia threshold. in study 2, selective adenosine A1 receptor antagonist (DPCPX 10mug) was administered to investigate the reversal of the mechanical antiallodynic effect in the 4 treated groups. in study 3, we observed the pretreatment effect of DPCPX 10mug. The mechanical allodynic thresholds for left hindpaw withdrawal to von Frey hairs were assessed and converted to %MPE. RESULTS: in study 1, the mechanical allodynic threshold was significantly increased in a similar pattern by intrathecal morphine (3, 10mug) and R-PiA (3, 10mug) (P<0.05). in study 2, the allodynic threshold of morphine was insignificantly decreased by intrathecal DPCPX pretreatment. The mechanical allodynic threshold of R-PiA 3mug was decreased by intrathecal DPCPX (P<0.05). in study 3, the antiallodynic effect of morphine was not influenced by DPCPX pretreatment. CONCLUSiONS: intrathecal morphine and R-PiA produced the antiallodynic effect. The antiallodynic effect of morphine was slightly decreased by DPCPX 10mug. Therefore, it was suggested that the antiallodynic effect of morphine might be, at least in part, mediated by adenosine in a rat model of spinal nerve ligation.

The Interaction of Morphine and Adenosine Receptor Agonists on Antiallodynia in Rats with a Nerve Ligation Injury / 대한마취과학회지

BACKGROUND: A Nerve ligation injury may produce a pain syndrome that includes tactile allodynia. Reversal effects on tactile allodynia have been demonstrated after an intrathecal administration of adenosine analogues or morphine. Adenosine receptor agonists have been known to have antinociceptive and antiallodynic effects in many animal and human studies. We examined the drug interactions between morphine and adenosine agonists in a rat model of a nerve ligation injury. METHODS: Male Sprague Dawley rats were prepared with a tight ligation of the left lumbar 5 th and 6 th spinal nerves and chronic lumbar intrathecal catheter implantation for drug administration. We measured the tactile allodynia by applying von Frey filaments ipsilateral to the lesioned hindpaw. Thresholds for paw withdrawal were assessed. Morphine (1 - 30ng), adenosine (1 - 30ng) and R-PIA (0.1 - 10ng) were administered to obtain the dose-response curves and the 50% effective dose (ED50). Fractions of ED50 values were administered to establish the ED50 of drug combinations. Drug interactions were evaluated by the fractional and isobolographic analyses. Allodynic thresholds for left lesioned hindpaw withdrawal to the von Frey hairs test were assessed and converted to % maximal possible effect (%MPE). RESULTS: The antiallodynic effect of morphine, adenosine, and R-PIA were produced in a dose dependent manner. The antiallodynic effects of combinations showed a similar pattern. Isobolographic analysis revealed a synergistic interaction for the morphine-R-PIA combination but not for the morphine-adenosine combination. However, fractional analysis produced a synergistic result for two combination groups. CONCLUSIONS: The results demonstrated that intrathecal co-administration of adenosine A1 receptors agonist and morphine showed the synergistic effect on nerve ligation injury induced allodynia.