Correlation of (-)N6-phenylisopropyladenosine blood levels with cardiac responses in the anesthetized guinea pig.

This study was designed to develop a high-performance liquid chromatography-based analytical method to measure the blood concentration of (-)N6-phenylisopropyladenosine (R-PIA) in order to correlate such levels with cardiac responses, and to determine the pharmacokinetics of R-PIA. Experiments were carried out in anesthetized adult guinea pigs instrumented for measurement of the surface ECG. After i.v. (50 micrograms/kg; n = 9) or i.p. (3.5 mg/kg; n = 5) administration of R-PIA, the atrial rate and P-R interval were determined, and arterial blood samples (0.5 ml) were collected. The R-PIA content of plasma ultrafiltrates was determined by reversed-phase high-performance liquid chromatography. The ratio of R-PIA concentrations in whole blood and in ultrafiltrated plasma (free or unbound) at 35-37 degrees C was 2.51 +/- 0.10 (n = 7) and was relatively independent of R-PIA concentration. The concentration of unbound R-PIA in whole blood correlated well with cardiac responses. Two distinct patterns of cardiac response to varying R-PIA levels were observed. In 4 of 14 animals, R-PIA caused a prolongation of the P-R interval at a relatively constant atrial rate, whereas in 10 animals, R-PIA caused both a slowing of atrial rate and a prolongation of the P-R interval. An increase in the unbound concentration of R-PIA caused a decrease in atrial rate and an increase in P-R interval. Unbound R-PIA was rapidly cleared from blood (CL = 40 +/- 7 ml/kg/min) and had a large volume of distribution (VSS = 1.45 +/- 0.21 L/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Central adenosinergic system involvement in ethanol-induced motor incoordination in mice.

To clarify if the behavioral interaction between ethanol and adenosine reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. adenosine agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), N6-(S-phenylisopropyl)adenosine, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. Adenosine agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of adenosine modulation of this effect of ethanol and confirmed our previous reports in which adenosine agonists and antagonists were given i.p. Enprofylline, a weak adenosine antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain adenosine receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of adenosine A1 subtype. However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of adenosine A2. No effect of ethanol on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest adenosine receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.(ABSTRACT TRUNCATED AT 250 WORDS)