n(6)-cyclopentyladenosine and Bradycardia

Mortality and occurrence of cholinergic symptoms upon sarin intoxication (144 micro g/kg s.c., approximately 2 x LD50) in rats is completely prevented by treatment with the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA, 2 mg/kg i.m.). Previously, we have shown that CPA treatment altered the distribution of sarin into the brain, presumably through its cardiovascular side effects. Therefore, the objective of the present study was to evaluate the contribution of the cardiodepressant effects of CPA to its therapeutic efficacy against sarin intoxication. Intramuscular treatment of rats with 0.5 and 2.0 mg/kg CPA 1 min after sarin poisoning attenuated most cholinergic symptoms and prevented mortality, which seemed to be directly associated with an immediate strong and long-lasting bradycardia and hypotension caused by CPA. Treatment with lower doses of CPA (0.1 and 0.05 mg/kg i.m.) caused similar levels of bradycardia and hypotension, albeit a few minutes later than at the higher doses of CPA. Upon sarin intoxication, this was correlated with increased incidence of cholinergic symptoms and decreased survival rates. Pretreatment with the peripheral adenosine A1 receptor antagonist 8- p-sulphophenyltheophylline (8-PST, 20 mg/kg i.p.) counteracted the cardiodepressant effects of 0.05 mg/kg CPA almost completely, thereby nearly abolishing its therapeutic efficacy against sarin poisoning. In conclusion, the present results strongly indicate that bradycardia and hypotension induced by the peripheral adenosine A1 receptor play a prominent role in the therapeutic efficacy of CPA in cases of sarin poisoning.

Topics: Adenosine; Animals; Bradycardia; Chemical Warfare Agents; Dose-Response Relationship, Drug; Drug Antagonism; Drug Therapy, Combination; Heart Diseases; Hypotension; Injections, Intramuscular; Male; Poisoning; Purinergic P1 Receptor Agonists; Rats; Sarin; Theophylline

Compelling clinical evidence implicates the potential role of adenosine in development of airway hyperresponsiveness and suggests involvement of pulmonary sensory receptors. This study was carried out to determine the effect of a low dose of adenosine infusion on sensitivity of pulmonary C-fiber afferents in anesthetized open-chest rats. Infusion of adenosine (40 microg x kg-1x min-1 i.v. for 90 s) mildly elevated baseline activity of pulmonary C fibers. However, during adenosine infusion, pulmonary C-fiber responses to chemical stimulants and lung inflation (30 cmH2O tracheal pressure) were markedly potentiated; e.g., the response to right atrial injection of capsaicin (0.25 or 0.5 microg/kg) was increased by more than fivefold (change in fiber activity = 2.64 +/- 0.67 and 16.27 +/- 3.11 impulses/s at control and during adenosine infusion, n = 13, P < 0.05), and this enhanced response returned to control in approximately 10 min. The potentiating effect of adenosine infusion was completely blocked by pretreatment with 8-cyclopentyl-1,3-dipropylxanthine (100 microg/kg), a selective antagonist of the adenosine A1 receptor, but was not affected by 3,7-dimethyl-1-propargylxanthine (1 mg/kg), an A2-receptor antagonist, or 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (2 mg/kg), an A3-receptor antagonist. This potentiating effect was also mimicked by N6-cyclopentyladenosine (0.25 microg x kg-1 x min-1 for 90 s), a selective agonist of the adenosine A1 receptor. In conclusion, our results showed that infusion of adenosine significantly elevated the sensitivity of pulmonary C-fiber afferents in rat lungs and that this potentiating effect is likely mediated through activation of the adenosine A1 receptor.

Topics: Adenosine; Anesthesia; Animals; Body Weight; Bradycardia; Bronchial Hyperreactivity; Capsaicin; Dose-Response Relationship, Drug; Infusions, Intravenous; Lung; Male; Nerve Fibers, Unmyelinated; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A1; Receptors, Purinergic P1; Xanthines

1. The purpose of the present study was to quantify the cardiovascular effects of the 2'-, 3'-, 5'-deoxyribose analogues of the selective adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA) in vivo. The blood concentration-effect relationships of the compounds were assessed in individual rats and correlated to their receptor binding characteristics. 2. The pharmacokinetics and pharmacodynamics of the compounds were determined after a single intravenous infusion of 0.80 mg kg (-1) (63 micromol kg(-1)of 2' dCPA. The heart rate (HR) and mean arterial blood pressure (MAP) were monitored continuously during the experiment and serial arterial blood samples were taken for analysis of drug concentration. 3. The relationship between blood concentrations and the reductions in both heart rate and blood pressure were described according to the sigmoidal Emax model. For the bradycardiac effect, the potencies based on free drug concentrations (EC50,u) of 5'dCPA, 3'dCPA, 2'dCPAin blood were 5.9 +/- 1.7, 18 +/- 4 and 260 +/- 70 ng ml (-1) (19 +/- 6, 56 +/- 11 and 830 +/- 210 nM), respectively, and correlated well with the adenosine A1 receptor affinity in vitro. The Emax value of 2'dCPA was significantly less than those of the other compounds, suggesting that this compound may be regarded as a partial agonist when compared to the other analogues. The rank order of the maximal reduction in heart rate of the compounds corresponded well with the order of the GTP-shifts, as determined in vitro. 4. It is concluded that deoxyribose derivatives of CPA may be partial agonists for the adenosine A1 receptor and may serve as tools for further investigation of adenosine receptor partial agonism in vivo.

Topics: Adenosine; Animals; Blood Pressure; Bradycardia; Deoxyribose; Dose-Response Relationship, Drug; Heart Rate; In Vitro Techniques; Infusions, Intravenous; Male; Purinergic P1 Receptor Agonists; Rats; Rats, Wistar; Receptors, Purinergic P1; Specific Pathogen-Free Organisms; Structure-Activity Relationship

Previous attempts to discern and quantify the selectivity of agonists for A1 versus A2 adenosine receptors in vivo have been confounded by the activation of baroreceptor reflexes and/or simultaneous expression of responses to both A1 and A2 receptor activation. In anesthetized, vagotomized rats with isolated in situ constant-flow perfused hindquarters (HQ), bradycardic responses to i.v. agonist injections measured A1 receptor activation and HQ vasodilation elicited by i.a. agonist injections measured the stimulation of A2 receptors. Adenosine and 5'-N-ethylcarboxamidoadenosine (NECA) produced A2 receptor-mediated HQ vasodilation at doses 8- and 4-fold lower (-log ED50 values, 7.3 +/- 0.04 mol and 8.7 +/- 0.06 mol, respectively) than those required to evoke A1 receptor-mediated bradycardia (-log ED50 values, 6.4 +/- 0.01 mol and 8.1 +/- 0.07 mol, respectively). N6-cyclopentyladenosine (CPA) was approximately 8-fold selective for A1 receptors (-log ED50 values, A1, 8.5 +/- 0.05 mol; A2, 7.6 +/- 0.16 mol). 2-(Phenylamino)adenosine (CV-1808) and 2[2(4-fluorophenyl)ethoxy]adenosine (FPEA) were at least 125- and 200-fold more potent agonists at A2 receptors (-log ED50 values, 7.7 +/- 0.10 mol and 8.0 +/- 0.24 mol, respectively) than at A1 receptors (-log ED50 values, 5.6 +/- 0.08 mol and 5.7 +/- 0.01 mol, respectively). These studies demonstrated that stimulation of A1 and A2 receptors may be discriminated in vivo and that such responses are selective, reproducible, dose-dependent and quantifiable.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Binding, Competitive; Bradycardia; Male; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1; Vasodilator Agents