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Role of exogenous adenosine as a modulator of theophylline toxicity
M R Ujhelyi1, G Hulula, K A Skau
1University of Cincinnati Medical Center, College of Pharmacy, OH.
Objective:
In animal models, exogenous adenosine can reverse theophylline-induced neurologic toxicity. Thus, we examined the ability of adenosine to oppose the cardiovascular toxicity of theophylline.
Design:
Open-label, dose-response trial.
Setting:
Animal laboratory within a college of pharmacy.
Subjects:
Ten chloral hydrate-anesthetized male Sprague-Dawley rats.
Interventions:
Indwelling catheters were surgically inserted into the right carotid artery and right external jugular vein. Subsequently, escalating doses of adenosine (5 to 2000 micrograms) were given at theophylline doses of 0, 10, 20, 30, 40, and 50 mg/kg until a maximum slowing in heart rate occurred.
Measurements And Main Results:
Left ventricular systolic pressure and maximum positive maximal change in pressure over time (+dP/dt) were determined at baseline and at the time of maximum heart slowing, during adenosine, for each theophylline dose (0 to 50 mg/kg). Escalating doses of adenosine resulted in progressive heart rate slowing until maximum slowing occurred. The adenosine doses required to reach maximum slowing of heart rate were 118 +/- 24, 410 +/- 197, 620 +/- 256, 855 +/- 264, 944 +/- 329 and 1062 +/- 463 (SD) micrograms at theophylline doses of 0, 10, 20, 30, 40, and 50 mg/kg, respectively, which were correlated (r2 = .57, p < .001). At baseline, increasing theophylline doses produced a progressive reduction in left ventricular systolic pressure. However, adenosine at maximum slowing doses reversed this effect where left ventricular systolic pressure at 0 mg/kg of theophylline was similar to left ventricular systolic pressure at 50 mg/kg of theophylline (p < .05). At baseline, 10 to 50 mg/kg of theophylline had no significant effect on +dP/dtmax. However, adenosine (at maximum slowing) decreased +dP/dtmax before theophylline administration (p < .01). Theophylline at doses of 10 to 50 mg/kg reversed adenosine's negative inotropic effect, where +dP/dtmax values at maximum slowing were greater than values at 0 mg/kg of theophylline (p < .05).
Conclusions:
Adenosine can reverse theophylline-induced electrophysiologic and hemodynamic instability, whereas theophylline can reverse the negative inotropic actions of adenosine. However, higher adenosine doses are needed to elicit these changes as the theophylline dose increases.