Aminophylline Pretreatment Research Articles

Prophylactic Intravenous Aminophylline for Preventing Bradyarrhythmias During Coronary Atherectomy: A 10-Year Single-Center Experience.

Aminophylline, an adenosine antagonist, can be used to prevent adenosine-mediated bradyarrhythmias. Retrospective, observational, descriptive analysis of patients undergoing rotational atherectomy with intravenous (IV) aminophylline pretreatment during a 10-year period (2010-2020). The primary composite outcome was the occurrence of a documented bradyarrhythmia requiring pharmacologic intervention and/or temporary pacemaker (TPM) implantation. A total of 296 patients received IV aminophylline pretreatment. The primary composite outcome occurred in 1.7% (n = 5) of patients. None of the patients required rescue TPM. Bradyarrhythmias were documented in 2.4% (n = 7) of patients. Pharmacologic interventions, typically with IV atropine, were used in 15% (n = 43) of patients. Per-vessel analyses demonstrated that patients undergoing atherectomy to the circumflex and right coronary arteries were more likely than those undergoing atherectomy to other vessels to have bradyarrhythmias requiring pharmacologic intervention (3.4% vs 0%, P = .01). In this 10-year single-center experience using IV aminophylline pretreatment to prevent major bradyarrhythmias in patients undergoing coronary atherectomy, none of the patients required rescue TPM implantation. These data demonstrate that coronary atherectomy can be performed safely without prophylactic TPM, with aminophylline pretreatment and selective use of atropine representing an effective noninvasive approach.

The potential effect of topical aminophylline on acute glaucoma model

Objectives: to study the oculo- hypotensive effect of non-selective phosphodiestrase inhibitor aminophylline. Methods: The study was conducted on fifteen albino rabbits (2.5–2.8 Kg) and model of acute ocular hypertension was obtained by 5% glucose water administration at 15ml/kg through the marginal vein of the rabbit’s ear. Aminophylline was dissolved in vehicle of phosphate buffer saline and diluted to desired concentration as 0.5%. Phosphate buffer saline solution also served as control. The left eye of rabbit was received one drop of aminophylline (0.5%) on the other hand the right eye treated by the vehicle and considered as control parameter. The pressure measurement was recorded at 15, 30, 45, 60, 90, 120, 135, 150 and 165 min after drug instillation. Results: After 30 minutes of topical 0.5% aminophylline administration the normal tension of the eye remain unchanged. However topical 0.5% aminophylline eye drop significantly (p < 0.05) successes in the decrease of the acute elevation of ocular pressure due to 5% glucose infusion. Moreover, in this study aminophylline pretreatment has the ability to facilitating the returns of the IOP to normal levels Conclusions: Topical administration of aminophylline (0.5%) significantly prevent acute rise in the ocular pressure induced by 5% glucose administration. The IOP lowering effect of aminophylline can be considered as potential antiglaucoma drug.

The Effect of Aminophylline on Quinidine Passage into the Central Nervous System of Rats

Abstract: Background and Objective: There is significant interest in mutual influence of substances during their passage into the central nervous system (CNS). Quinidine is a drug which can achieve significant concentration in CNS and cause side effects and aminophylline is a drug with possibility to change distribution of drugs in CNS. Thus the aim of this work was to study the effect of aminophylline on the transition of quinidine through the bloodbrain barrier into the central nervous system. Material and Methods: The experiments were carried out on Wistar rats, which received quinidine in the form of the retrograde intra-arterial bolus injection into the right axillary vein. The control group of animals received subcutaneously physiological solution 30 min before the intra-arterial quinidine application, whereas the test group animals also received subcutaneously aminophylline 30 min before quinidine application. The rats were sacrificed by decapitation in specified time intervals in order to determine quinidine concentration in different parts of CNS. Results: There were no significant changes in serum quinidine levels by comparing the results of experimental group with those of the control group of animals. In all parts of CNS aminophylline pre-treatment caused significant decrease in CNS quinidine concentration. Conclusion: The results suggest that co-administration of aminophylline and quinidine, decreases quinidine concentrations in the CNS of rats. Key words: Aminophylline, Quinidine, Blood-brain barrier, Drug interactions.

深部前梨状葉皮質の間欠的電気刺激によるてんかん発作重積モデル

Hippocampal damage induced by status epilepticus (SE) has been suggested as the developmental pathway of temporal lobe epilepsy. We developed an experimental model of SE induced by massed electrical stimulations into the deep prepiriform cortex. Stimulations under aminophylline pretreatment more effectively induced SE than those in the absence of aminophylline. Most SE episodes included secondary generalized seizures. Cresyl violet staining indicated neuronal degeneration in CA1 and CA3, 1-2 weeks after the SE. Mild neuronal loss was observed 8 weeks after the SE, although there were no obvious histological changes in the hilus. Immunoreactivity for GluR1, a subunit of the AMPA receptors, was reduced in CA3 and the hilus starting 1 week after SE, indicating a discrepancy between the distributions of neuronal damage and the GluR1 decrement. The present model serves as a useful model of SE. Further improvement of this method will make it an effective tool for understanding the developmental process of temporal lobe epilepsy.

Aminophylline Pretreatment Modulates the Nitric Oxide System of the Isolated Rat Diaphragm: the Role of Frequency of the Electrical Stimulation

The effect of different frequencies of direct subtetanic electrical stimulation (14, 20, and 30 Hz) and aminophylline (AMPh) pretreatment on the effect of NG-nitro-L-arginine methyl ester (L-NAME) (1 mM) on isolated rat diaphragm was investigated. L-NAME potentiated tension developed (Td) in the diaphragm pretreated with a single concentration of AMPh (1.08 mM) in a frequency-dependent manner. The effect was significantly different in comparison with muscle incubated 30 min with Tyrode solution only. In the muscle pretreated with cumulative concentrations of AMPh (0.36 – 3.60 mM), the frequency-dependent potentiation of Td induced by L-NAME and the difference between L-NAME-treated and untreated muscle were lost.

Carotid bodies and ventilatory response to hypoxia in aminophylline‐treated piglets

Peripheral chemoreceptors may be immature in neonatal animals, exhibiting maturational changes in the perinatal period. Even though methylxanthines are respiratory stimulants, many premature neonates do not respond to them. Thus, we hypothesized that carotid body activity is necessary for aminophylline to reverse hypoxia-induced respiratory depression. We exposed 16 anesthetized newborn piglets (age 2-7 days) to hypoxia (inhalation of 12% oxygen) for 5 min. Aminophylline (15 mg/kg iv) was administered either prior to (11 piglets) or following (5 piglets) carotid body denervation (CBD). Before CBD, hypoxia elicited transient initial increases in tidal volume (from 79 +/- 4 to 99 +/- 1% of maximum, mean +/- SE), minute ventilation (from 64 +/- 5 to 93 +/- 4%), and peak phrenic electroneurogram (from 63 +/- 8 to 91 +/- 6%, all P < 0.05). This was followed by a decrease in tidal volume, minute ventilation and phrenic electroneurogram (all P < 0.05). Prior to CBD, aminophylline pretreatment prevented the decrease in all the measures of respiratory output during late hypoxia. After CBD, hypoxia induced an initial and sustained depression of ventilation (tidal volume from 100 to 33 +/- 14%; frequency from 94 +/- 4 to 42 +/- 17%; minute ventilation from 100 to 32 +/- 14%, all P < 0.05) and phrenic electroneurogram (peak phrenic from 100 to 47 +/- 18%; minute phrenic from 85 +/- 6 to 55 +/- 21%, both P < 0.05). Administration of aminophylline after CBD did not prevent the profound respiratory depression elicited by hypoxia in the chemodenervated piglets.(ABSTRACT TRUNCATED AT 250 WORDS)

Interactions of aminophylline and three benzodiazepine compounds with amygdala-kindled seizures in rats

Fully amygdala-kindled rats were used to study the effect of diazepam, RO 15-1788, and CGS-8216 on aminophylline-induced prolongation of elicited kindled afterdischarges. Similar proportional reductions in seizure afterdischarge durations were seen with diazepam and with RO 15-1788 after aminophylline although the absolute length of the afterdischarge durations were increased significantly with both drugs after aminophylline. The partial agonist effect of the benzodiazepine antagonist RO 15-1788 was demonstrated before and after aminophylline pretreatment. However, no specific interaction (pro- or anticonvulsant) was demonstrated with the benzodiazepine antagonist CGS-8216 before or after aminophylline pretreatment. Together these data do not support the theory that the prolongation of elicited kindled seizures by the methylxanthine, aminophylline, is through a specific benzodiazepine receptor mechanism.

Modification of excitation and inhibition evoked in dentate gyrus by perforant path stimulation: Effects of aminophylline and kindling

Rats were implanted with chronic electrodes to stimulate the perforant path and record the elicited monosynaptic evoked potentials from the dentate gyrus of the hippocampal formation. Dentate responses were examined in awake and anesthetized animals after exposure to saline and aminophylline (100 mg/kg, IP). In the awake animal, aminophylline treatment did not significantly alter the threshold or elicited amplitude of either the excitatory post-synaptic potential (EPSP) or the population spike (PS). Aminophylline pretreatment markedly enhanced the length and severity of elicited seizures from hippocampal (dentate gyrus) or perforant pathway stimulation. After daily perforant pathway stimulations which established “kindled” seizures, aminophylline significantly increased only the amplitude of the evoked PS in awake animals. In animals anesthetized with chloropent, aminophylline increased significantly before kindling the amplitude of both the EPSP and PS without effecting thresholds for each. After perforant pathway kindling, only the PS amplitude was increased significantly by aminophylline. Inhibition, thought to be from GABA-mediated recurrent collaterals, was found to be increased rather than decreased by kindling. Further, aminophylline treatment did not result in reduction of this inhibition before or after kindling. These data suggest that at this dose of aminophylline neither enhanced transmitter release at this synapse as measured by the amplitude of the EPSP, nor reduced recurrent collateral inhibition significantly contributed to the prolongation of elicited seizure afterdischarge. The increase in PS amplitude reflecting an increased number of granule cells excited to discharge with perforant path stimulation after aminophylline was noted in awake animals but was greatest in the anesthetized animals. Although the number of granule cells excited to discharge was increased by aminophylline, the small increase in amplitude seen compared to the effects of other neurotoxins on this synapse makes this an unlikely explanation for the profound increased seizure response seen after aminophylline.

Intracoronary adenosine enhances myocardial reactive hyperemia after brief coronary occlusion.

Adenosine is a prime candidate for the role of mediator between myocardial metabolic state and coronary blood flow. However, there are few reports concerning the direct effects of exogenously added adenosine on coronary autoregulation. The present investigation in the open-chest dog studied the effects of a threshold dose of intracoronary adenosine infusion on reactive hyperemia following brief coronary occlusions. The infused dose did not increase nonocclusive flow by greater than 10%. Adenosine enhanced total hyperemic flow at all occlusions tested (5, 10, 15, 20, and 30 s). Aminophylline pretreatment reduced reactive hyperemia below the control level even in the presence of an intracoronary infusion of adenosine. Adenosine injected into the left atrium and intracoronarily infused papaverine did not affect hyperemic response to 5- and 15-s coronary occlusions. The results suggest that a minimum dose of exogenously added adenosine enhances myocardial reactive hyperemia, possibly by potentiating the effects of endogenous adenosine released during ischemia.

Aminophylline potentiates sodium nitroprusside-induced hypotension in the dog.

The biochemical mechanisms by which nitroso-vasodilators cause smooth muscle relaxation remain controversial. One theory states that the effects of nitroso-vasodilators are mediated by increased intracellular levels of cyclic GMP due to activation of guanylate cyclase. To test this hypothesis, the authors examined the effects of sodium nitroprusside (SNP) in anesthetized dogs with an without pretreatment with the phosphodiesterase inhibitor aminophylline. Aminophylline pretreatment resulted in a 2.8-fold potentiation of the hypotensive effects of a continuous infusion of SNP. Potentiation also was seen for the effects of SNP on stroke volume, heart rate, and plasma cyclic GMP levels. These results support the hypothesis that nitroso-vasodilators exert their effects via guanylate cyclase activation. The authors advise caution when vasodilator therapy with agents such as SNP, nitroglycerin, or hydralazine is instituted in patients receiving aminophylline and when aminophylline is either instituted or discontinued in patients on vasodilator therapy.

Aminophylline and kindled seizures

The effects of aminophylline on amygdaloid and cortically kindled rats was studied. Rats implanted with chronic amygdaloid electrodes received either saline or 150 mg/kg, i.p., aminophylline 20 min prior to their first stimulation. On the first stimulation, aminophylline-treated rats had dramatically longer afterdischarge durations and more severe seizure ranks. When fully kindled, the animals were retested with saline or aminophylline. Again, the aminophylline-treated animals had longer afterdischarge durations than the saline-treated rats. In a second experiment, fully amygdaloid kindled rats were pretreated with various doses of aminophylline and stimulated 20 min later. With suprathreshold stimulation, a dose-dependent increase was noted in the afterdischarge duration. During seizure threshold determinations, aminophylline pretreatment markedly prolonged afterdischarge durations without significantly changing seizure severity or threshold. When animals were treated with the adenosine agonist, 2-chloroadenosine, prior to kindled amygdaloid stimulation, the elicited afterdischarge was shortened. The effect was antagonized where treatment with both 2-chloroadenosine and aminophylline occurred prior to amygdaloid stimulation. Rats with neocortical electrodes were also exposed to various doses of aminophylline while in a stable, partially developed kindled stage and again when fully kindled. At both stages, afterdischarge duration was increased by aminophylline in a dose-dependent manner. The partially developed, cortically kindled animals were more responsive to aminophylline than were those fully kindled and they tended to have greater increases in afterdischarge duration and seizure rank. These data demonstrate that aminophylline acts to prolong afterdischarges elicited at various stages of kindling from both amygdaloid and cortical sites.

Effects of catecholamines and adenosine derivatives given into the brain of fowls.

1. Adult fowls (Gallus domesticus) with cannulae chronically implanted into the IIIrd cerebral ventricle and various other sites of the brain received microinfusions or injections of catecholamines, adenosine, 3',5'-cyclic AMP or its dibutyryl derivative. The effects of these substances on behaviour, electrocortical activity and body temperature were studied.2. Behavioural and electrocortical sleep with fall in body temperature were obtained with intraventricular noradrenaline, alpha-methylnoradrenaline and isoprenaline; dopamine was ineffective. The doses required to elicit sleep were smaller than those affecting body temperature. Following mebanazine, the effects of noradrenaline were prolonged and doses of dopamine, previously ineffective, lowered body temperature and induced behavioural and electrocortical sleep.3. Noradrenaline, alpha-methylnoradrenaline, isoprenaline and dopamine infused into the hypothalamus induced sleep and lowered body temperature. Effective doses of noradrenaline, alpha-methylnoradrenaline and isoprenaline infused into the hypothalamus were one-twentieth to one-fifth those for intraventricular injection. Tachypnoea developed with isoprenaline and dopamine. Additionally with dopamine, there was deviation of the head to the contralateral side, together with repetitive jerking movements of the head. These effects were prolonged and intensified by mebanazine, whereas the involuntary movements with dopamine were greatly reduced by haloperidol.4. Involuntary movements, but without sleep, were induced by infusing dopamine into the paleostriatum augmentatum; noradrenaline infused into this site was ineffective.5. In three of five fowls pretreated with aminophylline, 3',5'-cyclic AMP infused into the hypothalamus induced behavioural and electrocortical sleep; without aminophylline pretreatment, 3',5'-cyclic AMP was ineffective. Adenosine infused into the hypothalamus, following pretreatment of fowls with aminophylline, consistently induced behavioural and electrocortical sleep. Dibutyryl cyclic AMP infused into the hypothalamus of intact fowls elicited behavioural arousal, followed by bursts of electrocortical spikes (6 Hz) over both cerebral hemispheres, spikes subsequently becoming regular at 1 Hz. Clonic limb and body movements occasionally accompanied the bursts of spike activity, infrequently developing into convulsions. In fowl encéphale isolé preparations, in which dibutyryl cyclic AMP was infused into the hypothalamus, spike activity was confined to the ipsilateral hemisphere.

Opposite Effects of Aminophylline on Arginine-induced Glucagon and Insulin Secretion in Humans

The adenyl cyclase-cyclic AMP system, aside from being a mediator of the actions of several hormones, is believed to play an important role in the secretory mechanism of some of these hormones. In young, healthy, nonobese volunteers, we have studied the effect of a large dose (1 gm.) of a cAMP phosphodiesterase inhibitor (aminophylline) on basal plasma glucagon and insulin levels and on the responses of these two hormones to two different doses of arginine. With a high (468 mg./kg.) and a low (156 mg./kg.) dose of arginine, similar maximal peaks of glucagon concentration were reached, indicating that the level of aminoacidemia reached with the low dose was sufficient to elicit an almost maximal acute response. Plasma insulin and glucose increased as expected after the arginine doses. With aminophylline alone, plasma insulin and glucose increased slightly but consistently while the level of circulating glucagon did not change (range of the means, 111 pg./ml. ± 28 to 133 pg./ml. ± 25). Aminophylline pretreatment significantly lowered the glucagon response in the late part of the curve corresponding to the high dose of arginine. This inhibitory effect of the xanthine derivative could be due to: (1) peripheral effects of aminophylline, such as increased mobilization of FFA; (2) enhanced removal of glucagon from plasma; (3) direct suppressor effect of cAMP on the alpha cell secretory mechanism. At any rate, this effect of aminophylline seems to be either a retarded one or only present in the late phase of glucagon secretion.

ACTH-mediated insulin secretion: effect of aminophylline.

The effect of theophylline ethylenediamine, aminophylline, on ACTH-mediated insulin secretion was studied in mice. Aminophylline pretreatment markedly increased the magnitude of the plasma insulin rise following ACTH. It did not, however, increase the duration of the ACTH effect nor did it appreciably lower the minimum dose of ACTH which caused insulin release. The dose of aminophylline necessary to augment ACTH-mediated insulin secretion did not inhibit pancreatic protein synthesis as estimated by 14C-L-leucine incorporation. The aminophylline augmentation of ACTH-mediated insulin release occurred in both intact and adrenalectomized animals. Aminophylline also augmented glucagon and glucose-mediated insulin secretion. The data raise the question of the possible role of the adenyl cyclase system in the mechanism of ACTH action on the pancreatic β cell. (Endocrinology 81 : 558, 1967)