Propofol and aminophylline antagonize each other during the mobilization of intracellular calcium in human umbilical vein endothelial cells.

This study examined whether propofol and aminophylline affect the mobilization of intracellular calcium in human umbilical vein endothelial cells. Intracellular calcium was measured using laser scanning confocal microscopy. Cultured and serum-starved cells on round coverslips were incubated with propofol or aminophylline for 30 min, and then stimulated with lysophosphatidic acid, propofol and aminophylline. The results were expressed as relative fluorescence intensity and fold stimulation. Propofol decreased the concentration of intracellular calcium, whereas aminophylline caused increased mobilization of intracellular calcium in a concentration-dependent manner. Propofol suppressed the lysophosphatidic acid-induced mobilization of intracellular calcium in a concentration-dependent manner. Propofol further prevented the aminophylline-induced increase of intracellular calcium at clinically relevant concentrations. However, aminophylline reversed the inhibitory effect of propofol on the elevation of intracellular calcium by lysophosphatidic acid. Our results suggest that propofol and aminophylline antagonize each other on the mobilization of intracellular calcium in human umbilical vein endothelial cells at clinically relevant concentrations. Serious consideration should be given to how this interaction affects mobilization of intracellular calcium when these two drugs are used together.

Propofol and Aminophylline Antagonize Each Other During the Mobilization of Intracellular Calcium in Human Umbilical Vein Endothelial Cells

This study examined whether propofol and aminophylline affect the mobilization of intracellular calcium in human umbilical vein endothelial cells. Intracellular calcium was measured using laser scanning confocal microscopy. Cultured and serum-starved cells on round coverslips were incubated with propofol or aminophylline for 30 min, and then stimulated with lysophosphatidic acid, propofol and aminophylline. The results were expressed as relative fluorescence intensity and fold stimulation. Propofol decreased the concentration of intracellular calcium, whereas aminophylline caused increased mobilization of intracellular calcium in a concentration-dependent manner. Propofol suppressed the lysophosphatidic acid-induced mobilization of intracellular calcium in a concentration-dependent manner. Propofol further prevented the aminophylline-induced increase of intracellular calcium at clinically relevant concentrations. However, aminophylline reversed the inhibitory effect of propofol on the elevation of intracellular calcium by lysophosphatidic acid. Our results suggest that propofol and aminophylline antagonize each other on the mobilization of intracellular calcium in human umbilical vein endothelial cells at clinically relevant concentrations. Serious consideration should be given to how this interaction affects mobilization of intracellular calcium when these two drugs are used together.

Aminophylline does not protect against radiocontrast nephropathy in patients undergoing percutaneous angiographic procedures.

BACKGROUND: Radiocontrast nephropathy (RCN) is one of the leading causes of hospital-acquired acute renal insufficiency. Adenosine, a renal vasoconstrictor, is thought to play a role in RCN. In this study, aminophylline, a non-selective adenosine-competitive inhibitor, was evaluated as a potential agent to protect against RCN. METHODS: Twenty-six patients treated with 200 mg intravenous aminophylline immediately prior to percutaneous coronary and peripheral procedures were individually matched to 26 controls for baseline creatinine (Cr), diabetes mellitus and amount of contrast used. The aminophylline-treated group was also similar to control with respect to baseline ejection fraction, amount of post-procedure hydration, age, blood pressure and the use of nephrotic drugs. RESULTS: There was no significant difference between the change from baseline Cr to peak measured Cr in either cases or controls. Also, when a change in Cr > or =25% from baseline was considered significant, Fisher's exact test did not show a difference between the 2 groups. CONCLUSION: Aminophylline does not appear to add a protective role in preventing against RCN in patients undergoing percutaneous angiographic procedures.

Dose-finding study with nimodipine: a selective central nervous system calcium channel blocker on aminophylline induced seizure models in rats.

Nimodipine, a dihydropyridine derivative central nervous system (CNS) selective calcium channel blocker was studied at four different dosage schedules in five different models of seizures in rats. At a dose of 5 mg/kg, i.p. with pretreatment time of 15 min, nimodipine significantly antagonized aminophylline (175 and 200 mg/kg, i.p.), electroshock (150 mA for 0.2 s), pentylenetetrazole (60 and 75 mg/kg, i.p.), aminophylline (100 mg/kg i.p.) + electroshock (66mA for 0.2 s), and aminophylline (100 mg/kg, i.p.) + pentylenetetrazole (40 mg/kg, i.p.) induced seizures in rats. No hemodynamic alteration was observed with this dose of nimodipine. However, 2 mg/kg, i.p. (pretreatment time of 15 min and 30 min) and 5 mg/kg, i.p. (pretreatment time of 30 min) doses of nimodipine failed to demonstrate any significant anticonvulsant effect. The study highlighted the critical role of calcium ion flux into the neurons for the genesis of seizure activity to aminophylline, electroshock, and pentylenetetrazole in rats. Furthermore, the critical dose requirement for nimodipine could be explained on the basis of its short half-life and shorter duration of protection against seizures. Therefore, nimodipine may be tried clinically as an anticonvulsant in patients who are on aminophylline because of bronchial asthma or chronic obstructive pulmonary disease, when such patients have concomitant epilepsy or other seizure prone neurological deficits or are scheduled to undergo electroshock therapy.

Effects of dihydropyridines on the components of the ethanol withdrawal syndrome: possible evidence for involvement of potassium, as well as calcium?

Comparison was made of the ability of two dihydropyridine calcium channel antagonists, nitrendipine and felodipine, to prevent a range of signs of ethanol withdrawal. The increases in handling-induced behavior seen in mice during withdrawal from chronic ethanol treatment were prevented by administration of nitrendipine, 50 mg/kg, but not by, felodipine, 10 mg/kg, a dose that caused a similar displacement of dihydropyridine binding in central nervous system tissue, in vivo and in vitro. A higher dose of felodipine, 20 mg/kg, also had no effects. Nitrendipine, but not felodipine, prevented audiogenic seizures during the withdrawal phase. Similarly, nitrendipine prevented both the decrease in thresholds for N-methyl-DL-aspartate seizures and the increase in thresholds for convulsions due to 4-aminopyridine, which were seen during the withdrawal period, while felodipine did not alter either of these changes. Withdrawal from the ethanol chronic treatment increased the thresholds to seizures produced by intravenous aminophylline; this change was also prevented by nitrendipine. The significance of this increase in thresholds was lost after felodipine administration. In naive mice (not treated with ethanol) the doses of nitrendipine and felodipine used in the withdrawal studies were tested against the effects of convulsant drugs. Both dihydropyridines increased, to similar extents, the thresholds for seizures produced by bicuculline, pentylenetetrazol, and by N-methyl-DL-aspartate. The thresholds for aminophylline were unaltered by either dihydropyridine. In contrast, the thresholds for seizures due to 4-aminopyridine in the naive animals were not changed by felodipine, but were increased by nitrendipine. The results suggest that changes in potassium, as well as calcium, may possibly be involved in some of the stages of the ethanol withdrawal syndrome.

Reversión de la sedación por aminofilina en pacientes que recibieron diazepan, fentanil y tiopental

La aminofilina, un antagonista no específico de las benzodiazepinas, fue evaluada para determinar su acción en la reversión de la sedacción de pacientes sometidos a legrados uterinos o braquiterapia intrauterina bajo anestesia general. Veintiocho pacientes recibieron Fentanil 3ug.kg-1, Diazepán 0.2 mg.kg-1 y Tiopental 4mg.kg-1, y fueron ventiladas con Oxido Nitroso- Oxígeno (66/33 por ciento). Después del procedimiento quirúrgico, cada paciente recibió en forma randomizada y doble ciego, ®droga activa¼ (aminofilina 4 mg.kg-1n=14) o ®placebo¼ (solución Salina isotónica; n = 14). Ambos grupos fueron similares en sus variables demográficas y no se detectaron diferencias en las determinaciones de presión arterial, frecuencia cardíaca y frecuencia respiratoria después de la administración de aminofilina. La recuperación fue bien tolerada y significativamente más rápida en el grupo aminofilina (30.9 min+DS4.91) que en el grupo control (39.0 min. + DS 8.06) (p<0.01). Los niveles de sedación revirtieron antes que en el grupo control <0.05), pero esta deferencia desaparecio 30 minutos después de finalizado el procedimiento anestésico quirúrgico. Se infiere que en las pacientes que recibieron fentanil, diazepán y tiopental, la aminofilina acelera el despertar, probablemente debido al bloqueo de los receptores de adenosina

Antiepileptic drugs delay the onset of seizures induced by aminophylline in conscious rats.

Aminophylline, 285.7 +/- 2.19 mg/kg infused intravenously in unanaesthetized rats produced onset of seizures within 3.2 +/- 0.99 minutes. Seizures were repetitive and death occurred in 10.5 +/- 1.75 minutes. Pretreatment of rats with carbamazepine, sodium valproate and diazepam at doses that prevented electroshock induced seizures were effective in significantly postponing seizures and death, but did not reduce mortality. Concomitant EEG studies in aminophylline infused rats showed that cortical excitability evidenced by initial cortical spiking occurred at 42 secs and polyspiking at 165 seconds. Following diazepam, the initial cortical spike was delayed 50 fold, appearing after 36 minutes. Antiepileptic drugs and EEG monitoring may prove useful in patients with status asthmaticus receiving intravenous aminophylline.

Anxiolytic effect of carbamazepine in the elevated plus-maze: possible role of adenosine.

In order to extend previously reported observations with other animal models of anxiety, the effect of carbamazepine (CBZ) was presently measured in rats placed on the elevated plus-maze. Intraperitoneal injection of CBZ (5-40 mg/kg) increased the percentage of open arm entries as well as the percentage of time spent on the open arms of the maze, without affecting the total number of arm entries. This effect is characteristic of anxiolytic drugs. The inhibitor of adenosine neuronal uptake papaverine (5-40 mg/kg) caused a similar anxiolytic effect, whereas the adenosine receptor antagonist aminophylline (1-4 mg/kg) selectively decreased the percentage of open arm entries, indicative of an anxiogenic effect. Furthermore, the combination of an anxiogenic dose (4 mg/kg) of aminophylline with an anxiolytic dose (40 mg/kg) of CBZ resulted in cancellation of each other effects. Since reported neurochemical evidence shows that CBZ interacts with adenosine receptors, the present results provide preliminary support for a participation of this neurotransmitter in the anxiolytic action of CBZ.

Effect of aminophylline on the contraction threshold of rat diaphragm fibers.

We studied the effect of aminophylline (0.1-1 mM) on the contraction threshold (CT) of rat diaphragm fibers (25 degrees C). The CT was measured by direct visualization (x200) of the fiber under current-clamp conditions. The main findings are the following: 1) Aminophylline lowers the CT, in a dose-dependent manner, toward more negative values of the resting membrane potential (Vm). 2) Dibutyryl adenosine 3',5'-cyclic monophosphate (2 mM) shifts the CT, although this change is smaller than in the presence of xanthine. 3) Tetracaine (1 mM), a drug that diminishes Ca release from the sarcoplasmic reticulum, reduces the shift induced by 1 mM aminophylline; this is partially overcome by increasing aminophylline concentration to 5 mM. 4) Hyperpolarization of the fibers shifts the CT to more negative Vm. We suggest that the displacement in the CT to more negative Vm plays an important role in the potentiating effect of aminophylline. This could be the result of an enhancement of Ca release from the sarcoplasmic reticulum.

Diazepam-atenolol combination antagonizes aminophylline-induced convulsions and lethality in mice.

The present study was undertaken to identify protective drugs against aminophylline (240 mg/kg i.p.)-induced convulsions and lethality in mice. Diazepam (10 mg/kg) and valproic acid significantly prevented the convulsions, but were not effective in preventing mortality. Phenytoin, atropine, carbamazepine and atenolol were ineffective in protecting against convulsions and death. Ketamine gave partial protection against convulsions, but was not effective in preventing mortality. Diazepam (10 mg/kg) and atenolol (5 mg/kg) administered together gave total protection against convulsions and death. These results show that aminophylline-induced convulsions are relatively resistant to antiepileptic drugs, and that a combination of diazepam and a beta-blocker (atenolol) has potential as an anti-aminophylline agent.

Inhibition of aminophylline-induced convulsions in mice by antiepileptic drugs and other agents.

Common antiepileptic drugs and agents affecting different neurotransmitter systems were studied against aminophylline (280 mg/kg i.p.)-induced convulsions in mice. All drugs and agents were administered i.p. Diazepam and phenobarbital antagonized the whole seizure pattern and the respective ED50 values for the clonic phase were 3.5 and 62 mg/kg. Valproate at 500 mg/kg protected fewer than 50% of mice against the clonic phase. The remaining antiepileptics (acetazolamide, up to 1,000 mg/kg; carbamazepine and diphenylhydantoin, up to 50 mg/kg; ethosuximide, 500 mg/kg and trimethadione, 400 mg/kg) were totally ineffective in this respect. Propranolol (up to 20 mg/kg), baclofen (20 mg/kg), gamma-hydroxybutyric acid (300 mg/kg), aminooxyacetic acid (20 mg/kg), clonidine (up to 0.2 mg/kg), ketamine (30 mg/kg), atropine (20 mg/kg), papaverine (50 mg/kg) and L-phenylisopropyladenosine (2 mg/kg) did not affect the clonic phase either. Only antagonists of N-methyl-D-aspartic acid excitation, 2-amino-5-phosphonopentanoic acid and 2-amino-7-phosphonoheptanoic acid afforded protection against aminophylline-induced clonic seizure activity. The results show that aminophylline convulsions are relatively resistant to antiepileptic drugs and suggest that antagonists of excitatory transmission are potential antiaminophylline drugs.

Dissociation of adenosine from metabolic regulation of coronary flow in the lamb.

The objective of these studies was to evaluate the contribution of an adenosine mechanism to metabolic regulation of coronary flow. Cardiac O2 metabolism (MVO2) was altered by changing cardiac output while aortic pressure and heart rate were held constant (paced). Ganglionic (tetraethylammonium chloride) and beta blockade (propranolol) were employed. Relationships of coronary flow to MVO2 were determined in control and alloxan diabetic animals. The latter have previously been shown to have reduced sensitivity to adenosine [Am. J. Physiol. 243 (Heart Circ. Physiol. 12): H252-H258, 1982]. In each group, responses were measured before and after adenosine receptor blockade with aminophylline (10 mg/kg). Responses to infused adenosine were also compared. A linear relationship between adenosine infusion rate and flow was found in all conditions. Aminophylline caused a 70% reduction in adenosine sensitivity in controls. In the diabetics, adenosine sensitivity was much reduced and was identical with blocked controls. A close correlation between left ventricular work and MVO2 was found in both groups. Coronary flow increased linearly with MVO2, and the slopes before and after aminophylline were identical. Myocardial O2 extraction remained unchanged. The same relationships were found in the diabetics, and responses did not differ from controls. Thus, in two conditions of sharply reduced sensitivity to exogeneous adenosine, coronary flow (and resistance) were as equally well matched to MVO2 as in controls. These data suggest that mechanisms other than, or in addition to, adenosine provide the close link between MVO2 and coronary flow with changing cardiac work loads.