Influence of vesicular storage and monoamine oxidase activity on [11C]phenylephrine kinetics: studies in isolated rat heart. (1/855)

[11C]Phenylephrine (PHEN) is a radiolabeled analogue of norepinephrine that is transported into cardiac sympathetic nerve varicosities by the neuronal norepinephrine transporter and taken up into storage vesicles localized within the nerve varicosities by the vesicular monoamine transporter. PHEN is structurally related to two previously developed sympathetic nerve markers: [11C]-meta-hydroxyephedrine and [11C]epinephrine. To better characterize the neuronal handling of PHEN, particularly its sensitivity to neuronal monoamine oxidase (MAO) activity, kinetic studies in an isolated working rat heart system were performed. METHODS: Radiotracer was administered to the isolated working heart as a 10-min constant infusion followed by a 110-min washout period. Two distinctly different approaches were used to assess the sensitivity of the kinetics of PHEN to MAO activity. In the first approach, oxidation of PHEN by MAO was inhibited at the enzymatic level with the MAO inhibitor pargyline. In the second approach, the two hydrogen atoms on the a-carbon of the side chain of PHEN were replaced with deuterium atoms ([11C](-)-alpha-alpha-dideutero-phenylephrine [D2-PHEN]) to inhibit MAO activity at the tracer level. The importance of vesicular uptake on the kinetics of PHEN and D2-PHEN was assessed by inhibiting vesicular monoamine transporter-mediated storage into vesicles with reserpine. RESULTS: Under control conditions, PHEN initially accumulated into the heart at a rate of 0.72+/-0.15 mL/min/g wet. Inhibition of MAO activity with either pargyline or di-deuterium substitution did not significantly alter this rate. However, MAO inhibition did significantly slow the clearance of radioactivity from the heart during the washout phase of the study. Blocking vesicular uptake with reserpine reduced the initial uptake rates of PHEN and D2-PHEN, as well as greatly accelerated the clearance of radioactivity from the heart during washout. CONCLUSION: These studies indicate that PHEN kinetics are sensitive to neuronal MAO activity. Under normal conditions, efficient vesicular storage of PHEN serves to protect the tracer from rapid metabolism by neuronal MAO. However, it is likely that leakage of PHEN from the storage vesicles and subsequent metabolism by MAO lead to an appreciable clearance of radioactivity from the heart.  (+info)

Influence of a new antiulcer agent, ammonium 7-oxobicyclo (2, 2, 1) hept-5-ene-3-carbamoyl-2-carboxylate (KF-392) on gastric lesions and gastric mucosal barrier in rats. (2/855)

Antiulcer effects of KF-392 were studied in several experimental gastric ulcer models in rats. It was found that KF-392 given orally at 1.0 to 5.0 mg/kg had a marked suppression on the developments of Shay ulcer as well as the aspirin-, stress-, and reserpine-induced gastric lesions. The influence of KF-392 on gastric mucosal barrier was also studied. A back diffusion of H+ into the gastric mucosa and a fall of transmucosal potential difference were induced with KF-392 given orally at the above mentioned doses. KF-392 given s.c. at 5.0 mg/kg showed no inhibition of Shay ulcer and no induction of back diffusion of H+ into the gastric mucosa.  (+info)

A possible mode of cardiovascular actions of dopamine in dogs. (3/855)

A possible mode of cardiovascular actions of dopamine was studied using ephedrine. In the dog pretreated with repeated administrations of ephedrine (total dose, 40 or 80 mg/kg, i.v.) or with combined administrations of ephedrine (total dose, 90 mg/kg, s.c. and i.v.) and reserpine (2 mg/kg, s.c., 24 hr previously), pressor responses to dopamine were eliminated and reversed to depressor responses whereas depressor responses to dopamine were potentiated. Positive chronotropic effects of dopamine were almost eliminated. Pressor and positive chronotropic effects of tyramine were almost abolished. Sympathomimetic effect of noradrenaline and adrenaline were potentiated while those of isoprenaline were inhibited. In the heart-lung preparation of ephedrine-treated dogs (total dose, 40 mg/kg, i.v.), cardiac stimulating effects of dopamine and tyramine were strongly depressed, and those of noradrenaline, adrenaline and isoprenaline were reduced to some extent. In the open-chest dogs, after pretreatment of cocaine (4 mg/kg, i.v.), pressor, positive inotropic and chronotropic effects of noradrenaline were potentiated, whilst those of tyramine were inhibited. Those of dopamine were not visibly altered, but depressor, negative chronotropic and inotropic effects of dopamine appeared at small doses. In the ephedrine-pretreated dogs, these sympathomimetic effects of dopamine and tyramine after cocaine were strongly depressed and those of noradrenaline were inhibited to a certain degree. The results obtained with ephedrine suggest that dopamine differs from other catecholamines and tyramine in the mode of cardiovascular actions.  (+info)

Pharmacodynamic actions of (S)-2-[4,5-dihydro-5-propyl-2-(3H)-furylidene]-1,3-cyclopentanedione (oudenone). (4/855)

The pharmacodynamic actions of (S)-2-[4,5-dihydro-5-propyl-2(3H)-furylidene]-1,3-cyclopentanedione (oudenone) were studied in both anesthetized animals and isolated organs. Oudenone (10--40 mg/kg i.v.) induced an initial rise in blood pressure followed by a prolonged hypotension in the anesthetized rats. In unanesthetized spontaneously hypertensive rats (SHR), oudenone (5--200 mg/kg p.o.) caused a dose-related decrease in the systolic blood pressure. The initial pressor effect was diminished by pretreatments with phentolamine, guanethidine, hexamethonium and was abolished in the pithed rats. In addition, intracisternal administrations of oudenone (100--600 mug/kg) showed a marked increase in blood pressure in the anesthetized rats, suggesting that the pressor effect may be due to centrally mediated actions. Oudenone, given intra-arterially into the femoral artery (400--800 mug/kg), caused a long-lasting vasodilation in anesthetized dogs. At a relatively high dose (40 mg/kg i.v.), oudenone antagonized all pressor responses to autonomic agents and central vagus nerve stimulation in anesthetized rats and dogs, however, oudenone showed no anti-cholinergic,-histaminergic, beta-adrenergic and adrenergic neuron blocking properties.  (+info)

The role of the sympathetic nervous system in the regulation of leptin synthesis in C57BL/6 mice. (5/855)

The objectives of this study were to determine whether leptin synthesis is regulated by the sympathetic nervous system and if so whether beta-adrenergic receptors mediate this effect. We show that sympathetic blockade by reserpine increases leptin mRNA levels in brown but not white adipose tissue, while acute cold-exposure decreases leptin expression 10-fold in brown adipose tissue and 2-fold in white adipose tissue. The cold-induced reduction in leptin mRNA can be prevented by a combination of propranolol and SR 59230A but not by either antagonist alone, indicating that beta3-adrenergic receptors and classical beta1/beta2-adrenergic receptors both mediate responses to sympathetic stimulation. Circulating leptin levels reflect synthesis in white adipose tissue but not in brown adipose tissue.  (+info)

The effect of reserpine, an inhibitor of multidrug efflux pumps, on the in-vitro activities of ciprofloxacin, sparfloxacin and moxifloxacin against clinical isolates of Staphylococcus aureus. (6/855)

In Staphylococcus aureus, in addition to mutations in the grl and gyr gene loci, multidrug efflux pumps like NorA contribute to decreased fluoroquinolone susceptibility. Efflux pumps can be inhibited by the plant alkaloid reserpine, which, at 20 mg/L, reduced sparfloxacin, moxifloxacin and ciprofloxacin IC50s and MICs by up to four-fold in 11, 21 and 48 of the 102 unrelated clinical isolates tested, respectively. The effect was less pronounced with the hydrophobic drugs sparfloxacin and moxifloxacin than with the hydrophilic drug ciprofloxacin and was stable in all 25 clonally related isolates tested.  (+info)

Increased methamphetamine neurotoxicity in heterozygous vesicular monoamine transporter 2 knock-out mice. (7/855)

Methamphetamine (METH) is a powerful psychostimulant that is increasingly abused worldwide. Although it is commonly accepted that the dopaminergic system and oxidation of dopamine (DA) play pivotal roles in the neurotoxicity produced by this phenylethylamine, the primary source of DA responsible for this effect has remained elusive. In this study, we used mice heterozygous for vesicular monoamine transporter 2 (VMAT2 +/- mice) to determine whether impaired vesicular function alters the effects of METH. METH-induced dopaminergic neurotoxicity was increased in striatum of VMAT2 +/- mice compared with wild-type mice as revealed by a more consistent DA and metabolite depletion and a greater decrease in dopamine transporter expression. Interestingly, increased METH neurotoxicity in VMAT2 +/- mice was accompanied by less pronounced increase in extracellular DA and indices of free radical formation compared with wild-type mice. These results indicate that disruption of vesicular monoamine transport potentiates METH-induced neurotoxicity in vivo and point, albeit indirectly, to a greater contribution of intraneuronal DA redistribution rather than extraneuronal overflow on mediating this effect.  (+info)

Inhibition of the emergence of ciprofloxacin resistance in Streptococcus pneumoniae by the multidrug efflux inhibitor reserpine. (8/855)

Recent evidence supports the contribution of a multidrug efflux mechanism to fluoroquinolone resistance in Streptococcus pneumoniae. In this paper I show that reserpine, an inhibitor of multidrug transporters in gram-positive bacteria, dramatically suppresses the in vitro emergence of ciprofloxacin-resistant variants of S. pneumoniae, suggesting that the combination of a fluoroquinolone with an inhibitor of multidrug transport may help preserve the efficacy of this class of antibiotics.  (+info)