Biomedical subjects

S Bongrani

Publications and source records attributed to S Bongrani.

At least 19 recordsLinked to original sources

PubMed2001

CHF-1024, a DA2/alpha2 agonist, blunts norepinephrine excretion and cardiac fibrosis in pressure overload.

We compared the effects of an ACE inhibitor, captopril, with those of a DA2-dopaminergic/alpha2-adrenergic receptor agonist (CHF-1024) on neuroendocrine activation and cardiac fibrosis in a model of pressure-overload hypertrophy. Interrenal aortic stenosis was performed in 89 rats, treated with CHF-1024 (0.33, 2 or 6 mg kg(-1) day(-1)), or captopril (1 g/L). Hemodynamic variables were recorded. Cardiac and renal weights, plasma aldosterone, renin activity and urinary catecholamine excretion were measured, as well as cardiac collagen. Blood pressure was lower in stenotic animals treated with CHF-1024 compared to vehicle (161 +/- 10 vs 219 +/- 10 mmHg, p < 0.01), but LV weight was similar. CHF-1024 elicited a marked dose-dependent attenuation of urinary norepinephrine excretion (1.80 +/- 0.18 in controls compared to 0.40 +/- 0.14 microg/24 h at the highest dose, p < 0.01) and of LV perivascular fibrosis. Captopril provoked a marked hypotension, reduced cardiac and body weights, plasma aldosterone concentration, dopamine excretion and perivascular collagen. The DA2/alpha2 agonist CHF-1024 effectively blunts adrenergic drive and cardiac fibrosis in a rat model of pressure overload.

Adrenergic alpha-Agonists↗

PubMed1999

Effects of a DA2/alpha2 agonist and a beta1-blocker in combination with an ACE inhibitor on adrenergic activity and left ventricular remodeling in an experimental model of left ventricular dysfunction after coronary artery occlusion.

Renin-angiotensin-aldosterone and sympathetic nervous systems overactivity play a major role in worsening the extent of heart failure. Attenuation of neurohumoral activation with angiotensin-converting enzyme (ACE) inhibitors and beta-blockers has proven beneficial in congestive heart failure. Because ACE inhibition is a recommended treatment for heart failure, this study was designed to test the effects on neurohumoral activation, hemodynamics, and left ventricular (LV) volume of the combination of an ACE inhibitor (delapril) with a DA2-dopaminergic receptor/alpha2-adrenoceptor agonist (CHF-1024) or a beta1-adrenoceptor antagonist (metoprolol) after a moderate to large myocardial infarction (MI) in rats. MI was induced by left coronary artery ligation in 134 rats, and six were not operated on. After 2 months, the animals with ECG evidence of MI were treated for 1 more month with CHF- 1024, 0.33 mg/kg/day or with metoprolol (10 mg/kg/day), delivered through implanted osmotic minipumps, in addition to delapril (6 mg/kg/day) in the drinking water. Daily urinary excretion of norepinephrine (NE) and circulating concentration were measured. Hemodynamic variables were measured, and three-dimensional morphometric analysis was done on the diastole-arrested hearts to quantify infarct size and LV geometry. In conscious animals, delapril alone or with CHF-1024 or metropolol did not modify heart rate or systolic blood pressure. Both combination treatments, however, significantly reduced heart rate in anesthetized animals compared with the group receiving vehicle. Infarct size was not different between treatments, averaging 20-22% of LV volume. The threefold increase of LV chamber volume in infarcted rats was significantly attenuated by delapril alone or with CHF-1024 or metoprolol (-37 to -44%, p<0.05). Treatment with a combination of the ACEi and CHF-1024 tended to normalize the shape of the LV cavity. Urinary NE excretion was unaffected by delapril alone but was reduced by the addition of CHF-1024 or metoprolol. In conclusion, 1 month of treatment with doses of delapril having no hemodynamic effect, reduced LV volume in a model of chronic heart failure. When CHF-1024 or metoprolol was given with delapril, sympathetic activation decreased with no unwanted effects, such as excessive hypotension.

Adrenergic alpha-Agonists↗

PubMed1998

Comparative efficacy of a DA2/alpha2 agonist and a beta-blocker in reducing adrenergic drive and cardiac fibrosis in an experimental model of left ventricular dysfunction after coronary artery occlusion.

Attenuation of neuroendocrine activation may be beneficial in congestive heart failure. Sympathetic nervous system overactivity can be reduced by receptors blockade or by reducing norepinephrine (NE) spillover. This study evaluated and compared the effects of a DA2-dopaminergic receptor/alpha2-adrenoceptor agonist (CHF-1024) and a beta1-adrenoreceptor antagonist in terms of hemodynamics, ventricular remodeling, beta-adrenergic drive, and cardiac fibrosis after myocardial infarction (MI) in rats. MI was induced by left coronary artery ligation in 213 rats, whereas 12 were left unoperated on. After 2 months, the operated-on animals were treated for 1 more month with CHF-1024 at either 0.33 mg/kg/day (low dose) or 1 mg/kg/day (high dose) or with metoprolol (10 mg/kg/day), delivered through implanted osmotic minipumps. Plasma concentration and urinary excretion of NE were measured before the rats were killed. Hemodynamic variables were measured and morphometric analysis was done on the diastole-arrested hearts to quantify left ventricular remodeling and interstitial collagen density. Metoprolol treatment tended to normalize LV end-diastolic pressure (LVEDP). CHF-1024 at either dose, and metoprolol, significantly reduced collagen deposition in LV of infarcted animals (from 8.8 +/- 0.5% LV area in vehicle-treated rats to 6.6 +/- 0.2% or 6.4 +/- 0.2% after the low or high dose of CHF-1024, respectively; p < 0.05). Similarly, CHF-1024 at either dose reduced the plasma concentration of NE (from 224 +/- 53 pg/ml to 60 +/- 7 pg/ml or 87 +/- 13 pg/ml; p < 0.05) and urinary excretion of NE in rats with MI, whereas beta-blockade did not affect these variables. In conclusion, CHF-1024 infused for 1 month to rats with LV dysfunction reduced heart rate, NE spillover, and collagen deposition, without unwanted effects, only appearing at the higher dose. Effective beta-blockade with metoprotol reduced LVEDP with no effects on heart function. Neither DA2/alpha2 stimulation nor beta-blockade altered LV remodeling after coronary artery ligation.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1998

Protective effects of delapril, indapamide and their combination on stroke occurrence and lifespan in salt-loaded stroke-prone spontaneously hypertensive rats.

The effects of long-term oral administration of delapril (CAS 83435-67-0), indapamide (CAS 26807-65-8) and their combination on the occurrence of stroke and on mortality were investigated in young salt-loaded stroke-prone spontaneously hypertensive rats (SHRsp) for 31 weeks of treatment (8th-39th week of age) and up to 8 weeks thereafter. Body weight and saline consumption were investigated at regular intervals and cerebrovascular lesions, renal and heart weight were assessed after sacrifice. Untreated SHRsp served as controls. About 50% of control animals died within 6 weeks of saline administration and in 56% of surviving animals cerebral lesions were present at sacrifice, while no death and no cerebral lesions were observed in animals drinking saline, to which delapril, indapamide and their combination had been added, up to the end of treatment. This protective effect was maintained even in the withdrawal period. All treatments induced a highly significant (p < 0.001) reduction of heart weight/body weight and kidney weight/body weight ratios.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

Evaluation of potentially injurious effects of exogenous surfactant lysophospholipids on the alveolar epithelium and pulmonary mechanics.

Although lysophospholipids are normally found in the lung and their presence is connected to the metabolic pathway of surfactant phospholipids, several studies have reported that their intratracheal instillation is able to induce severe alveolar epithelial injury. Since lysophospholipids are normally present in exogenous surfactants as a consequence of the nonenzymatic hydrolysis of parent phospholipids during their production and shelf-life, the aim of this study was to test the potential toxicity of surfactant lysophospholipids in artificially ventilated newborn rabbits in comparison with that of pure lysophosphatidylcholine (Lyso-PC) suspensions. In premature (surfactant-deficient) animals, a commercially available Curosurf batch (0.56 mg Lyso-PC/ml) improved lung-thorax compliance and reduced lactate dehydrogenase (LDH), total protein and hemoglobin contents in bronchoalveolar lavage (BAL) fluid. The same batch submitted to thermal stress in order to increase the Lyso-PC content (10.2 mg Lyso-PC/ml) failed to improve lung mechanics but did not induce any significant change in biochemical markers in BAL fluid. When suspended in saline, pure Lyso-PC had a dramatic and dose-dependent tissue-damaging effect with increased LDH, hemoglobin and protein contents in BAL and a fall in the lungthorax compliance, in both immature and mature (near-term) animals. The lack of toxicity of Lyso-PC in Curosurf might be explained by an interaction with surfactant phospholipids.

Animals↗

PubMed1996

Ipriflavone does not alter bone apatite crystal structure in adult male rats.

We have previously found that a short-term treatment with high doses of ipriflavone increased bone density and improved the biomechanical properties of adult male rat bones, without altering their mineral composition. To determine whether this effect can be associated with alterations of bone crystal structure, we have performed X-ray diffraction analysis of bones obtained from rats treated with ipriflavone at doses that were effective in inducing favorable changes on bone density and biomechanics. Eighteen-week-old male Sprague Dawley rats were treated by oral route with either ipriflavone (200 or 400 mg/kg/day), or its vehicle for 12 weeks. The treatment was well tolerated and body weight increased to the same extent in all animals. As a measure of bone crystallinity, we examined the (310) and (002) reflections of the X-ray diffraction patterns, corresponding to the directions perpendicular and parallel to the c-axis of the crystals, respectively. No major differences were observed between ipriflavone-treated and control animals for the broadening parameter beta(1/2) for (310) and (002) peaks, as well as for lattice parameters. Therefore, a 12-week treatment with ipriflavone at high doses does not induce significant modifications of bone "crystallinity." Thus, the positive effect of ipriflavone on bone mineral density appears to be associated with an increased apatite crystal formation rather than an increase of crystal size. These results provide further evidence for the safety and usefulness of ipriflavone in the treatment of osteoporotic syndromes.

Animals↗

PubMed1996

Inhibition of parathyroid hormone-stimulated resorption in cultured fetal rat long bones by the main metabolites of ipriflavone.

Ipriflavone is an isoflavone derivative used in the prevention and treatment of postmenopausal and senile osteoporosis in humans. To assess the potential contribution of the main in vivo ipriflavone metabolites (M1, M2, M3, and M5) on the pharmacological properties of the drug, we investigated their effect on osteoclastic resorption induced by the well-known stimulator of bone resorption bovine parathyroid hormone fragment 1-34 (bPTH 1-34). The study was carried out using fetal rat long bones in stationary cultures. The amount of osteoclastic resorption was determined by assaying for 5 days the release from bones in the media of previously incorporated 45Ca. All metabolites were effective at inhibiting osteoclastic resorption. Maximal potency was shown by M3, characterized by a significant effect at 10 microM (P < 0.01) and by an IC50 value of 17 microM. M2 was about threefold less potent than M3 (IC50 = 46 microM). M1 and M5 were the least active compounds with an IC50 value of 117 and 200 microM, respectively. The present evidence indicates that metabolites of ipriflavone, in particular M3 and M2, inhibit bPTH 1-34-induced bone resorption in fetal rat long bones. Accordingly, they may play an important role in the pharmacological effects of the drug.

Animals↗

PubMed1996

The involvement of the release of nitric oxide in the pharmacological activity of the new furoxan derivative CHF 2363.

1. The mechanism of action and the pharmacological effects of the new furoxan derivative, CHF 2363 (4-ethoxy-3-phenylsulphonylfuroxan), were investigated. 2. Pre-incubation of CHF 2363 with human platelet-rich plasma produced a concentration-dependent inhibition of the platelet aggregation induced by collagen, adenosine diphosphate (ADP) and platelet activating factor (PAF). The test compound was about 5 times more potent than sodium nitroprusside. 3-Isobutyl-1-methyl-xanthine (IBMX) potentiated the antiaggregating effect of CHF 2363. 3. CHF 2363 was a potent inhibitor of rubbed endothelium rabbit aortic ring contraction induced by noradrenaline. Comparison of IC50 values showed that CHF 2363 was as potent as glyceryl trinitrate (GTN). 4. Increasing concentrations of CHF 2363 elevated platelet guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels. Adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were unaffected. 5. Oxyhaemoglobin reduced all the pharmacological actions of the test compound. Moreover, CHF 2363 concentration-dependently released nitric oxide (NO) in platelet-rich plasma. The NO release was correlated to its ability to increase platelet cyclic GMP levels. 6. After exposure of rat aortic strips to supramaximal concentrations of GTN (550 microM), the vasorelaxant activity of CHF 2363 did not change, although that of GTN decreased about 55 fold. 7. It has been concluded that the new furoxan derivative CHF 2363 exerts a potent antiaggregating and vasorelaxant activity via NO release and increase of cyclic GMP levels. No in vitro cross tolerance between GTN and CHF 2363 was observed.

1-Methyl-3-isobutylxanthine↗

PubMed1995

Effect of long-term treatment with L-deprenyl on the age-dependent microanatomical changes in the rat hippocampus.

Chronic treatment with L-deprenyl increases both mean and maximum life span and improves cognitive functions in the aged rat. The present study was designed to evaluate whether long-term treatment with L-deprenyl at a dosage not inhibiting the monoamine oxidase-B (MAO-B) (1.25 mg/kg/day) or inhibiting the enzyme activity (5 mg/kg/day) had any effect on the age-dependent microanatomical changes in the rat hippocampus. The hippocampus was chosen in view of its key role in learning and memory functions. Treatment with L-deprenyl started at 19 months and lasted until the 24th month of age. Age-matched untreated rats were used as a control, whereas 11-month-old rats were used as an adult reference group. The number of nerve cell and glial fibrillary acidic protein-immunoreactive astrocyte profiles in the CA1 and CA3 fields of the hippocampus and in the dentate gyrus was decreased and increased, respectively in aged compared with adult rats. Treatment with 5 mg/kg/day, but not with 1.25 mg/kg/day L-deprenyl increased the number of neuronal profiles and decreased the number of astrocytes in the hippocampus of aged rats. The density of zinc stores in the associative intrahippocampal pathway of mossy fibres, which was decreased in aged animals, was increased after treatment with the two doses of L-deprenyl. Lipofuscin accumulation within the cytoplasm of pyramidal neurons of the hippocampus was reduced dose dependently by L-deprenyl treatment. These results suggest that long-term treatment with L-deprenyl is able to counter the expression of age-dependent microanatomical changes in the rat hippocampus. These effects seem only partially correlated with the MAO-B inhibitory activity of L-deprenyl.

Aging↗

PubMed1994

Neuroanatomy of aging brain. Influence of treatment with L-deprenyl.

The present study was designed to assess the influence of long term L-deprenyl treatment on some microanatomical parameters of aging rat frontal cortex and hippocampus. Male Sprague-Dawley rats of 19 months of age were divided into three groups. Rats of the first group received an oral daily dose of 1.25 mg/kg L-deprenyl; animals of the second group were treated with an oral daily dose of 5 mg/kg L-deprenyl, whereas rats of the third group were left untreated and used as control. Treatment lasted for 5 months, and rats were sacrificed at 24 months. At this age they were considered to be old. Another group of 11-month-old rats was used as an adult reference group. The density of nerve cell profiles and of glial fibrillary acidic protein (GFAP) immunoreactive astrocytes was decreased and increased respectively in the frontal cortex and in the different portions of the hippocampus in old in comparison with adult rats. A decrease in the intensity of sulfide silver staining in the mossy fibers of the hippocampus was also observed in old rats. Moreover, a cytoplasmatic accumulation of lipofuscin was noticeable in old rats as well as a significant increase of the monoamine-oxidase (MAO) B reactivity both in the frontal cortex and in the hippocampus. A higher density of nerve cell profiles, of sulfide silver staining, and fewer astrocyte profiles were noticeable in the frontal cortex and in the hippocampus of old rats treated with 5 mg/kg/day of L-deprenyl. This dose of the compound also significantly reduced lipofuscin accumulation and MAO-B reactivity in old rats. However, the lower dose of the compound did not cause any statistically significant effect on the microanatomical parameters investigated with the exception of sulfide silver staining and lipofuscin accumulation, which were increased and decreased respectively after 1.25 mg/kg per day of L-deprenyl. The above results suggest that long-term treatment with L-deprenyl is able to counter some microanatomical changes typical of the aging frontal cortex and hippocampus in the rat. These changes seem to be in part related to the MAO-B inhibitory activity of L-deprenyl.

Aging↗

PubMed1994

CHF 2206, a new potent vasodilating and antiaggregating drug as potential nitric oxide donor.

The effects of the new 3,4-disubstituted furoxan, CHF 2206, on vascular tone, platelet aggregation and platelet cyclic 3',5'-guanosine monophosphate (cGMP) levels were investigated. The compound was a potent inhibitor of rabbit aortic ring contraction induced by norepinephrine, the stable prostaglandin F2 alpha analogue, U-46619, and KCl; this activity was independent of endothelium integrity. When pre-incubated with platelet-rich plasma, CHF 2206 potently reduced in a dose-dependent manner the aggregation induced by the threshold aggregating concentration of collagen, ADP or platelet activating factor (PAF). In the same experimental conditions, the test compound increased the platelet cGMP levels and this rise was clearly associated with the inhibition of platelet aggregation. Moreover, 3-isobutyl-1-methyl-xanthine (IBMX) 5 microM potentiated the antiaggregating activity of CHF 2206. These results indicate that the increase in cGMP plays a key role in the CHF 2206-elicited responses. Oxyhemoglobin reduced all the pharmacological actions of the test compound. This evidence, along with the capacity of CHF 2206 to cause inorganic nitrite production in the presence of platelet-rich plasma, strongly suggests that nitric oxide (NO) may be a common reactive intermediate responsible for the effects induced by the drug. In conclusion, the furoxan derivative CHF 2206 exerts a potent antiaggregating and vasodilating activity with a pharmacological profile similar to the one described for NO-donating pro-drugs.

1-Methyl-3-isobutylxanthine↗

PubMed1994

Repeated administrations of (-)-deprenyl increase [3H]MK801 binding in rat brain and antagonize the impairment of passive avoidance conditioning induced by N-methyl-D-aspartate receptor antagonists.

Repeated but not single administrations of the MAO type B inhibitor (-)-deprenyl (1 mumol/kg s.c. for 21 consecutive days) antagonized the impairment of passive avoidance retention induced by the N-methyl-D-aspartate (NMDA) receptor antagonists 2-amino-5-phosphonovalerate (APV), ketamine and dizocilpine (MK801), in rats. In well-washed membranes prepared from the hippocampi of rats repeatedly treated with (-)-deprenyl, the [3H]MK801 specific binding was increased. In contrast, repeated MAO B-selective doses of pargyline or (+)-amphetamine, as well as single injections with (-)-deprenyl failed to change [3H]MK801 binding. It is suggested that the effects of repeated (-)-deprenyl administrations upon NMDA receptors and upon the impairment of acquisition of a passive avoidance task induced by NMDA antagonists could be independent of MAO inhibition.

2-Amino-5-phosphonovalerate↗

PubMed1994

Influence of long-term treatment with L-deprenyl on the age-dependent changes in rat brain microanatomy.

The present study was designed to assess whether treatment with the monoamine oxidase-B (MAO-B) inhibitor L-deprenyl, which has been documented to increase both mean and maximum survival in aged rats as well as sexual performance and cognitive function, has any effect on the age-related microanatomical changes occurring in the rat brain. Male Sprague-Dawley rats received a subcutaneous injection of 0.25 mg/kg L-deprenyl every other day from the 19th to the 24th month of age. Age-matched control rats were injected with saline, whereas 11-month-old untreated rats were used as an adult reference group. Both body and brain weight were increased as a function of age, and they were unaffected by treatment with L-deprenyl. The density of nerve cell profiles in the frontal cortex, in the CA-1 and CA-3 subfields of the hippocampus, in the dentate gyrus and in the cerebellar cortex were decreased in aged rats in comparison with adult rats. The density of nerve cell profiles in the above brain areas of L-deprenyl-treated rats was not significantly higher in comparison with age-matched control animals with the exception of Purkinje neuron profiles. The intensity of Nissl's staining, which may be related to the protein synthetic capabilities of nerve cells, is reduced within pyramidal neurons of the hippocampus and Purkinje neurons of the cerebellar cortex of aged rats. The intensity of Nissl's staining in L-deprenyl-treated rats was not different from adult rats. Lipofuscin deposition was significantly increased within the cytoplasm of pyramidal neurons of the frontal cortex, of the CA-3 subfield of the hippocampus and of Purkinje neurons of the cerebellar cortex. L-Deprenyl administration decreased lipofuscin accumulation within the cytoplasm of the above mentioned nerve cell types. The density of sulphide-silver staining in the intrahippocampal pathway of mossy fibres, which participate in the elaboration of passive avoidance responses, is decreased in aged rats. Treatment with L-deprenyl counters this age-related reduction. The above results suggest that long-term treatment with L-deprenyl is able to counter the expression of some microanatomical changes typical of aging brain.

Aging↗

PubMed1994

Influence of treatment with L-deprenyl on the structure of the cerebellar cortex of aged rats.

Treatment with L-deprenyl increases mean and maximum life span in the rat and reverses memory and learning deficits associated with old age. Since only sparse information is available concerning the influence of L-deprenyl administration on the aging brain microanatomy, we have investigated the effect of long-term treatment with L-deprenyl on the structure of the cerebellar cortex in the aged rat. The cerebellar cortex was used since it represents a useful model for assessing age-related changes in nervous system anatomy and function. Male Sprague-Dawley rats were treated from the 19th to the 24th month of age with a daily oral dose of 1.25 mg/kg or 5 mg/kg L-deprenyl. Age-matched rats were left untreated and used as a control group. Eleven-month-old untreated rats were used as an adult reference group. The density of Purkinje and granule neuron profiles as well as the intensity of Nissl's staining within the cytoplasm of Purkinje neurons were reduced in 24-month in comparison with 11-month rats. Moreover, an increased accumulation of lipofuscin was noticeable in the cytoplasm of Purkinje neurons of old rats as well as an increase in MAO-B activity in the molecular layer of the cerebellar cortex. The two doses of L-deprenyl increased the density of both Purkinje and granule neuron profiles and the intensity of Nissl's staining in the cytoplasm of Purkinje neurons and reduced lipofuscin deposition within Purkinje neurons. The lower dose of L-deprenyl caused only a slight decrease in MAO-B activity, whereas the 5-mg/kg/day dose remarkably reduced it. These results suggest that long-term treatment with L-deprenyl counters the expression of some age-related microanatomical changes in the rat cerebellar cortex. The possible independence of the effects of the compound on age-related microanatomical changes of the cerebellar cortex and on MAO-B inhibitory activity is discussed.

Aging↗

PubMed1994

Lung gas volumes and expiratory time constant in immature newborn rabbits treated with natural or synthetic surfactant or detergents.

Immature newborn rabbits delivered at a gestational age of 27 days were tracheotomized and treated, via the tracheal cannula, with clinically recommended doses of natural or synthetic surfactant (Curosurf and Exosurf, respectively). Littermates received 0.1% tyloxapol, 5% Tween 20, or saline. The dose volume of Curosurf was 2.5 ml/kg, that of the other materials 5 ml/kg. Animals were kept in a multiplethysmograph system and ventilated for 30 min with a standardized sequence of insufflation pressures. End-expiratory lung gas volume was calculated at the end of the experiment from measurements of lung weight and total lung volume. Tidal volumes were significantly improved in all groups of animals receiving surfactant or detergents. However, expiratory time constant (determined from the tidal volume tracing) was significantly longer, and end-expiratory gas volume significantly larger, in animals treated with Curosurf than in those receiving Exosurf or detergents. These differences were confirmed by semiquantitative evaluation of alveolar air expansion in histological sections. In addition, airway epithelial necrosis was reduced in animals receiving Curosurf, Exosurf, or Tween 20, but not in animals treated with tyloxapol. The discrepancy between improvements in tidal volume, expiratory time constant, and end-expiratory gas volume reflects failure of lung stabilization in animals treated with Exosurf or detergents, probably due to absence of specific hydrophobic proteins in the synthetic products.

Animals↗

PubMed1992

Deficits in cholinergic neurotransmission markers induced by ethylcholine mustard aziridinium (AF64A) in the rat hippocampus: sensitivity to treatment with the monoamine oxidase-B inhibitor L-deprenyl.

Assessment was made of the effects of intracerebroventricular (i.c.v.) administration of ethylcholine mustard aziridinium (AF64A) and of the monoamine oxidase (MAO)-B inhibitor L-deprenyl on the acetylcholine (ACh) biosynthetic enzyme choline acetyltransferase (ChAT), on the ACh catabolic enzyme acetylcholinesterase (AChE) and on the density of ACh muscarinic M-1 and M-2 receptor sites. In addition, the effect of AF64A and of L-deprenyl treatment on the localization of AChE activity in the CA-1 and CA-3 fields of the hippocampus was evaluated by combined enzyme histochemistry and microdensitometry techniques. I.c.v. injection of AF64A induced, 4 weeks after administration of the neurotoxin, a remarkable increase of MAO-B activity, and a significant reduction of ChAT and AChE activities in the hippocampus but not in the neostriatum which was used as a reference tissue. Hippocampal muscarinic M-1 receptors were unaffected by AF64A administration, whereas M-2 sites were reduced after neurotoxin injection. Enzyme histochemistry analysis showed that the loss of AChE induced by AF64A was more pronounced in the CA-3 than in the CA-1 field of the hippocampus. Treatment with L-deprenyl induced, from a dose of 11.17 microM/kg/day, a significant reduction of MAO-B activity in the hippocampus. The expression of ChAT and AChE, as well as the density of M-2 receptors, was increased after L-deprenyl administration in the hippocampus but not in the neostriatum. An increase in AChE reactivity was noticeable in the CA-1 and CA-3 fields of the hippocampus of AF64A-injected rats treated with L-deprenyl.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗

PubMed1991

Modulation of arachidonic acid metabolism by orally administered morniflumate in man.

Unlike other classic NSAIDs, some fenamates given at therapeutic concentrations, have been shown to inhibit, both in vitro and in vivo, the 5-lipoxygenase pathway of arachidonic acid cascade as well as the synthesis of cyclooxygenase products. This dual inhibitory property might represent an improvement in anti-inflammatory therapy. The aim of this work was to characterize the effect of morniflumate, administered at therapeutic dosages to normal human volunteers, on leukotriene B4 (LTB4) and thromboxane (TXB2) synthesis, both in purified PMNs and in whole blood. PMNs, isolated two hours after a single oral administration of morniflumate and at steady-state condition, fully retain their capacity to release LTB4 and TXB2. Since intracellular concentrations of the drug were undetectable, in spite of its elevated concentrations in platelet poor plasma, the results obtained using PMNs suggest a drug loss during the cells purification procedure. In whole blood experiments, morniflumate reduced blood LTB4 synthesis induced by Ca-ionophore A23187 Bx approximately 50%, both after single dose and at steady state; the degree of inhibition showed a pattern similar to the plasma levels of the bioactive metabolite of morniflumate (M1). The inhibition of serum TXB2 levels was higher than 85%. Hence, morniflumate is capable of reducing arachidonic acid metabolism acting both on cyclooxygenase and 5-lipoxygenase. This characteristic might provide a better approach in anti-inflammatory therapy.

Administration, Oral↗

PubMed1990

Lack of cardiostimulant effects of bamifylline in in vitro and in vivo models.

The cardiac effects of bamifylline (Bamifix), an alkylxanthine derivative, were evaluated on in vivo and in vitro cardiac preparations and compared with those of theophylline and enprofylline. In isolated rat and guinea-pig right atria bamifylline, in contrast to the other xanthines, left the rate of contraction unchanged or reduced it. In isolated rat and guinea-pig left atria the compound induced only slight inotropic effects showing an intrinsic activity significantly lower than that of theophylline and enprofylline. In isolated rabbit papillary muscles bamifylline administration was without effect up to 10(-3) mol/l and decreased the contractile force at a higher concentration, while theophylline dose-dependently increased inotropism. Also in anaesthetized rabbits intravenous administration of bamifylline produced negative chronotropic and dromotropic effects that were associated, at the highest dose, with a reduction of myocardial contractility. Theophylline and enprofylline, at the same equimolar doses, induced positive chronotropic and inotropic effects. The results show that bamifylline is devoid of cardiostimulant effects in respect to other xanthine derivatives. Moreover, they suggest that bamifylline acts on cardiac muscle by a mechanism, probably linked to the Ca+(+)-movements across the cardiac membrane, able to outweigh the effects due to its antiphosphodiesterase activity.

Animals↗