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F Hefti

Publications and source records attributed to F Hefti.

At least 163 records · Page 9Linked to original sources
PubMed1990

Effects of angiotensin converting enzyme inhibitors and of hydralazine on endothelial function in hypertensive rats.

The function of the endothelium is impaired in hypertension. In spontaneously hypertensive rats (SHR), acetylcholine-induced relaxation is decreased and serotonin-induced constriction is increased. The goal of our study was to evaluate the effect of a long-term treatment with cilazapril, a new angiotensin converting enzyme inhibitor, or hydralazine, a vasodilator, on the endothelium-dependent responses in aorta of SHR. Wistar-Kyoto rats were used as normotensive reference. Isolated aortic rings with or without endothelium were suspended in organ chambers. The rings with intact endothelium were contracted with norepinephrine. Acetylcholine-induced relaxation was markedly enhanced by cilazapril treatment. The tension achieved at maximal relaxation was 8 +/- 4% of norepinephrine contraction in the cilazapril-treated SHR versus 55 +/- 5% in the untreated SHR (p less than 0.001). Hydralazine had no significant effect. The effect of serotonin was also markedly modified by cilazapril. In untreated SHR, serotonin induced the release of a vasoconstrictor substance by the endothelium as assessed by the ratio of maximal tension induced by serotonin in rings with endothelium over maximal tension in rings without endothelium, which was greater than 1. This ratio was reversed in cilazapril-treated SHR but not in hydralazine-treated SHR. Captopril had effects similar to cilazapril. Finally, evaluation of carotid arteries showed that cilazapril also prevented morphological changes of the intima in SHR (i.e., infiltration by mononuclear cells). We conclude that angiotensin converting enzyme inhibitors prevent the functional and morphological alterations in endothelium that are found in hypertension and speculate that this action might participate in their antihypertensive effect.

Acetylcholine↗
PubMed1990

[Femur head necrosis in childhood].

The natural history of avascular necrosis of the femoral head in children and adolescents shows significant differences compared to the course of this disease in adults. Depending on the remaining growth potential, even extensive damage of the femoral head can regenerate, as long as the epiphyseal growth plate is not involved in the process. Otherwise, the deformity will increase with time. Current knowledge on the etiology, natural history, diagnosis and treatment is described on Perthes' disease and other possible causes of avascular necrosis, such as CDH, epiphyseolysis of the femoral head, femoral neck fracture and some uncommon diseases.

Adolescent↗
PubMed1990

Antihypertensive properties of the novel calcium antagonist (1S,2S)-2-[2-[[3-(2-benzimidazolyl)propyl]methylamino] ethyl]-6- fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate dihydrochloride in rat models of hypertension. Comparison with verapamil.

(1S,2S)-2-[2-[[3-(2-Benzimidazolyl)propyl]methylamino]ethyl]-6- fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate dihydrochloride (Ro 40-5967) is a novel calcium antagonist. Its effect on systolic arterial blood pressure and heart rate was investigated in comparison with verapamil in conscious spontaneously hypertensive rats (SHR), renal hypertensive rats (2K1C), deoxycorticosterone acetate (DOCA)-NaCl hypertensive rats and normotensive Wistar rats. After single oral doses, Ro 40-5967 (3-30 mg/kg) and verapamil (10-100 mg/kg) produced a dose-related decrease in blood pressure in all three types of hypertensive rats. Ro 40-5967 was 3-5 times more potent than verapamil. DOCA-NaCl hypertensive rats were more sensitive to the antihypertensive action of Ro 40-5967 than renal hypertensive rats and SHR. Both compounds lowered blood pressure of normotensive rats to a lesser degree than that of hypertensive rats. The antihypertensive effects of Ro 40-5967 and verapamil occurred fast, with similar efficacies and reached maximal values 3 and 6 h postdrug (SHR). While the significant antihypertensive effect of Ro 40-5967 (30 mg/kg) persisted for 24 h, that of verapamil (100 mg/kg) recovered completely 16 h postdrug. The experimental data suggest that Ro 40-5967 might be suitable for clinical use as a once-a-day antihypertensive agent.

Animals↗
PubMed1990

Selective and nonselective stimulation of central cholinergic and dopaminergic development in vitro by nerve growth factor, basic fibroblast growth factor, epidermal growth factor, insulin and the insulin-like growth factors I and II.

To study the selectivity of neurotrophic actions in the brain, we analyzed the actions of several known growth factors on septal cholinergic, pontine cholinergic, and mesencephalic dopaminergic neurons in culture. Similar to nerve growth factor (NGF), basic fibroblast growth factor (bFGF) stimulated choline acetyltransferase activity in septal cultures. In contrast to NGF, bFGF also enhanced dopamine uptake in mesencephalic cultures and stimulated cell proliferation in all 3 culture types. Insulin and the insulin-like growth factors I and II stimulated transmitter-specific differentiation and cell proliferation in all culture types. Epidermal growth factor (EGF) produced a small increase in dopamine uptake by mesencephalic cells and stimulated cell proliferation in all culture types. In septal cultures, bFGF was most effective when given at early culture times, NGF at later times. The stimulatory actions of bFGF and insulin did not require the presence of glial cells and were not mediated by NGF. In mesencephalic cultures, the stimulation of dopamine uptake by bFGF and EGF was dependent on glial proliferation. The results suggest different degrees of selectivity of the neurotrophic molecules. NGF and, very similarly, bFGF seem to influence septal cholinergic neurons directly and rather selectively, whereas the neurotrophic actions of insulin and the insulin-like growth factors appear to be more general.

Animals↗
PubMed1989

Decreases of vascular hypertrophy in four different types of arteries in spontaneously hypertensive rats.

The goal of the present study was to describe the relative extent of vascular hypertrophy in four different types of arteries (coronary, renal, carotid, and mesenteric) of spontaneously hypertensive rats (SHR) and to evaluate the effects of long-term treatment with cilazapril, a new long-acting angiotensin-converting enzyme inhibitor on this vascular hypertrophy. For this purpose, a group of spontaneously hypertensive rats treated for four months with cilazapril (10 mg/kg orally) was compared with a group of spontaneously hypertensive rats treated with placebo. Another group of Wistar Kyoto (WKY) rats treated with placebo was used as a reference. At the end of the treatment period, the rats were perfused-fixed and morphometry of the carotid, renal, mesenteric and coronary arteries was performed. Vascular hypertrophy (increase of the thickness of the medial layer) was present in the four different types of arteries in a similar extent. Cilazapril normalized completely the arterial wall thickness:diameter ratio in the four different types of arteries. Further studies are required to determine whether this effect of cilazapril was due to the decrease of arterial blood pressure or to an effect of cilazapril on growth factors such as angiotensin II.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury.

The role of a local angiotensin system in the vascular response to arterial injury was investigated by administering the angiotensin-converting enzyme (CE) inhibitor cilazapril to normotensive rats in which the left carotid artery was subjected to endothelial denudation and injury by balloon catheterization. In control animals, by 14 days after balloon injury, the processes of smooth muscle cell (SMC) proliferation, migration of SMCs from the media to the intima, and synthesis of extracellular matrix produced marked thickening of the intima, with reduction of the cross-sectional area of the lumen. However, in animals that received continuous treatment with the CE inhibitor, neointima formation was decreased (by about 80 percent), and lumen integrity was preserved. Thus, the angiotensin-converting enzyme may participate in modulating the proliferative response of the vascular wall after arterial injury, and inhibition of this enzyme may have therapeutic applications to prevent the proliferative lesions that occur after coronary angioplasty and vascular surgery.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Acetaminophen metabolism by cytochrome P450 monooxygenases in Parkinson's disease.

It has been suggested that alterations in the activity of cytochrome P450 monooxygenases may play a role in the pathogenesis of Parkinson's disease, particularly in patients who had onset before the age of 40. We studied the P450-mediated metabolism of acetaminophen to 3-hydroxy-acetaminophen in 26 patients with Parkinson's disease and in 18 control subjects. After subjects ingested 1,000 mg acetaminophen, urine was collected under controlled conditions. Acetaminophen and 3-hydroxy-acetaminophen were measured in the urine using newly developed high-pressure liquid chromatography methods. The ratio of 3-hydroxy-acetaminophen to acetaminophen was calculated for each patient and no significant differences were observed in patients compared with control subjects. Abnormal metabolism was not observed in patients who had onset of Parkinson's disease at or before the age of 40. In addition, no difference in metabolic activity was observed between the patients who were treated with levodopa/carbidopa and those who were not treated. These findings suggest that there are no alterations of P450-mediated metabolism of acetaminophen in patients with Parkinson's disease.

Acetaminophen↗
PubMed1989

Effects of acute and chronic cilazapril treatment in spontaneously hypertensive rats.

1. The effects of acute and chronic treatment with cilazapril, a new ACE inhibitor, on peripheral vasculature and renal excretory function were assessed in spontaneously hypertensive rats. Regional blood flow and cardiac output were measured by the radioactive microspheres technique. 2. Acute treatment (3 mg kg-1 intravenously) reduced mean arterial blood pressure from 171 +/- 7 to 140 241 +/- 7 mm Hg (P less than 0.001), chronic treatment (1 x 10 mg kg-1 day-1 orally for 9 weeks) from 191 +/- 5 to 122 +/- 3 mm Hg P less than 0.001). With both kinds of treatments cardiac output was unchanged. Heart rate was slightly decreased (-9%, P less than 0.05) with chronic treatment. Acutely, the main effect of cilazapril was a decrease of the renal vascular resistance (-41%, P less than 0.001) associated with an increase of the fraction of the cardiac output distributed to the kidney (+46%, P less than 0.001). Chronically, cilazapril decreased regional vascular resistance in most of the peripheral vascular beds except the heart. 3. With a high dose of cilazapril (10 mg kg-1 orally) both acute and chronic treatment increased diuresis (+107% and +92%, P less than 0.001) and natriuresis (/124% and +111%, P less than 0.001) with a slight increase in kaliuresis. However, with a low dose (1 mg kg-1 orally) the kidneys responded only to chronic treatment. 4. It is concluded that chronic treatment with cilazapril decreases arterial blood pressure more than acute treatment. This effect seems to be due to a greater peripheral vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Selective visualization of rodent locus ceruleus by a radiolabeled N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine analog.

The neurotoxic metabolite of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenylpyridinium, selectively accumulates in dopaminergic neurons via the dopamine reuptake system. Consequently, nontoxic radiolabeled MPTP analogs may be potentially useful for visualizing catecholaminergic neurons in vivo. N-Methyl-4-(4-hydroxy-3-[125I]iodobenzyl)-1,2,3,6-tetrahydropyridine [( 125I]MHTP), an analog of the nontoxic N-methyl-4-benzyl-1,2,3,6-tetrahydropyridine, has been studied in rats and mice. After intravenous administration of [125I]MHTP to rodents, the initial accumulation of radioactivity within the brain was found to be comparable to that of radiolabeled MPTP. Following intravenous administration of [125I]MHTP, in vivo autoradiographic visualization of the rodent brain revealed selective accumulation of [125I]MHTP-derived radioactivity within the locus ceruleus; there was no accumulation of the radiotracer within dopaminergic fibers and cell bodies. The accumulation of radioactivity within the locus ceruleus was blocked by pretreatment with pargyline, a result suggesting that an MHTP metabolite formed by monoamine oxidase was responsible for the localization of the radiotracer within this structure. The anatomical distribution of the radiolabel demonstrates selective accumulation of this metabolite within noradrenergic cell bodies and those fibers making up the locus ceruleus. These findings further suggest that nontoxic metabolites of MPTP may become useful for in vivo labeling of selected populations of catecholaminergic neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Effects of cilazapril on the cerebral circulation in spontaneously hypertensive rats.

Chronic hypertension is associated with a lower cerebral vascular reserve due to thickening of the media of cerebral vessels. The goal of the present study was to determine if long-term inhibition of angiotensin converting enzyme with cilazapril, a new long-acting angiotensin converting enzyme inhibitor, could improve cerebral vascular reserve. For this purpose, two groups of 12 spontaneously hypertensive rats were compared. One group was treated with 10 mg/kg/day cilazapril from 14 weeks to 33 weeks of age and was compared with a group treated with placebo. A third group of 12 Wistar-Kyoto rats treated with placebo was used as reference. At the end of the treatment period, cerebral vascular reserve was evaluated by measuring cerebral blood flow (radioactive microspheres) at rest and during maximal vasodilation induced by seizures provoked by bicuculline. Then, the rats were perfusion-fixed, and morphometry of the cerebral vasculature was performed. Cerebral vascular reserve was severely impaired in the spontaneously hypertensive rats since their maximal cerebral blood flow was decreased by 52% compared with the Wistar-Kyoto rats. Cilazapril normalized cerebral blood flow reserve. This normalization was associated with a decreased thickness of the medial layer in the carotid artery, the middle cerebral artery, and in the pial arteries larger than 100 microns. Further studies are required to determine whether this decreased medial thickness is due to the normalization of blood pressure induced by cilazapril or to the reduction of trophic factors such as angiotensin II.

Animals↗
PubMed1989

Rationale for the planned clinical trials with nerve growth factor in Alzheimer's disease.

A large number of experimental studies on animals suggest that intraventricular administration of NGF to Alzheimer patients may attenuate the degeneration of cholinergic neurons and the behavioral consequences associated with the cholinergic deficits. Based on these findings clinical trials with NGF seem justified, if potential detrimental effects are ruled out. Once NGF administration is proven effective it will be possible to develop alternative ways of NGF administration.

Aged↗
PubMed1989

Effects of chronic ACE inhibition on cardiac hypertrophy and coronary vascular reserve in spontaneously hypertensive rats with developed hypertension.

Left ventricular hypertrophy due to hypertension is associated with a decrease of coronary vascular reserve. We have previously shown that chronic angiotensin converting enzyme (ACE) inhibition prevents cardiac hypertrophy and improves coronary vascular reserve when the treatment is started before appearance of hypertension in spontaneously hypertensive rats (SHR). However, the effects of starting chronic ACE inhibition when hypertension was already developed is not known. The goal of the present study was to assess the effects of chronic ACE inhibition on coronary vascular reserve and on the morphology of the coronary microvasculature when treatment was started after hypertension had developed. For this purpose, one group of SHR was treated from 3-8 months of age with cilazapril, a new ACE inhibitor, and compared with a group treated by placebo. At the end of treatment, cardiac hypertrophy, coronary vascular reserve, density and cross-sectional surface area of the myocardial capillaries (normalized for the myocardial mass) and wall/lumen ratio of the coronary arterioles were determined. Chronic ACE inhibition with cilazapril reduced cardiac hypertrophy and improved by more than 50% coronary vascular reserve in the left and right ventricles. In the left ventricle, the improvement was more pronounced in the subendocardium than in the subepicardium. Cilazapril increased the density and the cross-sectional surface area of the myocardial capillaries and decreased the wall/lumen ratio of the arterioles of the left ventricle. We conclude that chronic ACE inhibition can improve coronary vascular reserve, increase capillary density and capillary cross-sectional surface area and decrease the thickness of the media of coronary arterioles in SHR even when treatment is started after development of hypertension.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Toxic effects of potential environmental neurotoxins related to 1-methyl-4-phenylpyridinium on cultured rat dopaminergic neurons.

Dopaminergic rat mesencephalic neurons in culture were exposed to a group of potential environmental neurotoxins. These cultures, which contained 0.5 to 1% dopaminergic neurons, were a suitable tool for determining nonselective and selective dopaminergic cytotoxicity. Selective toxicity was quantitated as the concentration which destroyed half of the population of dopaminergic neurons as visualized by tyrosine hydroxylase immunocytochemistry. Nonselective toxicity was defined as the concentration of test drug which destroyed half of the entire population of cultured cells as visualized by phase contrast microscopy. The compounds tested were selected to fulfill two molecular criteria underlying the toxic activity of 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toward dopaminergic cells: 1) to be a substrate for the selective uptake system of the dopaminergic neurons and 2) to possess a delocalized positive charge related to their ability to inhibit mitochondrial electron transport. Of a total number of 29 compounds tested, MPP+ and its close derivatives, 2'-methyl-MPP+ and p-amino-MPP+, exhibited highly selective dopaminergic toxicity, hence the requirements for a selective dopaminergic neurotoxin are rather strict.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Pharmacological profile of moclobemide, a short-acting and reversible inhibitor of monoamine oxidase type A.

The novel antidepressant moclobemide is a reversible inhibitor of monoamine oxidase (MAO), preferentially of type A. Moclomide was active in three animal models considered predictive for antidepressant activity: 1) it prevented dose-dependently akinesia and blepharospasm induced in mice and rats by Ro 4-1284, a short-acting amine releasing agent. Prevention of akinesia by moclobemide also depended upon the dose of Ro 4-1284. For comparison also, effects of cimoxatone, harmaline, tranylcypromine and clorgyline are presented: 2) in cats, it selectively and dose-dependently suppressed rapid eye movement sleep without disturbing the sleep-wakefulness cycle; and 3) in the behavioral despair test in mice, it decreased the immobility score to a similar degree as amitriptyline or imipramine. In addition, moclobemide potentiated 5-hydroxytryptophan-induced stereotypies in rats with a potency similar to cimoxatone and with a duration of action of less than 24 hr. Moclobemide had almost no effect on the spontaneous behavior in mice, rats, cats and monkeys. Only in higher doses, marginal sedation and slight impairment in motor performance were seen. Moclobemide did not prevent pilcarpine-induced salivation in mice, demonstrating the absence of anticholinergic activity. Blood pressure and heart rate of freely moving, spontaneously hypertensive rats were only slightly decreased for less than 3 hr. Moclobemide moderately potentiated the pressor effect of p.o. tyramine in rats. In conclusion, the reversible MAO inhibitor moclobemide is active in animal models sensitive to all major drugs used in the treatment of depression. In contrast to imipramine-like antidepressants, it lacks anticholinergic activity and it differs from classic MAO inhibitors by potentiating only weakly the pressor effect of p.o. tyramine.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
PubMed1988

Cilazapril prevents the development of cardiac hypertrophy and the decrease of coronary vascular reserve in spontaneously hypertensive rats.

Cilazapril is a new inhibitor of angiotensin converting enzyme which has been shown to prevent development of high blood pressure and cardiac hypertrophy in spontaneously hypertensive (SHR) rats. The goal of the present experiment was to evaluate the effects of a chronic treatment with cilazapril on the decrease of coronary reserve in SHR rats. For this purpose, a group of 10 SHR rats which received by oral gavage 10 mg/kg/day of cilazapril for 9 weeks was compared with a control group of 9 SHR rats which received distilled water. Coronary reserve was evaluated by measuring coronary blood flow with the radioactive microspheres method before and after a dose of dipyridamole (2 mg/kg/min) which induces maximal coronary vasodilation. The left ventricular weight/body weight ratio was decreased in the cilazapril group compared to the placebo-treated group (p less than 0.001). Moreover, minimal coronary vascular resistance of the left ventricle and the right ventricle were 33% and 39%, respectively, lower in the cilazapril group as compared with the control group (p less than 0.01). We conclude that chronic treatment with cilazapril can prevent the development of left ventricular hypertrophy and the decrease of coronary vascular reserve in the left and right ventricles of spontaneously hypertensive rats.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Selective destruction of cultured dopaminergic neurons from fetal rat mesencephalon by 1-methyl-4-phenylpyridinium: cytochemical and morphological evidence.

Dopaminergic neurons in cultures of dissociated cells from fetal rat mesencephalon were exposed to the principal metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenyl-pyridinium ion (MPP+), and several of its structural analogues. At concentrations between 0.01 and 0.1 microM, MPP+ inhibited catecholamine accumulation as visualized by cytofluorescence. Between 0.1 and 10.0 microM, MPP+ resulted in disappearance of tyrosine hydroxylase immunoreactivity without affecting other cells in the cultures. At concentrations higher than 10 microM, MPP+ was toxic to all cells present in the cultures. The effect of low concentrations of MPP+ on catecholamine cytofluorescence of the dopaminergic neurons was partially reversible. The intermediate concentrations produced irreversible structural changes of tyrosine hydroxylase-positive cells, resulting in complete disappearance of these neurons. The morphological changes were specific to the dopaminergic neurons and were not evident in other cells viewed with phase contrast microscopy. Of the structural analogues tested, the 1-ethyl analogue of MPP+ was effective in selectively destroying dopaminergic neurons in our culture system. The antioxidants L-acetyl-carnitine, beta-carotene, and alpha-tocopherol failed to protect against MPP+ neurotoxicity when co-incubated with the toxin.

1-Methyl-4-phenylpyridinium↗
PubMed1988

Development of septal cholinergic neurons in culture: plating density and glial cells modulate effects of NGF on survival, fiber growth, and expression of transmitter-specific enzymes.

To characterize the role of NGF in the development of forebrain cholinergic neurons, we established primary cell culture systems to grow these cells under controlled in vitro conditions. Cultures of dissociated cells were prepared from the septal area of fetal (E17) rats, which contained part of the group of basal forebrain cholinergic neurons. Cultures were treated either with NGF (100 ng/ml) or with an antiserum against NGF (1:500 dilution). To assess the influence of non-neuronal cells, 2 types of high-density cultures were prepared: mixed neuronal-glial cultures and pure neuronal cultures. Cholinergic neurons were identified using choline acetyltransferase (ChAT) immunocytochemistry and AChE cytochemistry. Receptors for NGF (NGF-R) were located immunocytochemically using monoclonal antibodies against rat NGF-R. We report that, first, NGF-R are exclusively localized on cholinergic neurons in septal cultures. All neurons labeled with antibodies against NGF-R also contained AChE. Twenty-one percent of all AChE-positive neurons were not stained in NGF-R immunocytochemistry (AChE has earlier been shown to be colocalized with ChAT in septal cultures). Second, NGF treatment increases and anti-NGF treatment reduces the number of AChE-positive neurons in cultures of low plating density, suggesting that NGF promotes survival of septal cholinergic neurons in these cultures. In cultures of high plating density, NGF increased the number of NGF-R and ChAT-positive neurons without affecting the number of AChE-positive neurons in these cultures. These results suggest that exogenous NGF is not required for survival of cholinergic neurons in high-density cultures but stimulates the expression of ChAT and NGF-R. Third, NGF stimulates fiber growth of septal cholinergic neurons, as assessed by computerized image analysis of AChE-positive neurons. Fourth, NGF specifically increases ChAT and AChE activities in septal cultures. These NGF-mediated increases in enzyme activities are more pronounced when neurons are grown together with glial cells. In pure neuronal cultures, NGF increased ChAT and AChE activities by 101 and 16%, and in mixed neuronal-glial cultures by 318 and 87%, respectively. Anti-NGF blocked the effects of NGF but failed to reduce ChAT and AChE activities below control levels in cultures of high plating density. Fifth, astrocytes attenuate the expression of ChAT and AChE by septal neurons in the absence of NGF.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholinesterase↗