Biomedical subjects

F Amenta

Publications and source records attributed to F Amenta.

At least 73 records · Page 4Linked to original sources

PubMed1997

Muscarinic cholinergic receptor subtypes expression by human placenta.

The presence of a cholinergic system in the placenta is suggested by several data, but no information is available concerning cholinergic receptor expression by placenta. The present study was designed to investigate muscarinic cholinergic receptors in sections of human placenta using a radioligand binding techniques with [3H]N-methyl scopolamine ([3H]NMS) as a ligand. [3H]NMS was bound to sections of human placenta in a manner consistent with the labelling of muscarinic cholinergic receptors. The dissociation constant (Kd) value was 0.1 +/- 0.03 nM and the maximum density of binding site (Bmax) value was 10.82 +/- 0.09 fmol/mg of tissue. The binding was time-, temperature- and concentration-dependent, belonging to one class of high affinity sites. Analysis of [3H]NMS displacement curves by compounds acting on the different subtypes of muscarinic cholinergic receptor subtypes suggests that human placenta expresses the four subtypes (M1-M4) of muscarinic cholinergic receptor assayable with radioligand binding assay techniques. The demonstration of muscarinic cholinergic recognition sites in human placenta may contribute to define the possible significance of placental cholinergic system. Moreover, human placenta can be used as an easily obtainable human source of M1-M4 muscarinic cholinergic receptor subtypes.

Adult↗

PubMed1997

Postnatal development of dopamine D1-like and D2-like receptors in the rat kidney: a radioligand binding study.

Dopamine exerts important natriuretic and renal haemodynamic changes mediated through the interaction with dopamine D1-like and D2-like receptors. Dopamine-mediated natriuresis and renal vascular effects are less in younger than in older animals. The pharmacological profile and the density of dopamine D1-like and D2-like receptors were assessed in the kidney of rats ranging from 2 to 90 days of age by using radioligand binding assay techniques. [3H]SCH 23390 was used as ligand of dopamine D1-like receptors. [3H]Spiperone was used as a ligand of dopamine D2-like receptors. The dissociation constant (Kd) value of [3H]SCH 23390 binding was slightly decreased from the 21st day of age in comparison with animals of 2 and 7 days of age. The maximum density (Bmax) of [3H]SCH 23390 binding sites increased progressively until the 21st day of age and then plateauned. A similar trend was found for [3H]Spiperone binding sites. In [3H]Spiperone binding experiments, the Kd value was remarkably decreased from the 21st to the 90th day of life. Bmax value of [3H]Spiperone binding sites were similar in rats of 2 and 7 days of age and subsequently increased to values similar to those found in adult rats from the 21st day of life. The pharmacological profile of [3H]SCH 23390 and [3H]Spiperone was similar in rats of the different ages investigated. These findings suggest that renal dopamine D1-like and D2-like receptors undergo maturational changes in the first 3 weeks after birth and then are stabilized at the adult levels. The possibility that the increased expression of renal dopamine receptors postnatally may be linked with the gradual appearance of dopamine-mediated renal responses after birth is discussed.

Animals↗

PubMed1997

Use of [3H]-clozapine as a ligand of the dopamine D4 receptor subtype in peripheral tissues.

1. Molecular biology studies have documented the presence of peripheral dopamine D4 receptors. This site has not been characterized yet with classical radioligand binding assay techniques because of the lack of selective radioligands. 2. The atypical neuroleptic clozapine labelled with tritium ([3H]-clozapine) has been proposed and sold as a radioligand for brain dopamine D4 receptors. However, the selectivity of [3H]-clozapine for D4 receptor subtypes, and its specificity for brain dopamine receptors, have been questioned. 3. In this study dopamine D4 receptors were assayed in peripheral organs known to express them, such as rat atria and kidney, by using a radioligand binding assay technique with [3H]-clozapine as the radioligand. Parallel experiments were performed using Chinese hamster ovary (CHO) cells transfected with the D4 receptor clone (variant D4.2). 4. [3H]-Clozapine was bound to sections of rat atria and kidney. After appropriate blockade of sites other than dopamine receptors to which it can bind (i.e. muscarinic cholinergic, serotonergic and alpha-adrenergic receptors), the radioligand was bound to a site displaying a pharmacological profile similar to that expressed by CHO cells transfected with the D4 receptor. 5. The above findings indicate that with appropriate protocols, [3H]-clozapine may represent a radioligand for peripheral dopamine D4 receptors.

Animals↗

PubMed1997

Dopamine D3 receptor in peripheral mononuclear cells of essential hypertensives.

Dopamine D3 receptor was studied in peripheral mononuclear cells of high-normal, stage 1, stage 2, and stage 3 essential hypertensives using a radioligand binding assay technique with [3H]-7-hydroxy-N,N-di-n-propyl-2-aminotetraline (7-OH-DPAT) as a radioligand. A group of de novo Parkinsonian patients was also examined as a reference group of impaired dopaminergic function. [3H]-7-OH-DPAT was bound specifically to human peripheral mononuclear cells in a manner consistent with the labeling of a dopamine D3 receptor. No changes in free dopamine, norepinephrine, epinephrine and aldosterone levels, renin activity, dissociation constant of [3H]-7-OH-DPAT binding, or the pharmacological profile of [3H]-7-OH-DPAT binding were found between normotensive control subjects and essential hypertensives or Parkinsonians. The density of peripheral mononuclear cell [3H]-7-OH-DPAT binding sites increased in essential hypertensives parallel to blood pressure value augmentation. A higher density of [3H]-7-OH-DPAT binding sites was found in Parkinsonians. In these patients, the density of [3H]-7-OH-DPAT binding sites was similar to that observed in high-normal subjects and in stage 1 essential hypertensives. The increased density of peripheral mononuclear cell dopamine D3 receptor in hypertension as well as in Parkinson's disease may represent an upregulation mechanism consequent to impaired dopaminergic function. In view of the difficulty in identifying markers of peripheral dopamine function, analysis of dopamine D3 receptor in peripheral mononuclear cells may help evaluate whether the dopaminergic system is involved in hypertension.

Adult↗

PubMed1997

Use of frozen sections for the pharmacological characterization of compounds active on neurotransmitter receptors.

Radioligand binding assay represents an important technique in pharmacological and pharmaceutical research for assessing the receptor profile of new drugs or of compounds under development. In this study, the pharmacological profile and the receptor specificity of compounds active on dopamine and muscarinic cholinergic receptor subtypes were evaluated using as a receptor source, membrane preparations or frozen sections. Dopamine D1-like receptors were assayed in membrane preparations or frozen sections of rat striatum and kidney with [3H]-SCH 23390 as a ligand. Rat striatum, kidney and atrium were used as a source of dopamine D2-like receptors with [3H]-spiperone as a ligand. The non-selective muscarinic cholinergic receptor antagonist [3H]-N-methyl-scopolamine was used to label muscarinic cholinergic receptors in the rat. Frontal cortex represented the source of M1 receptor subtype, heart the source of M2 receptor subtype, sub maxillary gland the source of M3 receptor subtype and striatum the source of M4 receptor subtype. With the exception of cardiac tissue, no significant differences were noticeable in the affinity of dopaminergic or muscarinic cholinergic compounds tested using membrane particles or 8 microns thick slide-mounted section. In the heart, frozen sections gave lower dissociation constant and inhibition constant values than membranes. The above findings suggest that radioligand binding assay on slide-mounted tissue sections may represent a suitable technique for assessing the receptor profile of drugs under development for the treatment of disorders characterised by dopaminergic or muscarnic cholinergic dysfunction.

Animals↗

PubMed1997

Muscarinic cholinergic receptors and acetylcholinesterase activity in umbilical artery and vein in pregnancy-induced hypertension (pre-eclampsia).

The influence of pregnancy-induced hypertension (pre-eclampsia) on muscarinic cholinergic receptors and on acetylcholinesterase (AChE) activity was investigated using frozen sections of the umbilical artery and vein. Pre-eclamptic patients undergoing Caesarean delivery and normotensive pregnant control woman undergoing Caesarean delivery with similar parity, gestation length and age were examined. Muscarinic cholinergic receptors were assayed in frozen sections of the umbilical artery and vein by a radioligand binding assay technique, using [3H]-N-methyl scopolamine (NMS) as a ligand. AChE was demonstrated with a histochemical technique associated with microdensitometry. [3H]-NMS was specifically bound to sections of both umbilical artery and vein in a manner consistent with the labelling of muscarinic cholinergic receptors. The affinity of the radioligand was similar in the two vessels, whereas the maximum density of binding sites (Bmax) was higher in the umbilical vein than in the artery. A faint AChE reactivity was observed in the tunica media of both umbilical artery and vein. In pre-eclampsia, a loss of [3H]-NMS binding sites not accompanied by changes in the affinity of radioligand was found. The decrease of muscarinic cholinergic receptors involved to a greater extent the umbilical artery than the vein. No differences in AChE activity were found at the level of umbilical artery and vein between control and pre-eclamptic subjects. These findings suggest that pre-eclampsia is characterized by a loss of muscarinic cholinergic receptors in the umbilical circulation not accompanied by changes of the acetylcholine catabolizing enzyme AChE. It is possible that the decreased density of vascular muscarinic cholinergic receptors in pregnancy-induced hypertension contribute to the increased resistance of the umbilical circulation occurring in pre-eclampsia.

Acetylcholinesterase↗

PubMed1997

Effect of the thyrotropin releasing hormone analogue posatirelin (RGH 2202) on microanatomical changes induced by lesions of the nucleus basalis magnocellularis in the rat.

The effect of 4 and 8 weeks treatment with 10 mg/kg/day of the thyrotropin releasing hormone analogue posatirelin (L-6-ketopiperidine-2-carbonyl-L-leucyl-proline amide) on microanatomical changes induced by monolateral and bilateral lesions of the nucleus basalis magnocellularis (NBM) were investigated. The following parameters were assessed in the frontal cortex and hippocampus of NBM-lesioned and sham-operated rats: 1) number of nerve cell and glial fibrillary acidic protein (GFAP)-immunoreactive astrocyte profiles; 2) density of silver-gold impregnated fibres; 3) density of choline acetyltransferase (ChAT)-immunoreactive fibres; 4) intensity of acetylcholinesterase (AChE) staining. In NBM-lesioned untreated rats, no changes in the number of nerve cell or of astrocyte profiles were found either in the frontal cortex or in the hippocampus. The only exception was a decrease in the number of granule neuron profiles in the dentate gyrus at 8 weeks after lesioning. Silver-gold impregnated fibres, which express the width of interneuronal connections, were reduced in the hippocampus but not in the frontal cortex of NBM-lesioned rats. ChAT immunoreactivity and AChE reactivity, which were localised respectively in nerve fibre-like structures and in the neuropil, were decreased in the frontal cortex but not in the hippocampus from the fourth week after NBM lesioning. Lesions did not change the number of ChAT-immunoreactive nerve fibres or intensity of AChE staining in the hippocampus. Treatment with posatirelin was without effect on the number of nerve cell profiles or of GFAP-immunoreactive astrocytes both at 4 and 8 weeks after NBM lesioning. Treatment with the compound increased the number of silver-gold impregnated fibres in the hippocampus of NBM-lesioned rats and restored in part ChAT immunoreactivity and AChE reactivity in the frontal cortex. These effects were noticeable in NBM-lesioned rats after 8 weeks of treatment. The possible significance of the neuroprotective effect elicited by posatirelin treatment after lesions of the NBM is discussed.

Acetylcholinesterase↗

PubMed1997

Effect of treatment with the neuroactive peptide posatirelin on microanatomical changes of frontal cortex and hippocampus caused by lesions of the locus coeruleus.

The influence of monolateral and bilateral lesions of the Locus coeruleus (LC) on the number of nerve cell and glial fibrillary acidic protein (GFAP)-immunoreactive astrocyte profiles, on silver-gold impregnated fibres and on tyrosine hydroxylase (TH) immunoreactivity was assessed in the rat frontal cortex and hippocampus. The influence of treatment for 4 and 8 weeks with a 10 mg/kg/day dose of the neuroactive peptide posatirelin on the above parameters was also investigated. Lesions of the LC decreased the number of nerve cell profiles in the frontal cortex 8 weeks after lesioning and were without effect on nerve cell profiles in the frontal cortex 4 weeks after lesioning and in the hippocampus at both 4 and 8 weeks after LC lesioning. Glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes were not affected by lesions of LC. Silver-gold impregnated fibres were decreased in the frontal cortex but not in the hippocampus of LC-lesioned rats at 8 weeks after lesioning. TH immunoreactivity, which was localized in nerve fibre-like structures both in the frontal cortex and in the hippocampus was decreased in the frontal cortex and in the hippocampus from the 4th week after LC lesioning. Treatment with posatirelin was without effect on the number of nerve cell and of GFAP-immunoreactive astrocyte profiles at both 4 and 8 weeks after LC lesioning, with the exception of nerve cells of the frontal cortex in monolaterally-lesioned rats which were increased 8 weeks after lesioning. The compound increased silver-gold impregnated fibres in the frontal cortex of monolaterally lesioned rats after 8 weeks of treatment, but did not affect TH immunoreactivity both in the frontal cortex or in the hippocampus. The above results suggest that treatment with posatirelin exerts a neuroprotective effect on the frontal cortex consisting of the partial restoration of some microanatomical changes caused by lesions of LC. The possible significance of this effect is discussed.

Animals↗

PubMed1996

Peripheral nerve vascular changes in spontaneously hypertensive rats.

Circulation to the brain is affected by hypertension. Hypertension-dependent cerebrovascular changes were documented primarily in brain pial arteries, whereas no information is so far available concerning changes of peripheral nerve vascularization in hypertension. This study was designed to assess the occurrence of structural changes of interfascicular and intrafascicular arteries supplying peripheral nerves (the so called vasa nervorum) in spontaneously hypertensive rats (SHR). The investigation was performed in 8-month-old SHR, by using standard microanatomical techniques associated with quantitative image analysis. In SHR a significant increase of systolic pressure values accompanied by thickening of the arterial wall, narrowing of the lumen and increase of the wall-to-lumen ratio were observed in comparison with age-matched normotensive Wistar-Kyoto rats. Hypertension-related structural changes involved primarily interfascicular arteries and to a lesser extent intrafascicular arteries. These findings indicate that similarly as documented for cerebral arteries, the vascular supply to peripheral nerves is impaired in hypertension. Structural changes of interfascicular and intrafascicular arteries of SHR could lead to ischemia of peripheral nerves. Further work is in progress to evaluate the functional relevance of hypertensive changes to peripheral nerve vasculature.

Animals↗

PubMed1996

Synthesis, resolution, and preliminary evaluation of trans-2-amino-6(5)-hydroxy-1-phenyl-2,3-dihydro-1H-indenes and related derivatives as dopamine receptors ligands.

The present work reports the synthesis of enantiomeric pairs of the trans-2-amino-6-hydroxy-1-phenyl-2,3-dihydro-1H-indene [(+)-14a, (-)-14a] and trans-2-amino-5-hydroxy-1-phenyl-2,3-dihydro-1 H-indene [(+)-14b, (-)-14b] and their N,N-di-n-propyl [(+)-and (-)-15a,b], N-methyl-N-allyl [(+)-and (-)-16a,b], and N-methyl-N-n-propyl [(+) and (-)-17a,b] derivatives obtained by a combination of stereospecific reactions and optical resolution. The new compounds were evaluated for their affinity at the dopamine D1 and D2 receptors. The amines (+)- and (-)-14a, incorporating the D1 pharmacophore 2-phenyl-2-(3-hydroxyphenyl)ethylamine in a trans extended conformation, and their derivatives displayed D1 and D2 affinity in the nanomolar range. On the other hand, the enantiomers (+)- and (-)-14b, (+)- and (-)-15b displayed high affinity and selectivity for the D1 receptor. In a preliminary behavioral study on rats (+)-14b, and to a greater extent (+)-15b, promoted episodes of intense grooming, thus indicating that they act as central D1 agonists. The trans-2-amino-5-hydroxy-1-phenyl-2,3-dihydro-1H-indenes (+)-14b and (+)-15b represent selective D1 agonists lacking a catechol group, which should meet the prerequisites for a central nervous system penetration.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1996

Pharmacological characterization and autoradiographic localization of dopamine receptors in the rat adrenal medulla.

The pharmacological profile and the anatomical localization of dopamine D1-like and D2-like receptors were studied in sections of rat adrenal medulla, with radioligand binding and autoradiographic techniques, respectively. [3H]([R]-(+)-chloro-2,3,4,5-tetrahydro-5-phenyl-1 H-3benzazepin-al hemimaleate) (SCH 23390) was used as a ligand for dopamine D1-like receptors and [3H]spiperone was used as a ligand for dopamine D2-like receptors. Radioligand binding and light microscope autoradiography did not show specific [3H]SCH 23390 binding in sections of rat adrenal medulla. This suggests that rat adrenal medulla does not express dopamine D1-like receptors. [3H]Spiperone was specifically bound to sections of rat adrenal medulla. The binding was time-, temperature- and concentration-dependent, with a dissociation constant (Kd) of 1.05 nM and a maximum density of binding sites (Bmax) of 100.2 +/- 3.8 fmol/mg tissue. The pharmacological profile of [3H]spiperone binding to rat adrenal medulla was similar to that displayed by neostriatum, which is known to express dopamine D2 receptors. Light microscope autoradiography showed the accumulation of specifically bound [3H]spiperone as silver grains within sections of adrenal medulla. Silver grains were found primarily over the cellular membrane of chromaffin cells. The above data indicate that chromaffin cells of the rat adrenal medulla express dopamine receptors belonging to the dopamine D2 receptor subtype. These receptors are probably involved in the modulation of catecholamine release from chromaffin cells, as documented by functional studies.

Adrenal Medulla↗

PubMed1996

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

The influence of aging and of treatment with L-deprenyl on the structure of the kidney was investigated in 24-month-cld male Sprague Dawley rats by microanatomical techniques associated with image analysis. L-Deprenyl was administrated orally for 5 months at a dose not inhibiting monoamine oxidase (MAO) B activity (1.25/mg/kg/day) and at a dose inhibiting MAO B activity (5 mg/kg/day). In 24 month-old-rats the number and the volume of glomeruli was reduced in comparison with 12-month-old rats used as reference adult animals. Vascular changes characterised by increased thickness of the tunica media, decreased size of arterial lumen and increased wall-to-lumen ratio were also noticeable in 24-month-old rats. Moreover, an increased MAO B reactivity was noticeable within glomerular tufts and renal tubules. Treatment with the low dose of L deprenyl did not cause changes in MAO B reactivity, or in the number of glomeruli, but increased glomerular volume and reduced the wall-to-lumen ratio in medium-sized renal artery branches. The dose of 5 mg/kg/day of L-deprenyl significantly decreased MAO B reactivity within both glomerular tufts and tubules, increased the number and the volume of glomeruli and countered-age-related vascular changes. The above results suggest that treatment with L-deprenyl counters to some extent microanatomical changes occurring in the kidney of aged rats. The observation that the dose of the compound inactive on MAO B activity reduces in part age dependent renal microanatomical changes, indicates that the renal protective effect of L-deprenyl is only in part related to MAO B inhibition.

Aging↗

PubMed1996

Muscarinic cholinergic receptor subtypes in human peripheral blood lymphocytes.

The subtypes of muscarinic cholinergic receptors were studied in human peripheral blood lymphocytes with radioligand binding techniques and the non-selective muscarinic cholinergic receptor antagonist [3H]quinuclidinyl benzylate (QNB) as a ligand. [3H]QNB was bound to human peripheral lymphocytes in a manner consistent with the labelling of muscarinic cholinergic receptors. The dissociation constant (Kd) value was 0.60 +/- 0.08 nM and the maximum density of binding sites (Bmax) was 2.33 +/- 0.03 fmol/2.2 x 10(6) cells. The binding was time-, temperature- and concentration-dependent, belonging to a single class of high affinity sites. Analysis of the pharmacological profile of [3H]QNB binding in the presence of compounds specific for the different muscarinic receptor subtypes suggests that human peripheral blood lymphocytes express mainly muscarinic cholinergic M2 and M3 receptor subtypes and to a lesser extent muscarinic M4 receptors. The characterization of the subtypes of muscarinic cholinergic recognition sites expressed by human peripheral blood lymphocytes may represent a tool for investigating the possible relationships between immune and cholinergic systems in normal and pathologic conditions.

Adult↗

PubMed1996

Pharmacological characterisation of Ca2+ channels of the L-type in human peripheral blood lymphocytes.

Ca2+ channels of the L-type were characterised in intact human peripheral blood lymphocytes using a radioligand binding technique and the dihydropyridine-type Ca2+ channel antagonist [3H](+)-PN 200-110 (isopropyl-4-(2,1,3-benzoxadiazol-4-yl)1,4-dihydro-5-methoxycarbon yl-2, 6-dimethyl-3-pyridine carboxylate) as a ligand. [3H](+)-PN 200-110 binding to human peripheral blood lymphocytes was time-, temperature-, concentration-dependent and of high affinity. The dissociation constant (Kd) value was 0.4 +/- 0.02 nM and the maximum binding capacity (Bmax) was 33.5 +/- 1.6 fmol/10(6) cells. Pharmacological analysis of [3H](+)-PN 200-110 binding to human peripheral blood lymphocytes was consistent with the labelling of a Ca2+ channel of the L-type. In fact, dihydropyridine derivatives were the most potent competitors of [3H](+)-PN 200-110 binding, whereas phenylalkylamine and benzothiazepine compounds or non-selective Ca2+ channel modulators were weak or ineffective displacers. These findings are the first observation that human peripheral blood lymphocytes express Ca2+ channels of the L-type. The possibility that Ca2+ channel antagonists may interfere with immune system function is discussed.

Adult↗

PubMed1996

Increased density of dopamine D5 receptor in peripheral blood lymphocytes of migraineurs: a marker for migraine?

The expression of dopamine D5 receptor was investigated in peripheral blood lymphocytes of 11 migraine patients and of ten healthy control subjects using a radioligand binding technique with [3H]SCH 23390 as a ligand. [3H]SCH 23390 is a benzazepine derivative with potent antagonist properties at the dopamine D1-like receptors. [3H]SCH 23390 was specifically bound to peripheral blood lymphocytes of migraineurs and control subjects in a manner consistent with the labelling of a dopamine D5 receptor. In migraineurs a statistically significant higher density of lymphocyte dopamine D5 receptor compared with controls was noticeable, whereas the affinity of the radioligand was unchanged. The increased density of dopamine D5 receptor in peripheral blood lymphocytes may reflect the dopaminergic hypersensitivity displayed by migraineurs and may represent a relatively simple and reliable peripheral marker of altered dopaminergic function.

Adult↗

PubMed1996

Age-dependent changes in the expression of dopamine receptor subtypes in human peripheral blood lymphocytes.

The pharmacological profile and the density of dopamine D3 and D5 receptor subtypes expressed by human peripheral blood lymphocytes of subjects of different ages (ranging from 20 to 75 years) were assessed using radioligand binding techniques. Dopamine D3 receptor was assayed with [3H]7-hydroxy-N,N-di-n-propyl-2-aminotetraline ([3H]7-OH-DPAT) as a ligand. Dopamine D5 receptor was assayed using [3HIR]-(+)-(-chloro-2,3,4,5, tetrahydro-5-phenyl-1H-3-benzazepin-al-hemimaleate) ([3H]SCH 23390) as a ligand. The affinity and the pharmacological profile of [3H]7-OH-DPAT and [3H]SCH 23390 at dopamine D3 and D5 receptor, respectively, were similar in subjects of different ages. The density of dopamine D3 receptor binding sites was slightly decreased in subjects of 30-39 years in comparison with younger individuals. A remarkable loss of dopamine D3 receptor was then found between 40 and 49 years of age in comparison with younger subjects. A further slight decrease was noticeable between 50 and 59 years of age. The number of [3H]7-OH-DPAT binding sites was then stabilized after 60 years of age. The density of dopamine D5 receptor binding sites did not show age-dependent changes. The above findings indicate the occurrence of a decline in the density of lymphocyte dopamine D3 but not D5 receptor between adult and mature subjects. The possibility that dopamine D3 receptor assay in peripheral blood lymphocytes may represent a tool for investigating dopamine receptor function in aging and age-related neurological disorders is discussed.

Adult↗

PubMed1996

Muscarinic thioligands with cyclopentane nucleus.

Some thio- and the benzoyl-derivatives of deoxamuscarine were synthesized and tested as muscarinic agonists using radioligand binding assays and functional tests. In comparison with deoxamuscarine, used as reference compound, no dimension/distance modification is tolerated for correct lipophilic pocket recognition. The substitution of the ammonium group with a sulphonium group significantly decreased muscarinic potency. The so-called 'muscarinic sub-site' accepts relatively bulky functions as long as it is bound to the cyclopentane carrier by an oxygen bridge. Esterification of this moiety increases the M2 subtype selectivity, while etherification heightens that of M3.

Animals↗

PubMed1996

Vascular and neuronal hypertensive brain damage: protective effect of treatment with nicardipine.

AIM: The brain is sensitive to hypertension, which causes a variety of vascular and neuronal cerebral changes. The present study was designed to assess the effect of long-term treatment with the Ca2+ channel blocker nicardipine on intracerebral (intraparenchymal) arteries in spontaneously hypertensive rats (SHR) by using microanatomical techniques associated with image analysis. The effects of hypertension and treatment with nicardipine on nerve cells and glial fibrillary acid protein (GFAP)-immunoreactive glial cells were also evaluated. EFFECTS OF NICARDIPINE ON BLOOD PRESSURE: In SHR a significant increase in systolic blood pressure in comparison with age-matched normotensive Wistar-Kyoto (WKY) rats was noticeable. Treatment with nicardipine significantly reduced systolic pressure in the SHR. The media: lumen ratio and the thickness of the tunica media were increased in medium (diameter between 150 and 50 microns and small (diameter < 50 microns intracerebral arteries. This phenomenon was accompanied by luminal narrowing. Treatment with nicardipine significantly reduced the thickness of the tunica media, the media: lumen ratio and increased the luminal area, primarily at the level of small pial arteries and of intracerebral arteries. EFFECTS OF NICARDIPINE IN THE BRAIN: In control SHR, the number of neurones in the frontal and occipital cortex was reduced in comparison with normotensive WKY rats. GFAP-immunoreactive astrocytes were increased in number (hyperplasia) and in size (hypertrophy), both in the frontal cortex and in the occipital cortex of control SHR. In the CA1, field of the hippocampus, the number of neurones and their size were decreased in SHR in comparison with normotensive WKY rats. Hyperplasia of GFAP-immunoreactive astrocytes of white matter and hypertrophy of those of grey matter was also noticeable. No important changes were found in other portions of the hippocampus. Treatment with nicardipine increased the number of neurones in the frontal cortex and in the occipital cortex of SHR and countered hyperplasia and hypertrophy of GFAP-immunoreactive astrocytes. Moreover, it increased the number of neurones in the CA1 field of the hippocampus and decreased the number and the size of astrocytes of the white matter and grey matter, respectively. CONCLUSIONS: These findings show that treatment of SHR with nicardipine significantly reduced systolic blood pressure and induced moderate vasodilation of both extracerebral and intracerebral arteries regulating cerebrovascular resistance. The compound also countered some microanatomical changes occurring in the hypertensive brain. The frontal and occipital (visual) cortex and the CA1 field of the hippocampus were the cerebral areas more sensitive to treatment with nicardipine. This suggests that nicardipine induces moderate cerebrovascular dilation and exerts neuroprotective effects on SHR neurones. The possible relevance of the neuroprotective actions of nicardipine in the hypertensive brain deserves to be evaluated in future studies.

Animals↗