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C Pietra

Publications and source records attributed to C Pietra.

At least 19 recordsLinked to original sources
PubMed2003

Characterization of the effect of ganstigmine (CHF2819) on amyloid precursor protein metabolism in SH-SY5Y neuroblastoma cells.

We have investigated the effect of ganstigmine (CHF2819), a novel geneserine derived acetylcholinesterase (AChE) inhibitor, on the expression and metabolism of the amyloid precursor protein (APP) in neuroblastoma cell line SH-SY5Y. The rationale was based on the suggestion that cholinergic activity may also be involved in the regulation of APP metabolism. We studied the acute effect on APP metabolism following the secretion of sAPPalpha in the conditioned medium of cells. Following short term treatment (2h), ganstigmine promoted a slight increase in the release of sAPPalpha, the maximal effect approaching on average 1.5 fold baseline value. The data obtained in the long term experiments demonstrate that continuous inhibition of AchE obtained with 100 nM ganstigmine following an exposure of 24 hours did not influence APP isoforms expression. However, the compound appeared to increase the constitutive release of sAPPalpha, with a mechanism that is derived from an indirect cholinergic stimulation.

Acetylcholine↗
PubMed2001

Cyclodextrins in oligonucleotide delivery.

The aim of this contribution is to summarize recent findings on the potential use of cyclodextrins and their derivatives as carriers for oligonucleotide agents. Their peculiar properties could be exploited in such an emerging therapeutic area by virtue of their capability of interacting with cellular membranes, thus giving rise to improved cellular uptake. In particular, some specific derivatives could be considered as promising future excipients for the delivery of "naked" antisense and/or decoy oligonucleotides which are difficult to formulate with existing pharmaceutical excipients.

Animals↗
PubMed2001

Effects of ENA713 and CHF2819, two anti-Alzheimer's disease drugs, on rat amino acid levels.

The effects of oral ENA713 and CHF2819 (0.5, 1.5 and 4.5 mg/kg), two novel acetylcholinesterase inhibitors, on extracellular concentrations of amino acids in rat hippocampus, were evaluated using in vivo microdialysis. ENA713, at 4.5 mg/kg, but not CHF2819, significantly decreased glutamate, taurine, arginine and citrulline levels, without affecting aspartate concentrations. These results suggest that the modulation of amino acidergic transmission could represent an additional mechanism of action in Alzheimer's disease for some acetylcholinesterase inhibitors.

Alzheimer Disease↗
PubMed2001

The neuroprotective activity of the glycine receptor antagonist GV150526: an in vivo study by magnetic resonance imaging.

The neuroprotective activity of GV150526 (3-[2-(Phenylaminocarbonyl)ethenyl]-4,6-dichloroindole-2-carboxylic acid sodium salt), a selective glycine receptor antagonist of the NMDA receptor, has been evaluated by magnetic resonance imaging (MRI) in a rat model of middle cerebral artery occlusion. The aim of the work was to evaluate, using an in vivo method, whether GV150526 was able to reduce the extent of ischemic brain damage when administered both before and after (6 h) middle cerebral artery occlusion. GV150526 was administered at a dose of 3 mg/kg i.v. T2-weighted (T2W) and diffusion weighted (DW) images were acquired at 6, 24 and 144 h after the establishment of the cerebral ischemia. Substantial neuroprotection was demonstrated at all investigated time points when GV150526 was administered before the ischemic insult. The ischemic volume was reduced by 84% and 72%, compared to control values, when measured from T2W and DW images, acquired 24 h after middle cerebral artery occlusion. Administration of the same dose of GV150526, 6 h post-ischemia, also resulted in a significant (p < 0.05) neuroprotection. The ischemic volume was reduced by 48% from control values when measured from T2W images and by 45% when measured from DW images. No significant difference was found between volumes of brain ischemia obtained by either MRI or triphenyltetrazolium chloride staining. These data confirm the potential neuroprotective activity of the glycine receptor antagonist GV150526 when administered either before or up to 6 h after ischemia.

Animals↗
PubMed2001

Preclinical evaluation of CHF3381 as a novel antiepileptic agent.

CHF3381 [n-(2-indanyl)-glycinamide hydrochloride] has been selected on the basis of a screening program as the compound displaying the highest anticonvulsant activity in the maximal electroshock seizure (MES) test and the best therapeutic index with reference to the rotarod test in mice and rats. In this study, the antiepileptic activity and the behavioural toxicity of CHF3381 were characterised in multiple model systems. CHF3381 effectively prevented MES-induced convulsions when administered i.p. (ED50, 24 mg/kg and 7.5 mg/kg) or p.o. (ED50, 21 mg/kg and 21 mg/kg) in both mice and rats, respectively. The time course of oral anti-MES activity in the rat was related to the brain concentration profile of unchanged CHF3381. Interestingly, the brain drug levels were about 4-5 times higher than in plasma. CHF3381 was very effective in mice against picrotoxin-, and i.c.v. N-methyl-D-aspartate (NMDA)-induced hind limb tonic extension (ED50 Approximately/=10 mg/kg), but was a weaker antagonist of 4-amynopyridine- and bicuculline-induced tonic seizures (ED50 approximately/=100 mg/kg), and ineffective against pentylentetrazole- and picrotoxin-induced clonic seizures. CHF3381 antagonised the behavioural effects and lethality of i.p. administered NMDA (ED50 = 57 mg/kg p.o.), indicating that the compound may act as a functional NMDA antagonist. In keeping with this idea, CHF3381 weakly displaced [(3)H]-TCP from binding to NMDA receptor channels (Ki, 8.8 microM). In the rat amygdala kindling model, CHF3381 was more efficient against kindling development than against kindled seizures (minimally active dose = 80 vs. 120 mg/kg i.p). Furthermore, it significantly increased the seizure threshold in kindled rats at relatively low doses (40 mg/kg i.p.). In contrast with MK-801-induced hyperactivity, CHF3381 moderately reduced the spontaneous locomotor activity in mice at anticonvulsant doses. Toxic effects on motor performance (rotarod test) were found at high doses only (TD50 approximately/= 300 mg/kg p.o., congruent with 100 mg/kg i.p. in both mice and rats). Furthermore, CHF3381 did not impair passive avoidance and Morris water maze responding in the therapeutic range of doses. Finally, the development of tolerance after repeated doses was negligible. These data indicate that CHF3381 exerts anticonvulsant and antiepileptogenic effects in various seizure models and possesses good therapeutic window, with scarce propensity to cause neurological side-effects.

Animals↗
PubMed2001

Anticonvulsant preclinical profile of CHF 3381: dopaminergic and glutamatergic mechanisms.

Following intraperitoneal or oral administrations, CHF 3381 ([n-(2-indanyl)-glycinamide hydrochloride]) protected rats against maximal electroshock (MES) test seizures. As glutamatergic pathways play a pivotal role in epilepsy, to better characterize the molecular mechanisms of action of CHF 3381, the drug effects on the binding of the excitatory amino acid antagonist [3H]-MK-801 in the presence of n-methyl-D-aspartate (NMDA), spermidine, or the combination of both ligands, were studied. CHF 3381 inhibited the [3H]-MK-801 specific binding in a noncompetitive fashion in respect to NMDA and polyamines recognition sites. CHF 3381 failed to change the kinetic characteristic of glycine B receptors labeled with [3H]-glycine; in contrast, it significantly increased K(d) values when the receptors were labeled with the more specific compound [3H]-MDL 105,519. CHF 3381 antagonized dopamine (DA)-induced behavioral responses and inhibited, in a glycine-dependent manner, the NMDA-induced [3H]-DA release from rat striatal slices, but it failed to change either the kinetic characteristics of D1, D2, or D3 receptors in synaptic plasma membranes (SPM) or the [3H]-DA uptake from striatal synaptosomes. Moreover, in primary cell cultures of cortical neurons, this drug exhibited glycine-independent neuroprotective effects against glutamate-induced excitotoxicity. It is concluded that this compound could have a potential use in several disease states where a pathological high level of NMDA receptor activation is thought to occur.

Animals↗
PubMed2000

In vivo neurochemical effects of the acetylcholinesterase inhibitor ENA713 in rat hippocampus.

Oral ENA713 (0.5, 1.5 and 4.5 mg/kg), an acetylcholinesterase inhibitor (AChEI), dose-dependently enhanced extracellular acetylcholine concentrations in the hippocampus of freely moving rats. This effect was paralleled by changes in both noradrenergic and dopaminergic transmission. In particular, ENA713 significantly decreased noradrenaline concentrations, whereas it significantly increased homovanillic acid levels, without affecting dopamine concentrations. Neither serotonin nor gamma-aminobutyric acid levels were modified by ENA713. These findings extend the neurochemical profile of ENA713 and suggest that it could be useful for the treatment of Alzheimer-type dementia which is associated with multiple neurotransmitter abnormalities in the brain.

Acetylcholine↗
PubMed2000

4-Aminopyridine derivatives with antiamnesic activity.

Acetylcholine (Ach) enhancement, useful in the treatment of Alzheimer's disease (AD), may be obtained by means of ion channel modulators such as 4-aminopyridine (4-AP). 4-AP is also the central ring of tacrine, the first drug approved for the treatment of AD. The synthesis and pharmacological activity of three 4-AP derivatives, prepared with the aim of improving their antiamnesic activity, is here described. In two of these compounds 4-AP is connected to 4-aminobutyric acid (GABA), whereas in the third it is connected to 2-indolinone, i.e., the skeleton of linopirdine, another Ach enhancing agent. The new compounds showed potent antiamnesic activity in comparison with piracetam.

4-Aminopyridine↗
PubMed2000

Biochemical and neurobehavioral profile of CHF2819, a novel, orally active acetylcholinesterase inhibitor for Alzheimer's disease.

1,2,3,3a,8,8a-Hexahydro-1,3a,8-trimethylpyrrolo¿2,3-bĭndol-5-ol 2-ethylphenylcarbamate N-oxide hydrochloride (3aS-cis) (CHF2819) is a novel acetylcholinesterase inhibitor that produces central cholinergic stimulation after oral administration in rats. In vivo studies show that CHF2819 (0.5, 1.5, and 4.5 mg/kg p.o.) significantly increases acetylcholine levels in young adult rat hippocampus in a dose-dependent manner. Moreover, aged animals, which show a significant decrease in basal acetylcholine levels with respect to young adult rats, also exhibit a marked increase in the hippocampal concentrations of this neurotransmitter after the administration of CHF2819. This compound (1.5 mg/kg p.o.) significantly attenuates scopolamine-induced amnesia in a passive avoidance task. Furthermore, CHF2819 induces a significant decrease in dopamine levels and a significant elevation of extracellular concentrations of 5-hydroxytryptamine, whereas it does not modify norepinephrine and gamma-aminobutyric acid levels in the hippocampus of young adult rats. Functional observational battery screening demonstrates that CHF2819 (1.5 and 4.5 mg/kg p.o.) does not affect activity, excitability, autonomic, neuromuscular, and sensorimotor domains, as well as physiological end points (body weight and temperature). However, this compound induces involuntary motor movements (ranging from mild tremors to myoclonic jerks) in a dose-dependent manner. These findings suggest that the anti-amnestic properties of CHF2819, together with its stimulatory effect on cholinergic and serotonergic functions, might have a therapeutic potential mainly for the symptomatic treatment of Alzheimer's disease patients in which the cognitive impairment is accompanied by a depressive syndrome.

Acetylcholine↗
PubMed1999

Involvement of spinal NK1 and opioids receptors in modulating the inhibitory effect of capsaicin on micturition reflex in the acute spinalized guinea pig.

PURPOSE: The aim of this work was to study the role of capsaicin-sensitive afferent fibers in modulating the micturition reflex at spinal level in urethane-anesthetized guinea pigs after spinal cord transection at level T3-T4. MATERIALS AND METHODS: The intravesical effect of capsaicin was investigated in a series of cystometrograms performed in intact and spinalized animals. RESULTS: In both intact and spinalized animals capsaicin, at 30 microM, induced a significant increase of volume threshold only, whereas at 100 microM it induced a complete inhibition of the spinal micturition reflex in 60% and 85% of the animals tested, respectively. This capsaicin inhibitory effect (CIE) was unaffected by intravenous phentolamine and propranolol (0.5 and 1 mg./kg., respectively), indomethacin at 100 nmoles intrathecally (i.t.), the CGRP receptor antagonist hCGRP8-37 (3 nmoles i.t.) and the NK2 receptor selective antagonist GR 94800 (1 nmol. i.t.). However, both naloxone (30 microg. i.t.) and the NK1 antagonist GR 82334 (10 to 20 nmoles i.t.) prevented CIE in the majority of spinalized animals. CONCLUSIONS: These results suggest that CIE could be mediated by enkephalines released by dorsal root ganglion neurons through substance P release and subsequent activation of NK1 receptors in acutely spinalized guinea pigs.

Animals↗
PubMed1998

Pharmacological characterization of thromboxane and prostanoid receptors in human isolated urinary bladder.

1. Cumulative concentration-response curves (CRC) to prostaglandin E1 (PGE1), PGE2, PGD2 and PGF2alpha (0.01-30 microM) and to the thromboxane A2 (TXA2) receptor agonist U-46619 (0.01-30 microM) were constructed in human isolated detrusor muscle strips both in basal conditions and during electrical field stimulation. 2. All the agonists tested contracted the detrusor muscle. The rank order of agonist potency was: PGF2alpha > U-46619 > PGE2 whereas weak contractile responses were obtained with PGD2 and PGE1. Any of the agonists tested was able to induce a clear plateau of response even at 30 microM. 3. The selective TXA2 antagonist, GR 32191B (vapiprost), antagonized U-46619-induced contractions with an apparent pK(B) value of 8.27+/-0.12 (n = 4 for each antagonist concentration). GR 32191B (0.3 microM) did not antagonize the contractile responses to PGF2alpha and it was a non-surmountable antagonist of PGE2 (apparent pK(B) of 7.09+/-0.04; n = 5). The EP receptor antagonist AH 6809 at 10 microM shifted to the right the CRC to U-46619 (apparent pK(B) value of 5.88+/-0.04; n = 4). 4. Electrical field stimulation (20 Hz, 70 V, pulse width 0.1 ms, trains of 5 s every 60 s) elicited contractions fully sensitive to TTX (0.3 microM) and atropine (1 microM). U-46619 (0.01-3 microM) potentiated the twitch contraction in a dose-dependent manner and this effect was competitively antagonized by GR 32191B with an estimated pK(B) of 8.54+/-0.14 (n = 4 for each antagonist concentration). PGF2alpha in the range 0.01-10 microM (n = 7), but not PGE2 and PGE1 (n = 3 for each), also potentiated the twitch contraction of detrusor muscle strips (23.5+/-0.3% of KCl 100 mM-induced contraction) but this potentiation was unaffected by 0.3 microM GR 32191B (n = 5). 5. Cumulative additions of U-46619 (0.01-30 microM) were without effect on contractions induced by direct smooth muscle excitation (20 Hz, 40 V, 6 ms pulse width, trains of 2 s every 60 s, in the presence of TTX 1 microM; n = 3). Moreover, pretreatment of the tissue with 0.3 microM U-46619 did not potentiate the smooth muscle response to 7 microM bethanecol (n = 2). 6. We concluded that TXA2 can induce direct contraction of human isolated urinary bladder through the classical TXA2 receptor. Prostanoid receptors, fully activated by PGE2 and PGF2alpha are also present. All these receptors are probably located post-junctionally. The rank order of agonist potency and the fact that GR 32191B, but not AH6809, antagonized responses to PGE2 seem to indicate the presence of a new EP receptor subtype. Moreover, we suggest the presence of prejunctional TXA2 and FP receptors, potentiating acetylcholine release from cholinergic nerve terminals.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1997

Middle cerebral artery occlusion alters neurotransmitter activities in ipsilateral and contralateral rat brain regions: an ex vivo voltammetric study.

Differential pulse voltammetry with treated carbon fibre micro-electrodes has been successfully employed in in vivo analysis of neurotransmitter release and metabolism. This methodology has been now applied to ex vivo preparations (brain slices) in order to study diverse neurotransmitter activities in various brain regions ipsilateral and controlateral to a middle cerebral artery (MCA) occlusion performed in anaesthetised adult male rats. Data demonstrated that significant changes of voltammetric ascorbic acid levels related to the ischaemic state were monitored within the ipsilateral to MCA occlusion frontal cortex, striatum, nucleus accumbens and hippocampus which were the brain area studied. Furthermore, it appeared that voltammetric catecholaminergic and 5-hydroxy indolaminergic values measured within the nucleus accumbens controlateral to MCA occlusion differ significantly from the results monitored with the same technique in brain slices obtained from sham rats. In various studies, the brain regions contralateral to MCA occlusion are generally considered as control areas, however, the present data suggest that the nucleus accumbens contralateral to the MCA occlusion side is specifically affected by the ischaemic state.

Animals↗
PubMed1997

The glycine antagonist GV150526 protects somatosensory evoked potentials and reduces the infarct area in the MCAo model of focal ischemia in the rat.

The neuroprotective activity of the novel, selective glycine antagonist GV150526 was assessed in the middle artery occlusion (MCAo) model of focal ischemia. Postischemia administration of GV150526 (3 mg/kg i.v.) up to 6 h post-MCAo resulted in a significant reduction of the infarct volume measured histologically 24 h later. The neuronal protection by GV150526 was accompanied by functionally significant protection determined by somatosensory evoked potential (SEP) responses recorded from the primary somatosensory cortex of rats under urethane anesthesia. Experimental occlusion of the MCA 7 days prior to electrophysiological testing induced a clear reduction in the SEP amplitude. GV150526 (3mg/kg, i.v.) was able to protect SEP responses recorded from the hindpaw cortical field in two groups of animals treated either 1 (n = 9) or 6 h (n = 10) post-MCAo. SEP responses recorded from the forepaw cortical field, an area closer to the core of the ischemic damage, were significantly protected only in the group treated 1 h post-MCAo. Histological evaluation of the rat brain regions showed a correlated decrease in the ischemic area of GV150526-treated groups. The volumes of the ischemic brains of both GV150526 groups were statistically different from the MCAo group (P < 0.05). These findings demonstrate that GV150526 is able to prevent the ischemic damage assessed histologically and affect the functional correlates of the ischemia evaluated by the electrophysiological SEP measurements.

Animals↗
PubMed1997

Evidence against a permissive role of the metabotropic glutamate receptor 1 in acute excitotoxicity.

Excitotoxicity has been proposed to contribute to neuronal loss in a broad spectrum of neurodegenerative conditions such as ischemia, hypoglycaemic coma or cerebral trauma. Excitotoxic neuronal injury appears to be mediated mainly by the over-activation of glutamate receptors, especially N-methyl-D-aspartate receptors, with subsequent excessive Ca2+ influx. Concurrent with the activation of glutamate-gated ion channels, metabotropic glutamate receptors (mGluR), which are G-protein coupled receptors, are also expected to be activated. Excessive stimulation of phospholipase C-coupled mGluR, mGluR1 and mGluRS, has been suggested to have neurotoxic consequences. However, the contribution of mGluR activation on excitotoxicity is still unclear and controversial. Here we report that, following ischemic and excitotoxic brain injuries, inactivation of mGluR1 does not prevent excitotoxic neuronal damage. Given the evidence that agonists at this group of mGluR promoted neuronal death in cerebrocortical cultures after oxygen-glucose deprivation or after N-methyl-D-aspartate exposure, our findings suggest that mGluR-mediated excitotoxicity is unlikely associated with mGluR1 but rather with other PLC-coupled mGluR.

Analysis of Variance↗
PubMed1996

Induction of NADPH-diaphorase activity in the rat forebrain after middle cerebral artery occlusion.

Induction of NADPH-diaphorase (NDP) following ischemic infarction was studied by means of histochemistry in the rat cerebral cortex 1,2,7, and 14 days after distal occlusion of the right middle cerebral artery (MCA). The fine structure of cells in the penumbra region of the necrotic center was also investigated. MCA distal occlusion resulted in ischemic lesion of the frontoparietal cortex of variable extent; NDP induction was detected in neurons, astrocytes, macrophages, and endothelial cells, with regional specificity and a temporal gradient. One, two, and seven days after MCA occlusion, weak NDP positivity was consistently induced in some pyramidal neurons in cortical areas neighboring the necrotic area; NDP induction was also seen in pyramidal neurons of the ipsilateral anterior cingulate and infralimbic cortices and in the tenia tecta. In addition, numerous NDP-positive pyramidal neurons were detected in the contralateral frontoparietal cortex after relatively large ischemic lesions. Two weeks after MCA occlusion, NDP induction in neurons was only evident in the deep cortical layers near the lesion. NDP histochemistry combined with glial fibrillary acidic protein immunofluorescence, performed 7 days after MCA occlusion, indicated that the astrocytes at the periphery of the necrotic area were hypertrophic and some of them were also NDP-positive. One and two days after MCA occlusion, numerous macrophages displaying NDP positivity of variable intensity were seen at the periphery of the necrotic area and in the external capsule of the ischemic cerebral hemisphere. Many endothelial cells in the cortex and subcortical white matter were consistently NDP-positive in all rats. Electron microscopic studies indicated that the area adjacent to the necrotic center was composed of fibrous astrocytes, with the morphological characteristics of proliferation, and numerous lysosome-filled macrophages. Altogether the present results suggest that focal cerebral ischemia may induce in different cell types nitric oxide synthase, which is equivalent to NDP in fixed tissue. The induction of nitric oxide synthase may be related to (1) blood-flow regulation at relatively early postischemic stages, which may decline when collateral circulation is established, and/or (2) cytotoxic or neuroprotective mechanisms.

Animals↗
PubMed1996

The microvascular system in ischemic cortical lesions.

In the rat, normal blood flow can be restored in the territory of the occluded artery after an arterial occlusion. This event has been attributed to changes in the collateral vessels supplying the territory of the occluded artery. Since only a limited amount of data is available about the plasticity of the microvascular system after a cortical ischemic lesion, in the present study we have evaluated whether the restoration of blood flow to normal levels in the territory of the middle cerebral artery after permanent ischemia is due only to flow through preexisting collateral vessels or also to the development of new microvessels. Middle cerebral artery occlusion was performed in 45 rats. After 24 h of ischemia, magnetic resonance imaging was used to select 16 rats with cortical lesions of similar size and location. After 2 weeks, vascular corrosion casts were obtained from 8 rats by injection of low-viscosity resin and observed by scanning electron microscopy. A correlative light and electron microscopy study was performed using the remaining 8 rats. Two different patterns of vascular modifications were found, one dorsal and one ventral to the lesion. The dorsal portion of the lesion was vascularized by collateral arteries originating from the anterior or posterior cerebral arteries. Collateral trunks showed a meandering course, mainly in the occipital pole. In the ventral portion of the lesion a complex microvascular system was found characterized by an intense vascular proliferation. The arterioles showed a parallel, candelabrum-like pattern with dichotomic branching. Contraction rings were frequently seen. The capillaries showed a sinusoid-like structure, with a large lumen and a continuous endothelium with many micropinocytotic vesicles. A peripheral ring-shaped venous sinus was composed of a network of flat vessels. These results give the first comprehensive description of the microvascular modifications in a focal model of infarct and suggest that the restoration of blood flow to normal levels described in the territory of the middle cerebral artery after permanent ischemia may be due not only to flow through collateral vessels but also to the development of a new vascular system originating mainly from branches of the middle cerebral artery before the occlusion point.

Animals↗
PubMed1996

Pharmacological characterization of tachykinin NK2 receptors on isolated human urinary bladder, prostatic urethra and prostate.

The contractile effect of two highly potent, selective and peptidase-resistant neurokinin (NK) 1 and NK2 receptor agonists, namely delta-Aminovaleryl-[L-Pro9, N-MeLeu10]substance P-(7-11) (GR 73632) and [Lys3, Gly8-R-gamma-lactam-Leu9]NKA-(3-10) (GR 64349), respectively, was investigated on smooth muscle strips dissected from specimens of human detrusor, prostatic urethra and prostate. Furthermore, the potencies of two peptidic NK2 receptor antagonists, GR 87389 L 659,837, in antagonizing GR 64349-induced contractions were compared in these three tissues. In human detrusor muscle the rank order of agonist potency was: [beta Ala8 (NKA-(4-10)] > GR 64349 >> NKA-(4-10) >> SP = GR 73632 >> SP-methylester. The NK2 receptor antagonist, GR 87389, antagonized GR 64349-induced contractions in a competitive manner, whereas L 659,837 was a noncompetitive antagonist. In the prostatic urethra the rank order of agonist potency was GR 64349 > NKA-(4-10) > SP > GR 73632, whereas in the prostate it was: GR 64349 >> [beta Ala8 (NKA-(4-10)] > NKA-(4-10) > SP; GR 73632 was ineffective up to 30 microM. In the prostatic urethra and in the prostate GR 87389 was a noncompetitive antagonist with a potency similar to that exhibited in the detrusor. On the contrary, L 659,837 appeared to be a competitive antagonist in the prostate and in the prostatic urethra, having approximately the similar potency in these two tissues. The selective NK3 agonist senktide was ineffective up to 30 microM in all three tissues. These results are discussed in the view of the proposed NK2 receptor subtypes and considering possible therapeutic implications in the treatment of urinary bladder disorders.

Humans↗