Biomedical subjects

A Badia

Publications and source records attributed to A Badia.

At least 55 records · Page 3Linked to original sources

PubMed1996

Sustained increase in rat myocardial alpha 1A-adrenoceptors induced by 6-hydroxydopamine treatment involves a decelerated receptor turnover.

The biochemical mechanisms involved in the alpha 1-adrenoceptor up-regulation and possible changes in subtypes of adrenoceptors in the rat heart after chemical denervation were investigated. The effects of acute 6-hydroxydopamine treatment (two increasing doses 24 h apart) on the pseudo-steady state densities and turnover rates of alpha 1-adrenoceptors were studied in ventricular myocardium of the rat. We have assessed the repopulation kinetics of [3H]prazosin binding sites after irreversible inactivation of alpha 1-adrenoceptors induced by a single dose of phenoxybenzamine (1 mg/kg i.p.) in rats acutely treated either with 6-hydroxy-dopamine or with vehicle (control animals). Seven days after the last administration of 6-hydroxydopamine an enhanced density of [3H]prazosin binding sites (Bmax 58.7 +/- 3.6 fmol/mg protein vehicle-treated rats versus 82.6 +/- 5.3 fmol/mg protein 6-hydroxydopamine-treated rats) was observed. This was not accompanied by changes in the dissociation constant value. Furthermore, the proportion of high affinity sites for WB-4101 was altered (21 +/- 2% versus 72 +/- 3% for animals treated with vehicle and 6-hydroxydopamine, respectively). In rat myocardium, alpha 1-adrenoceptor turnover, evaluated during the 6-hydroxydopamine-induced up-regulation (7-19 days after the completion of treatment with 6-hydroxydopamine) revealed an increase in the half-life of the alpha 1-adrenoceptor (t1/2 of 67.2 h versus 38.7 h in control animals). The present study confirms an increase in alpha 1-adrenoceptors in rat myocardium after chemical denervation and reveals that the effect is almost completely confined to the alpha 1A-adrenoceptor subtype. Furthermore, the up-regulation of alpha 1A-adrenoceptors is the result of a decrease in the cellular processes that control the rate of receptor degradation.

Adrenergic Agents↗

PubMed1996

Effect of 1-aminocyclopropanecarboxylic acid on N-methyl-D-aspartate-stimulated [3H]-noradrenaline release in rat hippocampal synaptosomes.

1. The effect of 1-aminocyclopropanecarboxylic acid (ACPC), a partial agonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex that exhibits neuroprotective, anxiolytic and antidepressant-like actions, was investigated in a functional assay for presynaptic NMDA receptors. 2. NMDA (100 microM) produced a 36% increase of tritium efflux above basal efflux in rat hippocampal synaptosomes preincubated with [3H]-noradrenaline ([3H]-NA), reflecting a release of tritiated noradrenaline. This effect was prevented by 10 microM 7-chlorokynurenic acid, an antagonist of the glycine site of the NMDA receptor. 3. Glycine enhanced the effect of NMDA with Emax and EC50 values of 84 +/- 11% and 1.82 +/- 0.04 microM, respectively. ACPC potentiated the effect of NMDA on tritium overflow with a lower EC50 (43 +/- 6 nM) and a lower maximal effect (Emax = 40 +/- 9%) than glycine. Furthermore, ACPC (0.1 microM) shifted the EC50 of glycine from 1.82 microM to > or = 3 mM. 4. These results show that ACPC can reduce the potentiation by glycine of NMDA-evoked [3H]-NA release and hence, may act as an antagonist at the glycine site of presynaptic hippocampal NMDA receptors when the concentration of glycine is high.

Adrenergic alpha-Antagonists↗

PubMed1996

Endothelial modulation of alpha 1-adrenoceptor contractile responses in the tail artery of spontaneously hypertensive rats.

1. Vascular contraction induced by phenylephrine was studied in tail artery rings from spontaneously hypertensive (SHR) and Wistar Kyoto rats (WKY) with particular focus on the role of endothelium. The influence of receptor reserve and the density of alpha 1-adrenoceptors on the possible differences observed were also analysed. 2. Phenylephrine (0.01-100 microM) induced concentration-dependent vasoconstrictions. The maximum response (alpha, P < 0.001) was greater but the pEC50 (P < 0.05) smaller in rings from SHR than from WKY rats irrespective of the presence or absence of endothelium. 3. Removal of endothelial cells resulted in a decrease of the maximum contraction with no modification in the pEC50 in arteries from both WKY and SHR. 4. The density of alpha 1-adrenoceptors (Bmax) and the dissociation constant (KD) were found to be the same for preparations from SHR and WKY rats in [3H]-prazosin binding experiments. 5. The apparent affinity (pKA) determined by the nested hyperbolic method and the operational model was similar in tail arteries from the two rat strains, irrespective of the presence or absence of endothelium. However, in endothelium-denuded rings, the pKA value was enhanced when compared with intact rings, in both SHR and WKY rats. 6. In rings from hypertensive rats, the operational parameter maximum possible effect (Em) was greater and the agonist efficacy (tau) was smaller than in rings from normotensive rats. When the endothelium was removed log tau and Em diminished in preparations from both rat strains. 7. In summary, the increased maximum responsiveness to phenylephrine in rings from SHR could be due to enhancement in Em. The log tau values indicate a deterioration in the transduction of the stimulus provided by the agonist in tail arteries from hypertensive animals. This study also suggests that the absence of endothelium modifies the alpha 1-adrenoceptor-mediated vasoconstriction probably by altering the transduction signalling mechanisms. The importance of analysing the degree of endothelium functionality when comparing results from different groups of rats is stated.

Adrenergic alpha-Agonists↗

PubMed1996

Modelling the changes induced by chronic desipramine treatment on the factors governing the agonism at prejunctional alpha 2-adrenoceptors.

1. The adaptational changes induced after chronic desipramine treatment on functional responsiveness of alpha 2-adrenoceptor activation were investigated in prostatic portions of the rat vas deferens. 2. For this purpose, clonidine and xylazine were studied for their effects on twitch contractions elicited by electrical field stimulation of prostatic portions removed 48 h after the last injection to the animals of vehicle or desipramine (10 mg kg-1, i.p.; 14 days). Operational model-fitting and the nested hyperbolic method were used to analyse the effects of irreversible receptor alkylation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 300 nM) on the alpha 2-adrenoceptor-mediated effects of clonidine, either in vehicle- or in desipramine-treated animals. 3. Treatment with desipramine decreased the potency (increased the EC50) of clonidine and xylazine by about 12 and 9 fold respectively. However, the treatment did not modify the maximal effect (alpha) elicited by either agonist. The estimates of apparent affinity for clonidine did not depend on the method of calculation as the 'null' method and the 'operational' method gave similar answers. Estimates of tau values for both agonists revealed that chronic desipramine treatment resulted in significant decreases in the efficacy of agonists. However, desipramine treatment was not associated with significant changes in the affinity constant for clonidine while for xylazine, the operational model provided a higher estimate of KA (lower affinity) after desipramine treatment. 4. The results indicate a large receptor reserve at prejunctional alpha 2-adrenoceptors which is modulated by chronic desipramine treatment. 5. The comparison of results obtained after chronic desipramine exposure with those by using EEDQ suggests that chronic desipramine treatment is not a useful experimental intervention for the purpose of estimating agonist affinities and efficacies.

Adrenergic Uptake Inhibitors↗

PubMed1995

Early environmental stimulation produces long-lasting changes on beta-adrenoceptor transduction system.

Long-term behavioral and biochemical effects of exposure to differential early stimulation (postnatal handling and/or enriched environment) were studied in 18- to 20-month-old Sprague-Dawley rats. Postnatal handling treatment was given between 1 and 22 postnatal days. In the enriched environment procedure, the pups were maintained under enriched conditions from weaning until postnatal Day 100. At 18 months of age animals were tested for working memory in an object recognition test, based on the differential exploration of familiar and new objects. Animals reared in the enriched environment performed better in the working memory test than did control or postnatally handled rats. No interaction was observed between postnatal handling and environmental enrichment on cognitive parameters. At 20 months of age, the animals were sacrificed and cyclic AMP formation was determined under basal conditions and after activation of beta-adrenoceptors in cerebral cortex and hippocampus. Both postnatal handling and its combination with exposure to enriched environment significantly increased basal cyclic AMP accumulation in cerebral cortex, but not in the hippocampus. Environmental enrichment was able to induce a long-lasting modification in the responsiveness of the beta-adrenergic neurotransmitter system as reflected by a decreased cyclic AMP accumulation after beta-adrenoceptor activation by means of isoprenaline, in either anatomical structure. It is suggested that manipulations of the environment early in life leading to a reduction in age-related memory deficits produce subtle but long-lasting modifications of noradrenergic transmission.

Animals↗

PubMed1995

Action on noradrenergic transmission of an anticholinesterase: 9-amino-1,2,3,4-tetrahydroacridine.

The mechanism by which 9-amino-1,2,3,4-tetrahydroacridine (THA) inhibits beta-adrenoceptor linked cyclic AMP formation and its possible relationship with the cholinergic system were studied. In addition, the effect of THA on alpha 1-adrenoceptor coupled transduction systems was also investigated. THA was not able to influence the concentration-response curve for forskolin indicating that it is not acting on the catalytic subunit of the adenylate cyclase complex. On the other hand a cholinergic component seems to participate in the action of THA on beta-adrenoceptor stimulated adenylate cyclase activity since the blockade of muscarinic receptors with atropine (10 microM) partially prevented the reduction in cyclic AMP formation attained by THA in the hippocampus, in isoprenaline-stimulated conditions. This effect is not reproducible by another potent anticholinesterase physostigmine. Moreover, THA at concentrations up to micromolar did not affect alpha 1-adrenoceptor stimulated cyclic AMP formation or phosphoinositide hydrolysis. In conclusion, the neuropharmacological profile of THA is not to be restricted to the cholinergic system and its effectiveness in improving age-associated cognitive deterioration may involve an action on the beta-adrenoceptor coupled signal transduction system. Moreover, the action of THA on the beta-adrenergic and cholinergic systems in the brain could be relevant to the amelioration of cognitive deterioration and could lead to the development of new therapeutic strategies.

Animals↗

PubMed1995

Involvement of different types of voltage-sensitive calcium channels in the presynaptic regulation of noradrenaline release in rat brain cortex and hippocampus.

Transmitter release at the nerve terminal is mediated by the influx of Ca2+ through voltage-sensitive calcium channels (VSCCs). Many types of VSCCs have been found in neurons (T, N, L, and P), but uncertainty remains about which ones are involved in neuronal excitation-secretion coupling. Specific ligands for the L- and N-type VSCCs were used to determine which of these subtypes might be involved in the K(+)-evoked [3H]noradrenaline release from superfused rat brain cortical and hippocampal synaptosomes. In cortical presynaptic terminals the 1,4-dihydropyridine agonist Bay K8644 enhanced the K+ (15 mM)-evoked [3H]noradrenaline release. This effect was reversed by the 1,4-dihydropyridine antagonists nimodipine and nitrendipine. The L-type VSCC ligands had no effect on hippocampal synaptosomes. In contrast, the N-type VSCC blocker omega-conotoxin markedly reduced the K(+)-evoked [3H]noradrenaline release in nerve terminals from both regions. Inhibition was greater in hippocampal synaptosomes. When applied together the inhibitory actions of nimodipine and omega-conotoxin were approximately additive. These findings indicate that both L- and N-type VSCCs participate in noradrenaline release in rat brain cortex and suggest that noradrenergic terminals in the two regions examined may have distinct populations of VSCCs: L type in cortex and N type in hippocampus.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1995

Chronic administration of oxprenolol and metoprolol attenuate sympathetic cardiovascular responses only in non-adrenalectomized pithed rats.

1. Oxprenolol and metoprolol (30 mg kg-1) were injected intraperitoneally (i.p.) for 1 day (acute treatment) and 6 weeks (chronic treatment) to Sprague-Dawley rats. 2. Increases of mean blood pressure and heart rate to noradrenaline (0.1-10 micrograms kg-1) and to electrical stimulation (0.5 msec, supramax V, 0.25-5 Hz) of the entire sympathetic outflow were measured in non-adrenalectomized (acute and chronic) and adrenalectomized (chronic) pithed rats. 3. Acute beta-adrenoceptor antagonist administration was without effect on mean blood pressure and heart rate increases to noradrenaline and electrical stimulation. 4. Chronic administration with oxprenolol significantly diminished the stimulation-induced increases of mean blood pressure and heart rate in non-adrenalectomized pithed rats. 5. Increases in heart rate, elicited by stimulation of the entire sympathetic outflow in non-adrenalectomized but not in adrenalectomized pithed rats, were decreased by metoprolol treatment. Both treatments were without effect on noradrenaline responses. 6. These results indicate that chronic beta-adrenoceptor antagonist treatment is associated with a reduction in the cardiovascular responses to sympathetic nerve-stimulation. However, this mechanism only operates when adrenomedullary adrenaline is present to facilitate the noradrenaline release through activation of presynaptic beta 2-adrenoceptors.

Adrenalectomy↗

PubMed1994

Differential contribution of L- and N-type calcium channels on rat hippocampal acetylcholine release.

Bay K 8644, nimodipine and omega-conotoxin GVIA (omega-CgTx) were used to study the different contribution of voltage-sensitive calcium channels (VSCC) to [3H]acetylcholine ([[3H]ACh) release in rat hippocampal synaptosomes. In our experimental conditions, the percentage of calcium-dependent ACh release was approximately 80%. Nimodipine (0.01-10 microM) and Bay 8644 (0.01-10 microM) were not able to modify the [3H]ACh release under stimulating conditions (15 mM K+). Nevertheless, when K+ concentration was reduced to 8 mM, a significant increase in [3H]ACh release was observed at 1 and 10 microM of Bay K 8644. Nimodipine (0.01-10 microM) failed to reverse the effect of Bay K 8644 on [3H]ACh release. Finally, omega-CgTx (0.001-1 microM) caused a concentration-dependent reduction of [3H]ACh release in K+ (15 mM)-stimulating conditions. These results suggest that the N-type VSCC probably play a predominant role in regulating the [3H]ACh release in synaptosomes from rat hippocampus.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1994

Analysis of agonism at functional prejunctional alpha 2-adrenoceptors of rat vas deferens using operational and null approaches.

The alpha 2-adrenoceptors located prejunctionally on the postganglionic neurons that innervate the smooth muscle of the prostatic portion of the rat vas deferens were examined. For this purpose, three imidazolidine derivatives (structurally related to clonidine) were studied for their effects on twitch contractions elicited by electrical field stimulation of this tissue. In this study, operational model-fitting and the nested hyperbolic method were used to analyse the effects of irreversible receptor alkylation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on the alpha 2-adrenoceptor-mediated effects of clonidine (2-[2,6-dichlorophenylimino]imidazolidine) in stimulated vas deferens. The operational model provided an estimate of KA for clonidine which was not significantly different from the estimate obtained by using the nested hyperbolic method (null approach). The data indicate a large receptor reserve at prejunctional alpha 2-adrenoceptors for clonidine. The estimates of apparent affinity for St-587 (2-[2-chloro-5-trifluoromethylphenylimino]imidazolidine) and St-591 (2-[2-chloro-5-methylphenylimino]imidazolidine) did not depend on the method of calculation as the 'null' method and the 'operational' method gave similar answers. Further, estimates of the ratio of tau values for these partial agonists with respect to clonidine were numerically the same as those of their relative efficacies. Therefore, no limitations in the ability of the operational model to fit experimental data and provide reproducible estimates of affinity and efficacy have been revealed for agonists acting at prejunctional alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗

PubMed1994

Selective enrichment with alpha 1A- and alpha 1B-adrenoceptor subtypes in rat brain cortical membranes.

Recent evidences from molecular biology, radioreceptor binding and functional studies indicate that the alpha 1-adrenoceptor population is heterogeneous and can at least be divided into two subclasses named alpha 1A and alpha 1B. The present study was designed to obtain, a selective enrichment of rat brain cortical membranes with each subtype of alpha 1-adrenoceptor using alkylating agents. [3H]prazosin binding to rat cortical membranes was saturable and of high affinity (KD = 0.11 +/- 0.02 nM; Bmax = 132.5 +/- 7.2 fmol/mg protein). All ligands competed for specific [3H]prazosin binding in a statistically significant biphasic manner (%Rhigh = 30-40%; %Rlow = 60-70%). These sites meet generally accepted and recently described pharmacologic criteria for their identification as the alpha 1A- and alpha 1B-adrenoceptors. After pretreatment of membranes with benextramine (1 microM) in the presence of clonidine (1 microM), the antagonists, WB4101, (+)-niguldipine and phentolamine, displaced the radioligand with an inhibition curve steeper than in control membranes and with Ki values that agree with those obtained for the low affinity site present in control membranes. On the other hand, after pretreatment with chloroethylclonidine (10 microM) in the presence of WB4101 (1 nM), Hill coefficients for the displacement of the radioligand by WB4101, (+)-niguldipine, and phentolamine, were also increased, but in contrast to the situation described above, the Ki values agree with those obtained for the high affinity site present in control membranes. In conclusion, this method of partial alkylation of receptors could be a valuable tool for separately studying the pharmacological characteristics of the alpha 1-adrenoceptor subtypes in native membranes of cerebral tissue.

Adrenergic alpha-Antagonists↗

PubMed1994

In vivo recovery of alpha 1-adrenoceptors in rat myocardial tissue after alkylation with phenoxybenzamine.

The rate of recovery of rat myocardial alpha 1-adrenoceptor density and responsiveness after in vivo block with phenoxybenzamine (1 mg/kg, i.p.) have been investigated by measuring [3H]prazosin binding, and noradrenaline-stimulated [3H]inositol phosphate production. Repopulation of alpha 1-adrenoceptors was monoexponential, with a t1/2 of 33 h; functional recovery was also monoexponential, with t1/2 of 28 h. Furthermore, our results clearly demonstrate the absence of a receptor reserve for alpha 1-adrenoceptors mediating noradrenaline-stimulated phosphoinositide breakdown in rat myocardial tissue. These observations indicate a close relationship between the density of [3H]prazosin binding sites and the ability of alpha 1-adrenoceptors to respond to noradrenaline. Moreover, based on competition curves for inhibition of specific [3H]prazosin by WB-4101 to rat myocardial membranes 48 h and 7 days after the administration of phenoxybenzamine, the results suggest that rat myocardial membranes contain both alpha 1-adrenoceptors subtypes, i.e., alpha 1A and alpha 1B, in an approximate ratio of 20:80, and this relative ratio does not seem to be altered during the recovery process.

Alkylation↗

PubMed1993

Differential effects of physostigmine and 1,2,3,4-tetrahydro-9-aminoacridine on the beta-adrenoceptor transduction system.

The effects of 1,2,3,4-tetrahydro-9-aminoacridine (THA) and physostigmine on beta-adrenoceptor-linked cyclic AMP accumulation have been analyzed in vitro in rat cortex and hippocampus. A 10-min incubation with increasing concentrations of THA reduced isoprenaline (10 microM)-stimulated cyclic AMP accumulation in a concentration-dependent manner in cortical (IC50 = 1.31 +/- 0.13 microM) and hippocampal (IC50 = 0.02 +/- 0.003 microM) structures. Conversely, physostigmine did not modify cyclic AMP synthesis in any experimental condition. The action of THA was non-competitive since it induced a non-parallel shift to the right of the concentration-response curve for isoprenaline. The differential effects of THA and physostigmine on the beta-adrenoceptor transduction system may account for the difference in their ability to restore cognitive function.

Animals↗

PubMed1993

Comparative effects of velnacrine, tacrine and physostigmine on the twitch responses in the rat phrenic-hemidiaphragm preparation.

1. Cholinesterase inhibitors potentiated twitch responses induced by nerve stimulation, with physostigmine more potent than tacrine and velnacrine. However, at higher concentrations, tacrine decreased twitch responses in a concentration-dependent manner. 2. Tacrine strongly depressed directly-induced twitch responses, whereas the other drugs had minimal effects. 3. Physostigmine was the most potent drug in reversal of tubocurarine-induced blockade, but its antagonism index was similar to those obtained with tacrine and velnacrine at higher concentrations. When evaluating their ability to reverse neomycin-induced blockade, all drugs exhibited a similar effect. 4. It is concluded that tacrine and velnacrine are less potent than physostigmine in potentiating skeletal neuromuscular transmission. Additionally, the blocking effects of tacrine could limit its therapeutic efficacy.

Animals↗

PubMed1993

Alpha 1-adrenoceptor subtypes and inositol phosphates production in heart ventricles of spontaneously hypertensive rats.

To study potential cardiac alpha 1-adrenoceptor changes in the stage of established hypertension, [3H]prazosin binding characteristics and norepinephrine (NE) stimulated production of inositol phosphates in the ventricular tissue of spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto control rats (WKY) were determined. The maximum number of cardiac [3H]prazosin binding sites was significantly reduced in SHR as compared with WKY rats, but the Kd values were similar in both groups of animals. Distribution of the [3H]prazosin-labeled high- and low-affinity binding sites for WB 4101 was similar in SHR and WKY rats. Pretreatment of ventricular heart membranes with the irreversible alpha 1B-adrenoceptor-selective antagonist chloroethylclonidine resulted in the same percentage of loss of specific [3H]prazosin binding in both groups of rats. Together, these results showed a similar ratio of alpha and alpha 1B-adrenoceptor subtypes in SHR and WKY rats. In addition, [3H]inositol phosphate accumulation in response to cardiac alpha 1-adrenoceptor stimulation by NE was significantly reduced in SHR as compared with WKY rats although the EC50 values were not significantly different in the two strains of animals. Thus, we conclude that in an established stage of hypertension there is a specific loss in the number of cardiac alpha 1-adrenoceptors with consequently reduced inositol phosphate turnover. These results are compatible with the reported decrease in the positive inotropic effect mediated through myocardial alpha 1-adrenoceptors in spontaneous hypertension.

Adrenergic alpha-Antagonists↗

PubMed1993

Modulation of alpha 1-adrenoceptors and functional consequences in the bisected rat vas deferens following chronic inhibition of neuronal noradrenaline uptake.

1. The adaptational changes induced after chronic inhibition of neuronal noradrenaline uptake on both functional responsiveness of alpha 1-adrenoceptor activation and [3H]-prazosin binding were investigated in prostatic and epididymal portions of the rat vas deferens. 2. Contractile concentration-response curves to phenylephrine and saturation isotherms of [3H]-prazosin binding to homogenates of each of the portions of the bisected rat vas deferens were determined 48 h after the last injection of desipramine, nomifensine or nisoxetine (10 mg kg-1; i.p. for 14 days). 3. Treatment with both nomifensine and nisoxetine decreased the potency (pD2) of phenylephrine by about 10 and 8 fold respectively in the epididymal portion. However, administration of desipramine only reduced the potency of the alpha 1-adrenoceptor agonist by about 1.8 fold. None of the treatments modified the maximal effect (Emax) elicited by phenylephrine in this portion of the vas deferens. In the prostatic portion only the treatment with nomifensine (1.4 fold) and nisoxetine (1.8 fold) decreased the potency of phenylephrine; the maximal contraction elicited by the agonist after the treatments was also reduced. 4. Chronic treatment with either nomifensine or nisoxetine did not change the KD for [3H]-prazosin binding in either epididymal or prostatic membranes. However, these two treatments resulted in a significant decrease in the [3H]-prazosin Bmax in membranes in both portions of rat vas deferens. The reduction in density of alpha 1-adrenoceptors was higher in the epididymal than the prostatic half. Desipramine reduced the Bmax only in the epididymal portion. 5. These results indicate that differential regulation of ax-adrenoceptors in either portion of the rat vas deferens could result from a greater degree of activation of these receptors in the epididymal half after chronic inhibition of neuronal noradrenaline uptake. The different functional consequences of the loss of alpha l-adrenoceptors in each portion seems to be explained on the basis of a different relationship between the occupancy of the receptor and the response elicited.

Adrenergic alpha-Agonists↗

PubMed1993

Effects of age on alpha 1-adrenoceptor subtypes in the heart ventricular muscle of the rat.

The effects of ageing on alpha 1-adrenoceptor subtypes have been examined in heart ventricular muscle of young (2-3 months) and middle-aged (18 months) Sprague-Dawley rats. Radioligand binding studies with [3H]prazosin revealed an age-related loss of binding sites (Bmax 56.7 +/- 1.93 fmol (mg protein)-1 age 2 months vs 31.7 +/- 2.45 fmol (mg protein)-1 age 18 months) not followed by changes in the dissociation constant value (Kd 0.16 +/- 0.03 nM age 2 months and 0.10 +/- 0.03 nM age 18 months). Competition curves with WB 4101 showed two distinct sites with different affinities, the proportion of sites with high affinity being similar for both age groups (22.2 +/- 1.89% vs 17.8 +/- 1.96% for animals aged 2 and 18 months, respectively). Agonist displacement curves of [3H]prazosin indicate the existence of two different affinity sites for the agonist, that are maintained regardless of the ageing process (R(high) = 16.2 +/- 1.54% and R(low) = 83.8 +/- 1.89% in rats aged 2 months and R(high) = 16.3 +/- 3.23% and R(low) = 83.7 +/- 3.95% in rats aged 18 months). The fractional inactivation of alpha 1-adrenoceptors by chloroethylclonidine resulted in a loss of [3H]prazosin specific binding, and a percentage of 22.5 +/- 0.95 and 22.6 +/- 4.2 of remaining binding sites for the groups of 2 and 18 months of age, respectively. The percentage of chloroethylclonidine-insensitive [3H]prazosin binding sites was similar to those with high affinity for WB4101. The present study confirms a decline of alpha 1-adrenoceptors with increasing age and reveals that the equilibrium of the expression of the two existing subpopulations of the receptor is maintained during ageing.

Adrenergic alpha-Antagonists↗

PubMed1992

Effects of velnacrine, tacrine and physostigmine on tetanic twitch responses at the rat neuromuscular junction.

The effects of velnacrine (1-hydroxytacrine), tacrine and physostigmine on indirectly elicited twitch at low and high stimulation frequencies were analyzed in the rat phrenic hemidiaphragm preparation. At 0.2 Hz, velnacrine and physostigmine behaved in a similar manner, the latter showing a higher potentiating effect. This potentiation was observed at 3-100 microM velnacrine, whereas a slight depression appeared at higher concentrations. When tetanic responses were studied, the drug concentrations needed to depress tetanic tension and tetanic fade were quite different in the case of velnacrine (depression of tetanic tension from 1 microM and tetanic fade from 170 microM), whereas physostigmine and tacrine were able to affect these parameters at very similar concentrations. The results suggest that some effects of velnacrine could differ from those of tacrine in spite of the chemical similarity.

Animals↗