Biomedical subjects

S Z Langer

Publications and source records attributed to S Z Langer.

At least 127 records · Page 7Linked to original sources

PubMed1985

Rapid desensitization of presynaptic dopamine autoreceptors during exposure to exogenous dopamine.

When nomifensine is employed to inhibit neuronal uptake, exposure to dopamine (DA) (0.1-0.3 microM) or apomorphine (0.01-0.1 microM) inhibited, in a concentration-dependent manner, the electrically evoked release of [3H]dopamine from slices of the rabbit caudate nucleus. Apomorphine inhibited transmitter release independently of the time of exposure to the drug (6-32 min). On the other hand, the inhibitory effect of exogenous dopamine occurred only if a short period (4-12 min) of exposure was employed. In studies on the electrically evoked release of [3H]acetylcholine in slices of the rabbit caudate nucleus there was no evidence for desensitization to apomorphine or exogenous dopamine at the level of the dopamine receptors that inhibit [3H]acetylcholine release. These results indicate that the dopamine autoreceptors modulating [3H]dopamine release in the caudate nucleus become subsensitive after a few minutes of exposure to exogenous dopamine. This effect does not occur at the level of the dopamine receptors which inhibit the release of [3H]acetylcholine.

Acetylcholine↗

PubMed1985

[3H]diltiazem binding to calcium channel antagonists recognition sites in rat cerebral cortex.

The presence of a diltiazem recognition site within the macromolecular complex of the calcium channel in the brain had been hypothesized on the basis of binding studies with [3H]dihydropyridine calcium channel antagonists. In the present study, we therefore characterized [3H]diltiazem binding sites in the rat cerebral cortex. Saturable high affinity (Kd = 50-170 nM) [3H]diltiazem binding to the rat cerebral cortex was stereospecifically inhibited by the enantiomers of diltiazem according to their activity as calcium channel antagonists and modulators of [3H]dihydropyridine binding. An association between the [3H]diltiazem binding site and the calcium channel was further corroborated by the effects of chemically heterogeneous calcium channel antagonists on [3H]diltiazem binding. Dihydropyridines appeared to allosterically affect [3H]diltiazem binding according to their pharmacological effects; e.g. at 37 degrees C nitrendipine enhanced whereas the calcium agonist Bay K 8644 failed to affect [3H]diltiazem binding at concentrations fully inhibiting [3H]nitrendipine binding. The effect of nitrendipine may, at least in part, be explained by an increase in the affinity of [3H]diltiazem.

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

PubMed1985

Inhibition by yohimbine of the calcium-dependent evoked release of [3H]GABA in rat and mouse brain slices in vitro.

Calcium-dependent release of [3H]GABA was elicited by electrical stimulation in slices of rat and mouse cerebral cortex or by potassium stimulation in the mouse brain-stem. The stimulation-evoked release of [3H]GABA was inhibited by yohimbine in a concentration-dependent manner. High concentrations of other alpha-adrenoceptor antagonists such as phentolamine, RS 21361, idazoxan, rauwolscine and corynanthine also inhibited [3H]GABA release. This effect was not observed with pseudoyohimbine or prazosin. [3H]GABA release was not affected by exposure to the alpha-adrenoceptor agonists clonidine, M7, noradrenaline or methoxamine. In addition, clonidine did not antagonize the yohimbine-induced inhibition of [3H]GABA release. The inhibitory effect of yohimbine did not result from an interaction with endogenously released noradrenaline since the inhibition was still observed in reserpine-pretreated animals. It is concluded that yohimbine and other alpha 2-adrenoceptor antagonists inhibit the stimulation-evoked release of [3H]GABA through a mechanism which appears to be independent of the blockade of alpha 2-adrenoceptors and which does not involve an interaction with endogenous noradrenaline. The present results indicate that yohimbine exerts non-specific actions on the release of [3H]GABA and that similar effects can be observed with other alpha-adrenoceptor blocking agents in high concentrations. Consequently, when studying the effects of yohimbine and other alpha 2-adrenoceptor antagonists on noradrenergic neurotransmission, the possibility of non-specific effects should be taken into consideration, particularly in the high concentrations range.

Animals↗

PubMed1985

Inhibitory effects of alpha, beta-methylene ATP on nerve-mediated contractions of the nictitating membrane in reserpinised cats.

Residual responses of the cat nictitating membrane to nerve stimulation were obtained after reserpine pretreatment (40% of controls), in spite of a pronounced reduction in noradrenaline content. The putative ATP-receptor desensitising agent alpha, beta-methylene ATP (alpha, beta-MATP), administered intraarterially through the lingual artery produced a contraction of the nictitating membrane and subsequently inhibited the residual responses evoked by sympathetic nerve stimulation in reserpinised cats. These doses of alpha, beta-MATP did not modify the contractions evoked by exogenous noradrenaline (i.a.) but antagonized the contractions of the nictitating membrane elicited by beta, gamma-methylene ATP, which is an agonist at P2 receptors. These results are compatible with a co-transmitter role for ATP in the neurally mediated contractile responses of the nictitating membrane following depletion of endogenous noradrenaline stores by pretreatment with reserpine.

Adenosine Triphosphate↗

PubMed1985

[3H] beta-phenylethylamine but not [3H](+)-amphetamine is released by electrical stimulation from perfused rat striatal slices.

Perfused rat striatal slices were prelabelled with either [3H](+)-amphetamine or [3H] beta-phenylethylamine. Electrical stimulation released a significant amount of radioactivity only from the slices prelabelled with [3H] beta-phenylethylamine. The electrically evoked release of radioactivity from slices labelled with [3H] beta-phenylethylamine was entirely calcium-dependent and was abolished after pretreatment with reserpine (5 mg/kg s.c., 24 h). In addition, S-sulpiride (1 microM), which facilitates the electrically evoked release of radioactivity from slices labelled with [3H]DA by blocking dopamine autoreceptors, also induced an increase of the radioactivity released by electrical stimulation from slices labelled with [3H] beta-phenylethylamine. Our results indicate that, in spite of the structural similarities between AMPH and PEA, only the latter which is the naturally occurring analog of AMPH can be released by electrical stimulation in a calcium-dependent manner.

Amphetamine↗

PubMed1985

Dopamine preferentially stimulates postsynaptic alpha 2-adrenoceptors in the femoral vascular bed, but alpha 1-adrenoceptors in the renal vascular bed of the anaesthetised dog.

The decrease in blood flow in response to dopamine (DA) injected intraarterially (i.a.) into the femoral or renal vascular beds was examined in the anaesthetised dog. DA or noradrenaline (NA) were 10 times more potent as vasoconstrictor agents in the femoral than in the renal vasculature. In the femoral bed, the DA induced vasoconstriction was completely resistant to antagonism by prazosin (30-300 micrograms/kg i.v.), but was dose-dependently blocked by the alpha 2-receptor antagonist idazoxan (30-300 micrograms/kg i.v.). In the renal bed the vasoconstrictor effects of DA were resistant to blockade by idazoxan, but were prazosin sensitive indicating that alpha 1-adrenoceptors were involved in this response. The alpha-receptor agonist profile for DA was not modified in the femoral bed after blockade of dilatory D1-receptors with SCH 23390 (0.5 mg/kg i.v. and 0.1 mg/kg per h i.v.). However, this antagonist significantly increased the vasoconstrictor potency for DA in the renal bed. The decrease in femoral blood flow induced by an injection of DA, appears to be mediated by alpha 2-adrenoceptors. In the renal vascular bed where the predominant alpha-adrenoceptor corresponds to the alpha 1-subtype and there are few postsynaptic alpha 2-receptors subserving vasoconstriction, DA can stimulate alpha 1-receptors but this action requires higher doses of agonist than those needed for alpha 2-adrenoceptor stimulation.

Adrenergic alpha-Antagonists↗

PubMed1985

Influence of GABA mimetics and lithium on biochemical manifestations of striatal dopamine target cell hypersensitivity.

The potential mechanisms whereby GABA mimetics and the antimanic agent lithium stabilize dopaminergic transmission are discussed. Evidence is presented that GABA mimetics, and in particular progabide, affect dopamine-mediated events in the basal ganglia on at least three levels. First, they reduce dopamine neuron activity in both the basal and the activated states. Secondly, on a long-term basis, they antagonize the proliferation of striatal dopamine receptors subsequent to chronic neuroleptic treatment. Thirdly, they modulate the expression of dopamine receptor activation by acting distally to the dopaminergic synapse. Lithium and GABA mimetics have the last two properties in common. These effects may represent the biochemical basis for the therapeutic action of GABA mimetics in iatrogenic dyskinesias. Moreover, the similarity between the biochemical effects of GABA mimetics and lithium suggest that the former drugs may have a therapeutic potential in mania.

Animals↗

PubMed1985

Amphetamine induced release of endogenous dopamine in vitro is not reduced following pretreatment with reserpine.

The release of endogenous dopamine evoked by electrical stimulation or by exposure to (+)-amphetamine (10 microM) was determined in superfused striatal slices of the rat. The spontaneous and the electrically-evoked release of dopamine were significantly increased in the presence of nomifensine (10 microM). After reserpine pretreatment (5 mg/kg, s.c., 24 h), the striatal dopamine content was reduced by about 90%. Exposure to 10 microM (+)-amphetamine during 2 min released similar amounts of dopamine from striatal slices of untreated or reserpine pretreated rats. Similar results were obtained when monoamine oxidase activity was inhibited in vivo with pargyline. Pretreatment with reserpine does not modify the (+)-amphetamine-induced release of dopamine, in spite of the marked reduction of the striatal dopamine content. These results provide direct evidence for the view that (+)-amphetamine releases dopamine from a special, reserpine-resistant pool of newly synthetized transmitter.

Animals↗

PubMed1985

Sodium dependent [3H]cocaine binding associated with dopamine uptake sites in the rat striatum and human putamen decrease after dopaminergic denervation and in Parkinsons disease.

The binding of radiolabelled cocaine, an inhibitor of dopamine uptake, to the post-mortem human putamen was studied and compared to that in the rat striatum. Saturation analysis of [3H]cocaine binding to the human putamen revealed the presence of a high affinity component of binding with a Kd of 0.21 mumol/l and a Bmax of 1.47 pmol/mg protein. In addition a low affinity component (Kd = 26.4 mumol/l) was demonstrated, having a Bmax of 42.2 pmol/mg protein. Also in the rat striatum [3H]cocaine binding was both of high affinity (Kd = 0.36 mumol/l, Bmax = 5.56 pmol/mg protein) and low affinity (Kd = 25.9 mumol/l, Bmax = 35.6 pmol/mg protein). A pharmacological characterisation of high affinity [3H]cocaine binding to rat striatal membranes clearly indicates an association with the neuronal dopamine transporter. The IC50 values of 8 selected drugs for inhibition of [3H]cocaine binding in the rat striatum were highly significantly correlated with their potency to inhibit [3H]dopamine uptake into slices of the rat striatum. [3H]Cocaine binding was stereospecifically inhibited by (+)nomifensine and (+)diclofensine which were 50-80-fold more active than their respective (-)isomers. Drugs with dopamine releasing activity were more potent at inhibiting [3H]dopamine uptake than at competing for the high affinity site of [3H]cocaine binding. A highly significant correlation was found between IC50 values for [3H]cocaine binding in the rat striatum and the human putamen. Further evidence in support of an association of [3H]cocaine binding in the rat striatum with the dopamine transporter was obtained from lesion studies. Thus, intranigral 6-hydroxydopamine administration produced a marked (67%) decrease in striatal [3H]cocaine binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Pharmacological profile of the imidazopyridine zolpidem at benzodiazepine receptors and electrocorticogram in rats.

Zolpidem is a novel non-benzodiazepine related hypnotic, which possesses an imidazopyridine structure. This drug has preferential affinity for the 3H-diazepam binding site in the rat cerebellum, while it is only weakly active at inhibiting 3H-Ro 5-4864 binding to the rat kidney. The potency of zolpidem at displacing 3H-Ro 15-1788 binding to rat cerebral cortex membranes is enhanced in the presence of GABA. On the sleep pattern of the electrocorticogram in the curarised rat, zolpidem induces a physiological type of slow wave sleep with rapid onset of action. Zolpidem differs from classical benzodiazepine drugs, in possessing an atypical binding profile to 3H-benzodiazepine receptors, and because it does not affect the sleep patterns.

Animals↗

PubMed1985

Interaction between presynaptic facilitatory angiotensin II receptors and inhibitory muscarinic cholinoceptors on 3H-noradrenaline release in the rabbit heart.

The existence of a functional interaction between presynaptic receptors modulating the release of noradrenaline was studied in the rabbit heart. Isolated right atria were prelabelled with 3H-noradrenaline and the overflow of tritium was induced by field stimulation (2 Hz, 0.1 ms duration, supramaximal voltage for a total of 180 pulses). In atria superfused with Krebs' solution containing 10 mumol/l cocaine and 30 mumol/l corticosterone, angiotensin II (10 nmol/l) increased the stimulation-evoked overflow of 3H-transmitter by 2.8-fold. The addition of atropine (0.3 mumol/l) to the perfusion medium, either in the presence or in the absence of uptake inhibitors, further enhanced the facilitatory effect of angiotensin II (3H-transmitter release increased by 3.5-fold). Exposure to 1 mumol/l carbachol decreased by 65% the stimulation-evoked release of 3H-transmitter while the facilitatory effect of angiotensin II determined in the presence of the muscarinic cholinoceptor agonist was enhanced (3H-transmitter release increased by 6.6-fold). Conversely, during sustained activation of presynaptic angiotensin receptors producing a 2.5-fold increase in the release of 3H-transmitter, the inhibitory effect of carbachol remained unchanged. These results suggest a functional interaction between presynaptic inhibitory muscarinic cholinoceptors and the presynaptic facilitatory angiotensin receptor which modulate the release of noradrenaline from cardiac noradrenergic nerves.

Angiotensin II↗

PubMed1985

Preferential antagonism by diltiazem of alpha 2-adrenoceptor mediated vasoconstrictor responses in perfused tail arteries of spontaneous hypertensive rats.

Vasoconstrictor responses mediated by the alpha 2-adrenoceptor agonist TL99, were particularly sensitive to blockade by the calcium antagonist drug diltiazem in isolated perfused tail arteries of spontaneously hypertensive rats (SHR). In contrast, the vasoconstrictor responses induced by the alpha 1-adrenoceptor agonist methoxamine were significantly more resistant to antagonism by diltiazem. At higher concentrations (greater than 300 nmol/l) diltiazem became an effective antagonist of all alpha-adrenoceptor mediated responses. In normotensive Wistar Kyoto (WKY) or Sprague-Dawley (SD) rats diltiazem was significantly less potent against vasoconstrictor responses to TL99 than in SHR. The blockade of alpha 1-adrenoceptor mediated vasoconstriction by diltiazem was not significantly different when normotensive rats and SHR were compared. The vasoconstrictor responses evoked by 5HT in the perfused tail arteries were particularly resistant to blockade by diltiazem in SHR arteries. The responses to endogenously released noradrenaline, evoked by electrical field stimulation, were significantly antagonised by diltiazem (30 nmol/1-3 mumol/l) in SHR-tail arteries, while they were not modified in WKY-tail arteries. At the concentrations of diltiazem which blocked end organ responses to field stimulation, there was no modification of total tritium overflow from SHR-tail arteries after labelling the tissue with 3H-noradrenaline, indicating that diltiazem does not inhibit transmitter release at these concentrations. The tail artery preparation of SHR contains a population of postsynaptic alpha 2-adrenoceptors which mediate contraction in this blood vessel and the calcium entry blocker diltiazem is a potent antagonist of vasoconstrictor responses mediated by vascular alpha 2-adrenoceptors in hypertensive rats. These findings may be relevant to the antihypertensive action of diltiazem.

Adrenergic alpha-Agonists↗

PubMed1985

Non-benzodiazepine anxiolytics: potential activity of phenylpiperazines without 3H-diazepam displacing action.

Four phenylpiperazine derivatives exhibited an activity similar to benzodiazepines and meprobamate in the 4-plate test. One of these (compound IV) demonstrated anxiolytic like activity in a step-down avoidance technique, in electroshock induced aggression and in the staircase test. In contrast to benzodiazepines, compound IV was not anticonvulsant, myorelaxant or sedative. Confirmation of the anxiolytic activity of compound IV in animal models was obtained in 3 separate clinical trials in anxious patients. The mechanism of action of these phenylpiperazines appears to be different from the benzodiazepines as they do not displace 3H-diazepam binding nor do they interact with other elements of the GABA receptor macromolecular complex. Instead, compound IV interacts with both dopaminergic and serotoninergic neuron systems. Thus, from this data it would appear that an activity at the benzodiazepine recognition site is not obligatory for anxiolytic activity in man or in animals models.

Aggression↗

PubMed1985

Inhibition of the electrically evoked release of [3H]acetylcholine in rat striatal slices: an experimental model for drugs that enhance dopaminergic neurotransmission.

The activation by endogenous dopamine of the inhibitory 3,4-dihydroxyphenylethylamine (dopamine) receptors modulating the electrically evoked release of [3H]acetylcholine [( 3H]ACh) and [3H]dopamine in rat striatal slices is a function of the concentration of dopamine accumulated in the synaptic cleft during electrical stimulation. When the release of 3H-neurotransmitters was elicited with a 2-min period of stimulation at a frequency of 1 Hz, neither dopamine autoreceptors nor dopamine receptors modulating [3H]ACh were activated by endogenously released dopamine. On the other hand, exposure to (S)-sulpiride facilitated the release of [3H]dopamine and [3H]ACh elicited when the 2-min stimulation was carried out at a frequency of 3 Hz but this effect was not observed at a lower frequency of stimulation (1 Hz). In the presence of amphetamine the dopamine receptors modulating the electrically evoked release of [3H]ACh can be activated by endogenous dopamine even at the lower frequency of stimulation (1 Hz). Similar effects can be obtained if the neuronal uptake of dopamine is inhibited by cocaine or nomifensine. The inhibition by amphetamine of the release of [3H]ACh elicited by electrical stimulation at 1 Hz involves dopamine receptors and can be fully antagonized by clozapine, haloperidol, chlorpromazine, or pimozide. The stereoselectivity of this antagonism can be demonstrated with the optical enantiomers of sulpiride and butaclamol. This inhibitory effect of amphetamine on cholinergic neurotransmission appears to be the result of the stimulation of dopamine receptors of the D2 subtype, as they were resistant to blockade by the preferential D1 receptor antagonist SCH 23390.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1985

Tryptamine, a substrate for the serotonin transporter in human platelets, modifies the dissociation kinetics of [3H]imipramine binding: possible allosteric interaction.

Tricyclic antidepressants and nontricyclic serotonin (5-hydroxytryptamine) uptake blockers monophasically inhibit [3H]imipramine binding in human platelets. Similarly, serotonin and tryptamine inhibit the binding of [3H]imipramine in the low micromolar range and with a pseudo-Hill coefficient near unity. Dissociation of the [3H]imipramine receptor complex in the presence of uptake inhibitors follows first-order kinetics with a half-life of approximately 60 min. Although serotonin and tryptamine do not decrease [3H]imipramine binding when added under equilibrium conditions, simultaneous addition of serotonin or tryptamine with serotonin uptake inhibitors decreases the rate of ligand-receptor dissociation in a concentration-dependent manner. These data suggest a common site of action for serotonin, which is the substrate of the transporter system, and of tryptamine, its nonhydroxylated analog. This hypothesis is supported by the identification of a high-affinity (Km = 0.55 microM), saturable, and temperature-dependent uptake of [3H]tryptamine in human platelets. Uptake of [3H]tryptamine was inhibited potently by imipramine and nontricyclic serotonin uptake inhibitors with a potency similar to that observed for [3H]serotonin uptake. These data support the hypothesis that in platelets, [3H]imipramine, tricyclic, and nontricyclic serotonin uptake inhibitors bind to a common recognition site that is associated with the serotonin transporter but that differs from the substrate recognition site of the carrier through which serotonin and tryptamine exert a heterotropic allosteric modulation on [3H]imipramine binding.

Allosteric Regulation↗

PubMed1985

5-Methoxytryptoline, a competitive endocoid acting at [3H]imipramine recognition sites in human platelets.

5-Methoxytryptoline potently inhibits [3H]imipramine binding to membranes from the cerebral cortex and platelets. Since 5-methoxytryptoline, which appears to occur endogenously with particularly high levels in the human pineal gland, also inhibits 5-hydroxytryptamine (5-HT, serotonin) uptake, it should be considered as a putative endogenous ligand modulating 5-HT transport. As the 5-HT transporter complex comprises the imipramine and the substrate recognition sites, which interact allosterically, it was essential to define the mechanism of inhibition of [3H]imipramine binding by 5-methoxytryptoline. Human platelets show an active and saturable uptake of 5-HT and tryptamine. The uptake of both substrates appears to be mediated by the same carrier and it is inhibited by 5-methoxytryptoline at submicromolar concentrations. 5-HT and tryptamine inhibit [3H]imipramine binding in human platelets with a Hill slope for inhibition close to unity and IC50 values of 3,265 and 3,475 nM, respectively. This inhibition is, however, not competitive because both 5-HT and tryptamine significantly decrease the rate of [3H]imipramine-receptor dissociation. Although 5-methoxytryptoline potently inhibits [3H]imipramine binding (IC50 = 44 nM) in human platelets with a Hill slope of unity, it does not affect the receptor-ligand dissociation rate of [3H]imipramine even at concentrations up to 100 microM. The present experiments show that 5-methoxytryptoline, in spite of its chemical similarity to the indoleamine transporter substrates, interacts with the imipramine receptor through a mechanism of competitive inhibition. This conclusion is supported by a selective effect of 5-methoxytryptoline on the Kd of [3H]imipramine binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding, Competitive↗

PubMed1985

Differential blocking actions of idazoxan against the inhibitory effects of 6-fluoronoradrenaline and clonidine in the rat vas deferens.

The prejunctional inhibitory effects of clonidine and 6-fluoronoradrenaline (6-FNA) have been evaluated in the isolated prostatic segment of the rat vas deferens, against the twitch response evoked by low frequency (0.1 Hz) field stimulation. The inhibitory potency of 6FNA was significantly increased in the presence of cocaine (1 microM) or pargyline (10 microM), but was not modified in the vas deferens from rats pretreated with reserpine when the endogenous levels of noradrenaline (NA) were decreased by 97%. Clonidine was significantly more potent than 6-FNA as an inhibitory agonist, and the potency of clonidine was not modified after cocaine, pargyline or reserpine. The alpha 2-adrenoceptor blocking agent idazoxan, was a competitive antagonist against the inhibitory effects of clonidine under all experimental conditions. In contrast, the only antagonism shown by idazoxan against the inhibitory effects of 6-FNA was in the presence of cocaine (1 microM), and this antagonist effect of idazoxan was not concentration-related. Low concentrations of 6-FNA caused concentration-dependent facilitatory effects on the twitch response, which were significantly greater after treatment with idazoxan (1 microM) in reserpine-treated vas deferens. These facilitatory effects of 6-FNA were always observed in the presence of prazosin (300 nM) and also after treatment of the preparations with phenoxybenzamine (10 microM), a concentration which abolished the inhibitory actions of both clonidine and 6-FNA. The facilitatory effects on the twitch response induced by low concentrations of 6-FNA are therefore unlikely to be due to either alpha 1- or alpha 2-adrenoceptor stimulation. In conclusion, the failure of idazoxan to block the inhibitory effects of 6-FNA, while exerting a potent competitive antagonism of clonidine-induced inhibitory effects, supports the proposal that alpha 2-adrenoceptors may in fact be subdivided into two subclasses, involving imidazoline and phenylethylamine recognition sites.

Adrenergic alpha-Antagonists↗

PubMed1985

Pharmacologic and therapeutic significance of alpha-adrenoceptor subtypes.

The concept that neurotransmitters can modulate their own release through presynaptic inhibitory autoreceptors is well established. The presynaptic inhibitory autoreceptors involved in a negative feedback mechanism that modulates the release of norepinephrine are of the alpha 2-subtype. Stimulation of central alpha 2-adrenoceptors by drugs like clonidine, guanfacine, and guanabenz produces an antihypertensive and bradycardiac effect through a decrease in sympathetic tone. In vascular smooth muscle, the alpha 1-adrenoceptor subtype predominates and mediates vasoconstriction although alpha 2-adrenoceptors mediating vasoconstriction are also present in some vascular beds. Phenylephrine preferentially stimulates alpha 1-adrenoceptors and guanabenz preferentially stimulates alpha 2-adrenoceptors in vascular smooth muscle, whereas norepinephrine is an agonist at both alpha 1- and alpha 2-subtypes. The pressor response to phenylephrine was markedly reduced by prazosin. In contrast, the response to norepinephrine was relatively resistant to blockade, and that to guanabenz, totally resistant to blockade by prazosin. Inhibition of neuronal uptake by cocaine or desipramine and pretreatment of cats with 6-hydroxydopamine increased the effectiveness of prazosin in blocking the pressor responses to norepinephrine, but not to guanabenz or phenylephrine. These results support the proposal that postsynaptic alpha 1-adrenoceptors are preferentially innervated (i.e., within the neuroeffector junction), while the postsynaptic alpha 2-adrenoceptors are in extrasynaptic locations. The subclassification of alpha-adrenoceptors into alpha 1- and alpha 2-subtypes opens the possibility of designing selective drugs to act as agonists or antagonists on these receptor subtypes. These compounds have useful therapeutic applications, and in the case of selective alpha 2-adrenoceptor antagonists, novel potential uses may exist, both at the level of the central nervous system and in the periphery.

Adrenergic alpha-Agonists↗