Direct and indirect actions of dopamine on tracheal smooth muscle

Summary The effects of dopamine (DA) were studied on guinea-pig isolated tracheal chains. At a low concentration (10^–6M) DA occasionally produced a small contraction; this was followed by a dose-dependent relaxation 3×10^–6–3×10^–3 M).On a molar basis, DA was about 40 times less potent than noradrenaline (NA) in relaxing tracheal chains, and about 2700 times less potent than isoprenaline (ISO). The maximum degree of relaxation obtained with each drug was the same.Pretreatment of the guinea-pig with reserpine (5 mg/kg) resulted in a 3-fold shift of the DA curve to the right without concomitantly affecting the ISO doseresponse curve. Reserpine completely abolished the relaxant effects of tyramine, but a small contractile response remained.Desipramine (DMI), at a concentration of 10^–5 M, caused a 4-fold shift of the DA curve to th right. The same concentration of DMI resulted in a shift to the left of the NA dose-response curve by about 8-fold. Benztropine (10^–5 M) and haloperidol (10^–5 M and 3×10^–5 M) did not affect the DA dose-response curve.The DA-induced relaxation was inhibited by propranolol (10^–8–10^–6 M) in a dose-dependent manner. The higher concentrations of propranolol (10^–7 and 10^–6 M) unmasked the contractile effect of DA. In the presence of propranolol, phentolamine (10^–5 M) abolished the contractile effect of DA.It is concluded that DA has both direct and indirect actions on guinea-pig isolated tracheal smooth muscle. The relaxant effects of DA are predominantly due to a direct action on smooth muscle -adrenoceptors, with a component due to release of NA from adrenergic nerves. The contractile effects, which under normal conditions are masked by the relaxant effect of DA, are mediated by functional -adrenoceptors. There is no evidence for either specific dopaminergic nerves, uptake mechanisms or receptors in guinea-pig trachealis muscle.     

Studies on the positive inotropic effect of dopamine in the guinea-pig heart

Summary The positive inotropic effect of dopamine has been studied in isolated ventricular strips of guinea-pig heart.The concentration-inotropic response curve for dopamine was significantly shifted to the right by pretreatment with reserpine.In preparations obtained from animals pretreated with reserpine (2.5 mg/kg, 24 h prior to the experiment) the dose-response curve was not significantly affected by haloperidol, a dopamine vascular receptor antagonist (10^–6–3×10^–6 M).The inotropic effect of dopamine was antagonized by practolol (3×10^–7–10^–6 M), but not by phentolamine (3×10^–6–10^–5 M); moreover the alpha-adrenoceptor blocking drug (10^–5 M) did not affect the curve for dopamine in the presence of practolol (3×10^–7 M).In preparations in which fast sodium channels were blocked by K⁺-rich medium, slow electrical responses (calcium-mediated action potentials) as well as contractions were induced by high concentrations of dopamine (10^–4–3×10^–4 M); again these responses were unaffected by phentolamine or haloperidol, but were blocked by practolol.It was concluded that in the guinea-pig ventricular muscle dopamine induced a positive inotropic effect through both indirect and direct action, and that the latter is due to the activation of beta-adrenoceptors.     

Differential effects of benzamides and thioxanthenes on dopamine-elicited accumulation of cyclic AMP in isolated rabbit retina

Summary Benzamides or thioxanthenes were tested as potential antagonists of the cyclic AMP accumulation induced by 10^–4 M dopamine in intact rabbit retinae in vitro in the presence of 5 to 7 mM theophylline. The neuroleptic sulpiride (10^–4 M) was found to be totally inactive whereas a substituted benzamide (clebopride) had small but significant antagonist effect at the same concentration. Among thioxanthenes, isomers of cisconfiguration, which are potent neuroleptics, completely inhibit the cyclic AMP accumulation induced by dopamine, in contrast to trans-isomers which had no inhibitory effects. These data would confirm that retina in vitro is another suitable model for screening antipsychotic activity of classical neuroleptics and that the mechanism of action of sulpiride still needs further investigation.     

In vitro acetylcholine release from rat caudate nucleus as a new model for testing drugs with dopamine-receptor activity

Summary The effects of a number of dopamine-receptor agonists on depolarization-induced (26 mM K⁺) release of ³H-acetylcholine from slices of rat caudate nucleus were examined with a superfusion method. Apomorphine (10^–6 M) and N,N-dipropyliso-ADTN (10^–7 M) inhibited acetylcholine-release in vitro by about 50% and these inhibitory effects were antagonized by haloperidol. For N,N-dipropyl-iso-ADTN an EC₅₀ of approximately 3×10^–9 M was estimated from its dose-response curve. However, dopamine (10^–6 M) itself and bromocriptine (10^–6 M) inhibited acetylcholine-release less. Presumably: the weak effect of exogenous dopamine is due to its (partial) uptake in dopaminergic nerve terminals and to the fact that released endogenous dopamine already partially activates the receptors involved in the inhibition of acetylcholine-release.Pretreatment of young rats with 6-hydroxydopamine (+ desipramine) increased the inhibitory effects of dopamine-receptor agonists, including dopamine itself, on acetylcholine-release from caudate slices, indicating dopamine-receptor supersensitivity. This was corroborated by the finding that apomorphine-induced stereotyped behavior was significantly higher in rats lesioned with 6-hydroxydopamine than in controls.It is suggested that K⁺-induced release of radiolabelled acetylcholine from caudate nucleus slices provides a functional model to study the characteristics of post-synaptic dopamine-receptors in vitro. The concentrations of dopamine-receptor agonists needed to inhibit acetylcholine-release appear to be in the nanomolar range, in agreement with their affinities as determined in dopamine-receptor binding studies. In contrast, these concentrations are much lower than those required for stimulation of dopamine-sensitive adenylate cyclase activity.     

Field stimulation-induced responses of circular smooth muscle from guinea-pig stomach

Summary Field stimulation of circular smooth muscle of guinea-pig stomach from the regions of the cardia and fundus caused contraction responses at low stimulation frequencies (0.25–1 Hz) with relaxation at higher frequencies (1–10 Hz), whilst tissues of the body and antrum responded with contraction throughout the frequency range. Atropine (10^–9–10^–8 M) antagonised the contraction responses of all tissues, with relaxation developing at higher concentrations (except for antral tissue). In contrast, metoclopramide (10^–8–10^–6 M) caused modest (cardia, fundus) or marked (body, antrum) enhancement of contractions to field stimulation, whilst domperidone (10^–8–10^–7 M), haloperidol (10^–8–10^–6 M), prazosin, propranolol and methysergide (10^–8–10^–6 M) failed to modify the contraction responses. However, whilst yohimbine and guanethidine failed to modify the contractions of the cardia, fundus and body tissues, those of the antral preparations were antagonised by nanomolar concentrations of yohimbine and by guanethidine (10^–6–5×10^–5 M). To optimise the relaxation responses for study, atropine was included in the physiological solution. Relaxation to field stimulation of preparations from the body and cardia, but not the fundus, was antagonised by reserpine pretreatment (5 mg/kg i.p., 24h), addition of guanethidine (10^–5–10^–4 M), phentolamine, prazosin or propranolol (10^–7–10^–6 M) (the effects of prazosin and propranolol being additive). Higher concentrations of haloperidol and domperidone antagonised the relaxation responses of the body preparations only. Metoclopramide, yohimbine and methysergide (10^–8–10^–6 M) were ineffective. Thus, it is concluded that the contractile effects of the 4 stomach areas to field stimulation reflects a major cholinergic involvement, with an additional ₂-adrenoceptor contractile component in antral tissue. Relaxation responses of cardia and body tissue involve ₂- and -adrenoceptors plus a further, unidentified, non-adrenergic component; the latter represents the total relaxation response of the fundic preparation.     

Differential effects of continuous administration for 1 year of haloperidol or sulpiride on striatal dopamine function in the rat

Administration of haloperidol (1.4–1.6 mg/kg/day) for up to 12 months or sulpiride (102–109 mg/kg/day) for between 6 and 12 months increased the frequency of purposeless chewing jaw movements in rats. N,n-propylnorapomorphine (NPA) (0.25–2.0 mg/kg SC) did not induce hypoactivity in haloperidol-treated rats at any time; sulpiride treatment for 9 and 12 months caused a reduction in the ability of NPA to induce hypoactivity. Haloperidol, but not sulpiride, treatment enduringly inhibited low dose apomorphine effects (0.125 mg/kg SC). After 12 months, sterotypy induced by high doses of apomorphine (0.5–1.0 mg/kg) was exaggerated in haloperidol-, but not sulpiride-treated rats.B_max for specific striatal ³H-spiperone binding was increased by haloperidol, but not sulpiride, treatment throughout the study. B_max for ³H-NPA binding was elevated only after 12 months of both haloperidol and sulpiride treatment. B_max for ³H-piflutixol binding was not alfered by chronic haloperidol or sulpiride treatment. Striatal dopamine-stimulated adenylate cyclase activity was inhibited for the 1st month of haloperidol treatment, thereafter returning to control levels; dopamine stimulation was increased after 12 months of sulpiride treatment. Striatal acetylcholine content was increased after 3 and 12 months of treatment with haloperidol, but was not affected by sulpiride.Chronic administration of sulpiride does not induce identical changes in striatal dopamine function to those caused by haloperidol.     

Inhibitory actions of catecholamines on electrically induced contractions of the submucous plexus-longitudinal muscularis mucosae preparation of the guinea-pig oesophagus

1 The submucous plexus-longitudinal muscularis mucosae preparation of the guinea-pig oesophagus was used to study the actions of catecholamines on the twitch responses to electrical stimulation.

2 When the preparation was stimulated coaxially (0.1 Hz, 0.5 ms, supramaximal voltage), stable twitch-like contractions were obtained. These were abolished by tetrodotoxin (0.1 μM) and atropine (0.1 μM), potentiated by physostigmine (0.1 μM), and were mediated presumably by stimulation of intramural cholinergic nerves.

3 The twitch contractions of the muscularis mucosae were inhibited by catecholamines, in a concentration-dependent manner. The order of potency was isoprenaline > adrenaline > noradrenaline > dopamine.

4 The inhibitory actions of noradrenaline (1 μM) and adrenaline (1 μM) were partly reversed by phentolamine (1 μM) or by propranolol (1 μM), and completely abolished by both antagonists together. The inhibitory effect of dopamine (300 μM) was largely reversed by phentolamine (1 μM), but not by propranolol (1 μM), while the inhibitory action of isoprenaline was competitively antagonized only by propranolol (pA₂ of 7.6).

5 The contraction of the muscularis mucosae to exogenously applied acetylcholine (ACh, 20 nM) which was comparable in magnitude with that to electrical stimulation was also inhibited by isoprenaline (0.1 μM), adrenaline (1 μM) and noradrenaline (1 μM), but not by dopamine (300 μM). In the presence of propranolol (1 μM), noradrenaline, adrenaline and dopamine potentiated the ACh-induced contraction, while the effect of isoprenaline was mainly antagonized. The potentiating effects were antagonized by further treatment with phentolamine (1 μM).

6 Adrenaline, noradrenaline and dopamine but not isoprenaline, produced a weak contraction of the longitudinal muscularis mucosae in the presence of propranolol (3 μM). The contractile responses were completely inhibited by phentolamine (3 μM). Tone in the muscularis mucosae induced by carbachol (3 μM) in the presence of phentolamine (10 μM) was inhibited by catecholamines, in a concentration-dependent manner, an effect that was competitively antagonized by propranolol.

7 In the submucous plexus-longitudinal muscularis mucosae preparation of the guinea-pig oesophagus there are three types of adrenoceptor, inhibitory prejunctional α-adrenoceptors, excitatory postjunctional α-adrenoceptors and inhibitory postjunctional β-adrenoceptors, and cholinergic neurotransmission is inhibited by catecholamines acting at both prejunctional α- and postjunctional β-adrenoceptors.

     

Effects of dopamine on whole kidney function and proximal transtubular volume fluxes in the rat

Summary The renal effects of dopamine were studied using clearance and micropuncture techniques in rats. Intravenous infusion of dopamine (4.7 · 10^–6 mol · kg^–1 · h^–1) increased glomerular filtration rate and renal blood flow. Renal blood flow was measured by an electromagnetic flowmeter. The increase in filtered fluid and sodium was nearly completely matched by increased tubular reabsorption. Thus, only a small rise in urine flow and in urinary sodium excretion was observed.The micropuncture experiments using the split oil droplet method of Gertz demonstrated a stimulation of the transepithelial fluid transfer after injection of dopamine (10^–4M) into the proximal tubular lumen. This effect was abolished by simultaneous injection of propranolol (10^–3 M) which, by its own, did not affect transtubular volume fluxes. It is concluded that dopamine, by stimulation of -adrenoceptors, may increase reabsorptive capacity of the proximal tubular epithelium independent of changes in renal hemodynamics.Supported by Deutsche Forschungsgemeinschaft     

Effect of extracellular dopamine on the release of dopamine in the rabbit caudate nucleus: Evidence for a dopaminergic feedback inhibition

Summary Slices of the head of the rabbit caudate nucleus were preincubated with 10^–7 M ³H-dopamine and then superfused, and the effect of unlabeled dopamine on the outflow of tritium was investigated. In most experiments, nomifensine was added throughout superfusion in order to block uptake of the unlabeled amine. Nomifensine was a potent inhibitor of the uptake of ³H-dopamine into rabbit caudate synaptosomes, with an IC₅₀ of 5·10^–8 M at a ³H-dopamine concentration of 4·10^–8 M.In the absence of nomifensine, unlabeled dopamine (10^–7 M and higher concentrations) accelerated the basal outflow of tritium from preincubated slices. 10^–5 M nomifensine strongly counteracted the acceleration. In the presence of nomifensine, unlabeled dopamine (10^–7 to 10^–6 M) caused a concentrationdependent decrease of the overflow of tritium evoked by electrical stimulation at 0.1 Hz. Chlorpromazine and haloperidol (in the presence of nomifensine) increased the stimulation evoked overflow and antagonized the inhibitory effect of dopamine.It is concluded that extracellular dopamine shares with other dopaminergic agonists the ability to inhibit action potential-evoked release of intraneuronal dopamine. The inhibition is mediated by specific receptors. The results support the hypothesis that previously released dopamine, by an action on these receptors, can inhibit further release of dopamine.     

Differential alterations in striatal dopamine receptor sensitivity induced by repeated administration of clinically equivalent doses of haloperidol,sulpiride or clozapine in rats

Rats received therapeutically equivalent doses of either haloperidol (1.7–1.9 mg/kg/day), sulpiride (112–116 mg/kg/day) or clozapine (30–35 mg/kg/day) continuously for 4 weeks. Treatment with haloperidol, but not sulpiride or clozapine, caused inhibition of stereotyped behaviour induced by apomorphine (0.125–0.25 mg/kg SC). Following drug withdrawal for up to 7 days, haloperidol and sulpiride, but not clozapine treatment caused an exaggeration of stereotyped behaviour induced by apomorphine.B_max values for striatal ³H-spiperione binding were erevated in animals treated for 2 and 4 weeks with haloperidol, but not with sulpiride or clozapine. Following drug withdrawal, haloperidol, but not sulpiride or clozapine, treatment caused an increase in B_max for striatal ³H-piperone binding.B_max values for striatal ³H-NPA binding revealed no change during haloperidol or clozapine treatment. Sulpiride treatment for 1 week caused an increase in B_max for ³H-NPA binding, which returned to control levels at 2 and 4 weeks. Following drug withdrawal, there was an increase in B_max for ³H-NPA binding in rats treated with haloperidol and sulpiride, but not clozapine.On continuous treatment and following withdrawal from haloperidol, sulpiride, or clozapine the ability of dopamine to stimulate striatal adenylate cyclase activity did not differ from that in control animals.Repeated administration of sulpiride or clozapine may not induce striatal dopamine receptor supersensitivity when given in clinically relevant doses, although haloperidol does.     

Cardiac electrophysiology of four neuroleptics: Melperone,haloperidol, thioridazine and chlorpromazine

Summary Effects of dopamine receptor agonists and antagonists on the release of dopamine were studied in the caudate nucleus of the rabbit. The nucleus contained 6.7 g/g of dopamine, but negligible levels of noradrenaline and dopamine--hydroxylase. No formation of ³H-noradrenaline was detected in caudate slices preincubated with ³H-dopamine, and more than 95% of the tritium content of the tissue consisted of ³H-dopamine.When caudate slices were preincubated with ³H-dopamine and then superfused with amine-free medium, there was a basal outflow of tritium that was not or only slightly changed by tetrodotoxin (10^–7 and 10^–6 M), apomorphine (up to 10^–5 M), bromocriptine (up to 10^–6 M), chlorpromazine (up to 10^–6 M), haloperidol (up to 10^–7 M), or omission of calcium. Electrical stimulation (3 Hz, 24 mA, 2 ms pulse duration, 2-min periods) greatly increased the outflow of tritium. The stimulation-evoked overflow was abolished by tetrodotoxin (10^–7 and 10^–6 M) and in calcium-free medium. Apomorphine (10^–8–10^–5 M) and bromocriptine (10^–8–10^–6 M) reduced, whereas chlorpromazine (10^–7 and 10^–6 M) and haloperidol (10^–8 and 10^–7 M) enhanced the evoked overflow. The inhibitory effect of apomorphine and bromocriptine was antagonized by chlorpromazine and haloperidol, but not by phentolamine.Silicone tubings that had been in contact with ³H-haloperidol retained tritiated material that was slowly eluted during perfusion with water or physiological salt solution. The material was identified as ³H-haloperidol. When silicone tubings pretreated with unlabelled haloperidol were used in subsequent dopamine release experiments, the inhibitory effect of apomorphine was not reproduced.It is concluded that, in the caudate nucleus of the rabbit, apomorphine and bromocriptine depress, whereas chlorpromazine and haloperidol facilitate action potential-evoked release of dopamine. The effects are mediated by specific receptors which may be located on the dopaminergic nerve terminals. The receptors appear to be normally activated by released dopamine itself, which thus inhibits its own further release. Part of the discrepancies in the literature concerning dopaminergic modulation of dopamine release may be due to retention of neuroleptic drugs in superfusion assemblies, followed by slow elution and interference with subsequent experiments.     

Modulatory role of catecholamines on tyrosine hydroxylase induction

Summary The possible modulatory role of cytoplasmic catecholamines on tyrosine hydroxylase induction was studied. Rat superior cervical ganglia were kept in organ culture and after 48 h tyrosine hydroxylase activity was determined. Exposure to 10^–4 M carbachol during 4 h almost doubled the control activity. Incubation with 10^–5 M noradrenaline or 10^–5 M dopamine impaired the carbachol-mediated induction of the enzyme. This effect was not blocked by 10^–7 M propranolol, 2.4×10^–6 M haloperidol or 3.1×10^–6 M phentolamine. Inhibition of monoamine oxidase activity by 5.1×10^–4 M pargyline inhibited the effect of carbachol. When the pool of endogenous catecholamines was decreased by -methyl-p-tyrosine, carbachol induced tyrosine hydroxylase to the same extent as in non-depleted ganglia. It is suggested that the long-term regulation of tyrosine hydroxylase is modulated by a strategic cytoplasmic pool of catecholamines.     

Adrenaline-induced enhancement of the blood pressure response to sympathetic nerve stimulation in adrenal demedullated pithed rats

Summary The influence of the prejunctional -adrenoceptor-mediated control mechanism of noradrenaline release on the cardiovascular response to preganglionic nerve stimulation (PNS) and the role of adrenaline as endogenous activator of this facilitatory mechanism were studied in pithed rats. The increases in mean arterial blood pressure and heart rate responses to eight PNS (0.8 Hz, 1 ms, 75 V, for 20 s at 12 min intervals) were measured in control, adrenal demedullated and sham-operated pithed rats, respectively.Repeated stimuli of the sympathetic outflow elicited similar blood pressure responses in control and sham-operated rats, whereas the blood pressure responses were attenuated in adrenal demedullated rats. Administration of the non-selective -adrenoceptor antagonist propranolol (5 mg × kg^–1, i.v.) decreased the blood pressure response in control, but not in adrenal demedullated rats. The increase in heart rate during PNS was abolished in both groups after administration of propranolol. Infusion of adrenaline (0.06 g × kg^–1 × min^–1) increased the circulation levels of adrenaline from 0.4 nmol × 1^–1 to 4.8 nmol × l^–1, but did not modify the blood pressure response to PNS in control rats. In adrenal demedullated rats, however, the blood pressure response to PNS was enhanced during as well as after the infusion of adrenaline. This facilitatory effect of adrenaline on the blood pressure response in adrenal demedullated rats was blocked by pretreatment with propranolol (5 mg × kg^–1, i.v.).Taken together the present findings give further support to the hypothesis that neuronal adrenaline of adrenal medullary origin is the endogenous agonist at prejunctional -adrenoceptors mediating a facilitation of neuronal noradrenaline release. Send offprint requests to V. I. Tarizzo at the above address     

Relations between the effects of histamine,pheniramin and metiamide on spontaneous motility and the formation of cyclic AMP in the isolated rat uterus

Summary Histamine (5×10^–6 to 10^–3M) depressed the spontaneous motility of the isolated rat uterus in a dose-dependent manner. Under these conditions uterine cyclic AMP was raised up to 92%. Both effects, uterine relaxation and cyclic AMP accumulation after 2 min could be inhibited dose dependently by the H₂-antihistaminic compound metiamide (1.7×10^–6 M to 1.7×10^–4 M). By contrast, the H₁-antagonist pheniramin (4.4×10^–5 M) was ineffective. It was concluded that the histamine-induced inhibition of rat uterine motility is mediated by cyclic AMP which is formed in response to stimulation of H₂-histaminergic receptors.     

Characterization of adrenoceptors mediating positive inotropic responses in the ventricular myocardium of the dog

1 The pharmacological characteristics of adrenoceptors mediating the positive inotropic action in the dog heart were assessed by the use of blood-perfused papillary muscles and isolated strips of ventricular myocardium.

2 On the blood-perfused papillary muscle driven at 2 Hz and in sinus node preparations, phenylephrine induced positive inotropic and chronotropic responses in the same dose range and was much less potent than isoprenaline. The dose-response curve for the chronotropic action of phenylephrine was parallel to that of isoprenaline, whilst the dose-response curve for the inotropic action of phenylephrine was less steep than that of isoprenaline.

3 The infusion of pindolol, a β-adrenoceptor blocking agent, at a rate of 1 μg/min, shifted the isoprenaline dose-response curves to the right, and to the same extent, in both papillary muscle and sinus node preparations. In contrast to isoprenaline, the antagonism of phenylephrine by pindolol was noncompetitive. Phentolamine did not affect the positive inotropic and chronotropic actions of phenylephrine.

4 On isolated ventricular strips α-adrenoceptor blockade by 10^-6 M phentolamine did not affect dose-response curves to phenylephrine or dopamine. Pindolol shifted the dopamine dose-response curves to the right in a competitive manner and those of phenylephrine in a noncompetitive manner.

5 On ventricular strips from reserpine-pretreated dogs phenylephrine and tyramine dose-response curves were shifted markedly to the right and downwards. Desipramine (10^-5 M) which enhanced the action of noradrenaline considerably reduced the myocardial responses of phenylephrine.

6 Papaverine (10^-5 M) decreased the threshold concentration of phenylephrine required to stimulate the myocardium and shifted phenylephrine dose-response curves to the left.

7 Raising the temperature from 32°C to 37°C shifted phenylephrine dose-response curves to the right; when the temperature was raised from 37°C to 42°C the affinity of the drug was not changed.

8 Other α-adrenoceptor stimulants, methoxamine and clonidine, decreased the active tension of ventricular strips. The responses to noradrenaline and adrenaline (in the presence of pindolol; 3 × 10^-8 M) were not affected by phentolamine (10^-6 M).

9 The results indicate that adrenoceptors mediating positive inotropic responses in the dog ventricle are of the β-type and that post-synaptic α-adrenoceptors are not involved. Phenylephrine acts mainly by releasing noradrenaline from adrenergic nerve endings and partly by a weak direct action on β-adrenoceptors.

     

Further study of the adrenoceptors of the saphenous vein of the dog: Influence of factors which interfere with the concentrations of agonists at the receptor level

In the present study the affinities of some sympathomimetic amines for α- and β-adrenoceptors of the dog saphenous vein tissue were determined after all known factors interfering with the concentration of these agonists at the receptor level had been assessed and excluded. It was observed that in control experiments the relative potencies of sympathomimetic agonists for inducing contractions were: adrenaline (1.6) > noradrenaline (1.0) > phenylephrine (0.38) > isoprenaline (0.009).The elimination of neuronal uptake by cocaine, 4 × 10^?6M, enhanced predominantly the effects of noradrenaline (by a factor of 7.5), whereas block of catechol-O-methyl transferase (COMT) by U-0521, 10^?4 M, only enhanced those of adrenaline (by a factor of 2.6) and block of β-adrenoceptors by propranolol, 5 × 10^?7 M, enhanced those of isoprenaline (by a factor of 3) and adrenaline (by a factor of 1.8).Block of COMT enhanced the effects of adrenaline approximately as much as did the blockade of neuronal uptake; this seems to indicate that the affinity of adrenaline for extraneuronal and neuronal uptake processes is approximately the same.Regarding the relaxation-inducing capacity of sympathomimetic agents it was observed that isoprenaline, adrenaline and noradrenaline are full agonists, whereas phenylephrine was not able to produce relaxation amounting to more than 5% of the maximum. Denervation did not modify the relaxant effects of isoprenaline. After elimination of all known factors interfering with the concentration of the sympathomimetic agonists in the biophase, the ratios between the ED₅₀'s of each amine for α- and β-adrenoceptors were: adrenaline = 34, noradrenaline = 109 and isoprenaline = 0.0041.     

A comparison of the effects of sibutramine hydrochloride,bupropion and methamphetamine on dopaminergic function: evidence that dopamine is not a pharmacological target for sibutramine

Sibutramine hydrochloride, a novel monoamine reuptake inhibitor antidepressant, has been studied to determine whether it alters dopaminergic function in the brain. Its effects have been compared with bupropion, a dopamine reuptake inhibitor, and methamphetamine, a dopamine reuptake inhibitor and releasing agent. Sibutramine (0.1–3 mg/kg PO) and methamphetamine (0.3–30 mg/kg PO) both prevented reserpine (0.75 mg/kg IV) ptosis in rats with ED₅₀ values of 0.6 mg/kg and 4.2 mg/kg, respectively. Bupropion (10–100 mg/kg PO) was ineffective against reserpine ptosis. The efflux of [³H]-dopamine from preloaded rat striatal slices was not altered by 10^–7–10^–5 M concentrations of sibutramine, BTS 54 354, BTS 54 505 (secondary and primary amine metabolites, respectively) or bupropion. In contrast, methamphetamine (10^–8–10^–4 M) caused a significant concentration-dependent increase in [³H]-dopamine release. Sibutramine (3 mg/kg IP or 6 mg/kg PO) and bupropion (10 mg/kg IP or 430 mg/kg PO) did not alter 3-methoxy-tyramine (3-MT) levels in rat striatum. Striatal 3-MT concentrations were, however, dose-dependently increased by methamphetamine (0.3–10 mg/kg IP or 0.42–4.2 mg/kg PO). Sibutramine (6 mg/kg PO) did not induce circling in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopaminergic neuronal tract. Bupropion (10–100 mg/kg PO) did not induce circling at the lowest dose, but caused increasing ipsilateral rotation at higher doses. Methamphetamine (0.42 or 4.2 mg/kg PO) induced ipsilateral circling with marked effects at the higher dose. In a two-choice lever pressing model using rats trained to discriminated-amphetamine (0.5 mg/kg IP) from saline, sibutramine (0.3–3 mg/kg IP) generalised to the saline lever. Bupropion (3–30 mg/kg IP) generalised tod-amphetamine at the highest dose, while methamphetamine (0.1–5 mg/kg IP) generalised to this lever at doses as low as 0.3 mg/kg. Overall, the rank order of potency for enhancing central dopaminergic function is methamphetamine > bupropion >> sibutramine. The data therefore indicate that dopamine is unlikely to be an important pharmacological target for reuptake inhibition by sibutramine.     

Die indirekt sympathicomimetische Wirkung von Heptaminol auf den Herzmuskel

Summary On the isolated guinea-pig papillary muscle heptaminol causes half maximal inotropic effect in a concentration of 4×10^–4 M. A variation of the extracellular potassium concentration between 2.4 and 9.6 mM as well as a reduction of the extracellular sodium concentration from 140 mM to 70 mM have no influence on the action of heptaminol; this would have been characteristic for a digitalis-like action. The positive inotropic effect is suppressed by 5×10^–4 M propranolol and by pretreatment of the animal with 5 mg/kg reserpine. The action of heptaminol, therefore, is clearly that of an indirectly acting sympathomimetic amine.Tachyphylaxis can be demonstrated only with concentrations higher than the ED₅₀ (4×10^–4 M). A concentration of 5.5×10^–4 M has no inotropic effect after the muscle has been treated with 10^–2 M heptaminol.The inotropic effect of norepinephrine is increased twentyfold by 5.5×10^–4 M heptaminol after pretreatment with 3.5×10^–2 M heptaminol.Heptaminol does not influence the dose-response curves of dihydro-ouabain and of calcium.

Ich danke Frl. Monika Klein für ihre kompetente Mitarbeit.     

Adrenaline, anti-adrenaline drugs and potassium movements in rabbit auricles

Adrenaline (2×10^-6 M) or isoprenaline (7.5×10^-8 M) increased the rate of ⁴²K uptake and the potassium content of right (spontaneously beating) auricles, but had no effect on potassium movements in quiescent left auricles. Although faster beating induced by electrical stimulation increased the rate of ⁴²K uptake, the actions of adrenaline were also apparent in auricles which were electrically stimulated so that they beat at a constant rate. The increase in ⁴²K uptake produced by adrenaline accounted entirely for the increase in potassium content of the tissue. Adrenaline, in concentrations ranging from 2×10^-6 M to 2×10^-4 M, had no effect on ⁴²K loss from electrically stimulated auricles. The action of adrenaline on ⁴²K uptake was blocked by dichloroisoprenaline (4×10^-6 M) but not by phenoxybenzamine (1.6×10^-6 M).     

Prostaglandin F2 alpha modifies the action of norepinephrine on alpha- and beta-adrenoceptors of isolated rat uterus

Cumulative dose-response curves were constructed for the effect of norepinephrine (NE) and isoproterenol (ISO) on the contractions of uterine strips from proestrous, estrous and metestrous rats. Both adrenergic agonists inhibited uterine spontaneous contractions in all three stages of the cycle. However strips isolated from estrous rats were more sensitive to the inhibitory action of NE or ISO than preparations obtained from proestrous or metestrous animals. It was also observed that PGF-like material released by uterine horns was significantly higher during estrus than during proestrus or metestrus, whereas PGE-like material was significantly higher in metestrus than in estrus or proestrus. The EC₅₀ of NE and ISO and the amount of PGF-like material generated by uterine horns correlated significantly during the three stages of the sex cycle. No correlation was found between the β-adrenergic inhibitory action of catecholamines and the PGE-like material released in the medium. A sub-threshold dose of PGF_2α (10^?10 M) shifted to the left the dose-response curves to NE of strips isolated from metestrous rats. When the tissue was pretreated with indomethacin and propranolol the dose-response curve to NE showed a clear shift to the left. On the other hand, the combination of indomethacin and propranolol shifted the NE dose-response curve to the right in the presence of sub-threshold doses of PGF_2α. Dose-response curves to methoxamine were constructed in the presence or absence of several PGs using uterine strips isolated from estrous rats. With indomethacin, a threshold dose of PGE₁ (10^?8 M) and PGE₂ (10^?8 M) shifted to the left the control curve of methoxamine, whereas PGF_2α (10^?8 M) shifted the curve to the right. The interaction between sex hormones, PGs and catecholamines acting on α- and β-adrenoceptors in the isolated rat uterus is discussed.