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PubMed2003

Sulfation of apomorphine by human sulfotransferases: evidence of a major role for the polymorphic phenol sulfotransferase, SULT1A1.

1. The relative roles of various members of the human sulfotransferase (SULT) enzyme family in the metabolism of apomorphine, a dopamine receptor antagonist used in the treatment of Parkinson's disease and, more recently, erectile dysfunction, were examined. In humans, sulfation is the major route of metabolism of this drug. 2. Using recombinant SULTs expressed in Escherichia coli, R(--)-apomorphine sulfation was studied using the universal barium precipitation assay in the presence of [35S] 3'-phosphoadenosine 5'-phosphosulfate and SULTs 1A1, 1A2, 1A3, 1B1, 1C2, 1E1 and 2A1. It was shown that SULTs 1A1, 1A2, 1A3 and 1E1 all sulfated apomorphine to varying extents. Low activity with SULT1B1 was only seen at the highest concentration (100 microM) and no activity with SULT1C2 or SULT2A1 was observed. 3. Kinetic analysis using purified recombinant SULTs showed that 1A1, 1A3 and 1E1 all had similar Vmax/Km values, although SULT1E1 had a slightly lower Km at around 1 microM compared with approximately 4 microM for the other SULTs. 4. By correlating apomorphine sulfation (at 10 microM) in a bank of 28 liver cytosols with SULT activity towards 10 microM 4-nitrophenol (SULT1A1) and 0.2 microM 17beta-oestradiol (SULT1E1), a strong correlation with SULT1A1 activity was clearly demonstrated, suggesting this enzyme was primarily responsible for hepatic apomorphine sulfation. 5. These findings were confirmed using immuno-inhibition experiments with antibodies against SULT1A and SULT1E1, which showed preferential inhibition of apomorphine sulfation in human liver cytosol by anti-SULT1A. 6. The results strongly implicate SULT1A1 as the major enzyme responsible for hepatic apomorphine metabolism. As SULT1A1 is subject to a common functional polymorphism, sulfation phenotype may be an important determinant of susceptibility to side-effects of apomorphine and/or efficacy of treatment.

Apomorphine↗
PubMed1989

Motor response following repeated apomorphine administration is reduced in Parkinson's disease.

Ten patients with Parkinson's disease (PD) with motor fluctuations under levodopa treatment were given repeated equal subcutaneous injections of apomorphine [minimal effective dose (MED)] in 1 day. The MED was defined as the dose of apomorphine necessary to induce at least 60% reduction of motor disability for a minimum period of 10 min. MED was found for each patient in previous study days. In eight a subcutaneous infusion of apomorphine was performed on a different day. Four patients with simple fluctuations ("wearing off") showed a progressive reduction of the motor response to apomorphine injections, but three of the four had a stable response (continuous "on") to apomorphine infusion. Six patients with complicated fluctuations also exhibited a decreasing response to successive apomorphine injections and often completely failed to respond to some of the boluses. The response to a subcutaneous infusion of apomorphine was unstable in three of four cases. These findings indicate that a reduction of striatal dopaminergic receptor sensitivity is associated with repeated "pulsatile" apomorphine administration in parkinsonian patients with oscillations of motor performance. It is suggested that altered regulation of dopaminergic receptor sensitivity following pulsatile stimulation with levodopa may be a relevant phenomenon in the pathogenesis of motor fluctuations in PD.

Adult↗
PubMed1991

Sublingual apomorphine in Parkinson's disease: a clinical and pharmacokinetic study.

The clinical response and the pharmacokinetic parameters of 3 mg subcutaneous (SC) and 30 mg sublingual (SL) apomorphine were compared in nine patients with Parkinson's disease. The magnitude of the motor responses (evaluated by tapping and walking tests and the Webster scale) was similar for SC and SL apomorphine. However, the onset to action was delayed after SL when compared with SC apomorphine. No significant difference was found in bioavailability (area under the curve: AUC) or peak plasma concentration (Cmax) between SC and SL apomorphine, whereas time to peak plasma concentration (Tmax) was shorter after SC apomorphine. Eight other patients were treated for a mean time of 4 months with SL apomorphine with a significant reduction in daily "off" hours. However, four of these eight patients developed stomatitis after some weeks of treatment. These results indicated that (a) pharmacokinetics parallel the clinical response to SL apomorphine, (b) SL apomorphine can reduce severe off periods in parkinsonian patients when used chronically, and (c) its long-term use is limited by a severe side effect (stomatitis).

Administration, Sublingual↗
PubMed1992

Differences in the motor response to apomorphine between untreated and fluctuating patients with Parkinson's disease.

Behavioral hyposensitivity to repeated apomorphine administration has been observed in fluctuating parkinsonian patients. To investigate whether a similar phenomenon occurs in patients never treated with levodopa, we studied the response to apomorphine in 20 de novo patients with Parkinson's disease. Six patients showed no or minimal improvement after apomorphine injections (maximal dose 3.5 mg). Fourteen patients responded and were then given up to four repeated subcutaneous injections of apomorphine [minimal effective dose (MED)]. The responses of de novo patients were compared with responses in 10 patients with motor fluctuations previously studied by the same protocol. There was no significant difference in latency and duration of motor responses after repeated apomorphine injections in de novo patients. MED was similar in de novo and fluctuating patients, but duration of improvement induced by each apomorphine bolus was longer in the de novo group. These results indicate that response duration to apomorphine is longer in previously untreated patients and that behavioral tolerance associated with pulsatile dopaminergic stimulation by apomorphine occurs mainly in patients with more advanced disease under chronic levodopa therapy.

Adult↗
PubMed1994

Effects of apomorphine and L-methionine sulphoximine on the release of excitatory amino acid neurotransmitters and glutamine in the striatum of the conscious rat.

The effects of apomorphine, a D1-, D2-dopamine receptor agonist, on the extracellular concentrations of excitatory amino acids, glutamic and aspartic acids, and on that of their precursor, glutamine, were investigated using an intracerebral perfusion system. Apomorphine produced a concentration-related rise in glutamic acid concentration in cerebral perfusates (P < 0.01) whereas only the highest concentration of apomorphine (3 x 10(-3) micrograms/microliters) increased the concentration of aspartic acid (P < 0.05). These effects were seen in the sample taken at the same time as the apomorphine injection. The rise in glutamine concentration (P < 0.01) produced by apomorphine continued for 10 min beyond perfusion with apomorphine. These effects were attenuated by previous injections of D1-, D2-dopamine receptor blocker. To investigate further the release of glutamine, the glutamine synthetase inhibitor L-methionine sulphoximine (MSO) was injected intracerebrally before apomorphine perfusion. After MSO pre-injection, the extracellular concentration of glutamine decreased (P < 0.01) to near zero concentrations. In MSO-treated animals, apomorphine did not induce the release of glutamic acid, aspartic acid or glutamine. These results indicate a role for dopamine in the release of excitatory amino acids and glutamine in the neostriatum of the rat. A possible volumetric interaction between dopamine and glutamic acid as well as the hypothesis of a striato-pallido-thalamo-cortico-striatal feedback loop are discussed.

Analysis of Variance↗
PubMed1986

A comparison of motor behaviours in groups of rats distinguished by their climbing response to apomorphine.

Administration of apomorphine hydrochloride (0.5 mg kg-1 s.c.) to adult male or female Wistar rats previously acclimatized to the test environment induced climbing behaviour in approximately 50% of animals examined. The proportion of animals climbing was related to age, being maximal at 8-9 weeks. Those animals showing an initial climbing response to apomorphine (0.5 mg kg-1 s.c.), climbed when challenged with this dose of apomorphine on subsequent occasions. In 'climbing' animals the intensity of response was related to the dose of apomorphine administered; no dose-response relationship was observed in 'non-climbing' animals. No overall differences in the spontaneous motor behaviour of 'climbing' and 'non-climbing' animals were apparent as assessed by measurement of spontaneous climbing behaviour, by holeboard activity, and by locomotor activity measured in either photocell cages or in a treadwheel. There was no overall difference in the ability of apomorphine to induce locomotor activity or stereotyped behaviour in 'climbing' and 'non-climbing' animals. However, the administration of apomorphine induced rearing and treadwheel activity only in those animals classified as 'climbers'. There was no difference between the number (Bmax) of specific [3H]-spiperone binding sites or the dissociation constant (KD) in striatal or mesolimbic tissue preparations for 'climbing' and 'non-climbing' rats. The ability of an animal to climb in response to apomorphine appears to be dependent on an ability to orient vertically, since this is a component of behaviour common to climbing, rearing, and treadwheel activity. The ability to climb does not appear to be related to differences in dopamine receptor numbers in brain or to the penetration of apomorphine into brain.

Age Factors↗
PubMed1989

Interactions of apomorphine and a novel neuroleptic dibenzodioxazocine derivative, as evidenced by changes of somato-autonomic reflexes and spontaneous sympathetic activity in cats.

The apomorphine-antagonistic effects of EGYT-2509, a novel neuroleptic compound, has been studied by two different methods suitable for investigating the dopaminergic modulation of sympathetic output. (1) In cats lightly anaesthetized with urethane (600 mg kg-1 i.p.), blood pressure (BP) reflexes evoked by electrical stimulation of the sciatic nerve were inhibited by apomorphine (0.2 mg kg-1 i.v.) at low frequencies of stimuli (2-8 Hz), while the BP reflexes were facilitated by apomorphine at higher frequencies of stimulation; the evoked contractions of the nictitating membrane were depressed in the entire range of frequencies applied. EGYT-2509 (1.5 mg kg-1 i.v.) antagonized both the inhibition and facilitation of pressor reflexes induced by apomorphine. EGYT-2509, given alone, in doses exceeding 1.5 mg kg-1 either did not influence or inhibited the responses of nictitating membrane and of BP; the inhibition could be antagonized by haloperidol. The apomorphine-induced sustained hypotension was inhibited by EGYT-2509 (18.5 mg kg-1): after EGYT-2509, higher doses of apomorphine (0.7 vs 0.2 mg kg-1) were required for the effect. Sustained hypotension could be elicited by EGYT-2509, too; after apomorphine, smaller doses of EGYT-2509 (8.5 vs 18.5 mg kg-1) were enough to decrease BP. (2) In cats anaesthetized with chloralose and urethane (50 and 400 mg kg-1 i.p., respectively), apomorphine (0.2 mg kg-1) inhibited the spontaneous activity of the postganglionic renal sympathetic nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Central mechanisms regulating penile erection in conscious rats: the dopaminergic systems related to the proerectile effect of apomorphine.

Apomorphine has been used as a pharmacological probe of dopaminergic receptors in a variety of central nervous system disorders. The utility of apomorphine as an agent for the treatment of erectile dysfunction has also been demonstrated clinically. Apomorphine is a nonselective dopaminergic receptor agonist with potent binding affinity (Ki) of 101, 32, 26, 2.6, and 10 nM for D1, D2, D3, D4, and D5, respectively. When administered either subcutaneously (s.c.) or intracerebroventricularly (i.c.v.), apomorphine fully evoked penile erections in conscious rats with maximum effect at 0.1 micromol/kg s.c. and 3 nmol/rat i.c.v., respectively. Apomorphine was less efficacious when injected intrathecally (i.t.) to L4-L6 spinal levels (50% at 30-100 nmol/rat i.t.). Penile erection facilitated by apomorphine was blocked by haloperidol and clozapine (i.p. and i.c.v.) but not by domperidone (a peripherally acting dopaminergic receptor antagonist). In this model using conscious rats, penile erection was significantly induced by quinpirole (D2-D3-D4 receptor agonist), but not by R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol (SKF38393) and R(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzapine (SKF81297) (D1 receptor agonists), or a D2 receptor agonist R-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine (PNU-95666E). The role of D4 receptors in penile erection was demonstrated using selective D4 receptor agonists [(4-phenylpiperazinyl)-methyl]benzamide (PD168077) and 5-fluoro-2-[[4-(2-pyridinyl)-1-piperazinyl]methyl]-1H-indole (CP226269), whether administered systemically (s.c.) or locally in the brain (i.c.v.). The ability of apomorphine to activate D3 receptors in relation to its proerectile activity remains to be elucidated by use of selective subtype agonists. These results suggest that the proerectile action of apomorphine in rats is mediated at supraspinal levels and that this effect is not mimicked by a D2 receptor agonist but associated with activation of D4 receptors.

Animals↗
PubMed2005

Apomorphine in idiopathic restless legs syndrome: an exploratory study.

BACKGROUND: Dopaminergic and opioidergic drugs have been found to be effective in patients with restless legs syndrome (RLS). OBJECTIVES: To test the effect of apomorphine--a combined opioidergic and dopaminergic agonist--and subsequent selective antagonism by naloxone and metoclopramide on subjective and objective symptoms in patients with idiopathic RLS. METHODS: Nine patients with RLS were pretreated with oral domperidone for three days. A modified suggested immobilisation test (SIT) was carried out between 8 pm and 1 am under the following conditions of intravenous drug administration: baseline-apomorphine-apomorphine plus naloxone-apomorphine plus metoclopramide. Outcome variables were a visual analogue scale (VAS) of subjective RLS symptoms and EMG documented periodic leg movements while awake (PLMW). RESULTS: Compared with baseline, apomorphine resulted in a rapid and significant improvement in subjective RLS symptoms as measured by VAS (54.5% improvement; p = 0.011), and an almost immediate cessation of PLMW, measured by PLMW index (98.0% improvement; p = 0.012). Neither additional naloxone nor metoclopramide blocked this effect significantly. While given apomorphine with metoclopramide, there was a trend to reappearance of PLMW. CONCLUSIONS: Apomorphine may be an effective treatment for idiopathic RLS. Its effectiveness may reflect both to its dopaminergic and its opioidergic activity, and is not diminished significantly by blocking only one of these pathways. The trend to a worsening of the PLMW index with metoclopramide hints at a primarily dopaminergic effect of apomorphine in idiopathic RLS.

Administration, Oral↗
PubMed1982

[3H]Apomorphine binding to a GTP-sensitive dopaminergic site in bovine anterior pituitary gland.

The characteristics of binding of the potent dopaminergic agonist [3H]apomorphine have been studied in bovine anterior pituitary membranes. A high affinity binding site with an apparent dissociation constant (KD) of 0.7 nM and a number of binding sites of 56 fmol/mg protein has been measured when 10(-5) M dopamine was used to assess nonspecific binding. The order of potency of various agonists to compete with [3H]apomorphine binding is consistent with an interaction at a typical dopaminergic receptor: apomorphine greater than dopamine greater than (-)-epinephrine = (-)-norepinephrine much greater than (-)-isoproterenol. Competition for [3H]apomorphine binding by antagonists shows marked stereoselectivity, (+)-butaclamol being 4000 times more potent than (-)-butaclamol. Dihydroergocryptine, a potent dopaminergic agonist on prolactin release, as well as the dopaminergic antagonists spiroperidol, haloperidol, and (+)-butaclamol, compete for [3H]apomorphine binding at nanomolar concentrations. By contrast, adrenergic (phentolamine, propranolol, and clonidine) and serotonergic (serotonin, cyproheptadine, and methysergide) agonists and antagonists do not compete or are weak competitors at micromolar concentrations. Guanosine triphosphate (GTP) decreases [3H]apomorphine binding, the affinity of this ligand for the receptor being decreased 10 times by 300 microM GTP. The close correlation observed between the affinity of a series of agonists and antagonists for the [3H]apomorphine binding sites and their potency as modulators of prolactin release suggests that [3H]apomorphine binding sites are those involved in the control of prolactin secretion.

Animals↗
PubMed1994

Apomorphine-and oxytocin-induced penile erection and yawning in intact and castrated male rats: effect of sexual steroids.

The effect of apomorphine (80 micrograms/kg s.c.) and oxytocin (30 ng i.c.v.) on penile erection and yawning was studied in intact and castrated male rats. In castrated rats both apomorphine and oxytocin responses were abolished. In these animals, testosterone (100 microgramS/kg s.c. once a day for 3 days), restored penile erection while estradiol benzoate (10 micrograms/kg s.c. once a day for 3 days) restored yawning induced by both compounds. 5-Dihydrotestosterone (DHT) or progesterone (each at a dose of 100 micrograms/kg s.c. once a day for 3 days) were ineffective. Given together, estradiol benzoate and DHT partially restored apomorphine- and oxytocin-induced yawning and penile erection, whereas estradiol benzoate and progesterone restored only yawning. Estradiol benzoate-induced recovery of yawning was prevented by the antiestrogen tamoxifen (1 mg/kg s.c. once a day for 3 days). In intact rats, progesterone increased and estradiol benzoate decreased apomorphine- and oxytocin-induced yawning without modifying penile erection, although oxytocin-induced yawning was prevented much less by estradiol benzoate than that induced by apomorphine. Testosterone or DHT were ineffective on both responses. Estradiol benzoate inhibition of apomorphine- and oxytocin-induced yawning was prevented by tamoxifen, which per se failed to modify apomorphine and oxytocin responses, as well as by testosterone or progesterone. The present results suggest that apomorphine- and oxytocin-induced penile erection and yawning are endocrine-dependent and differentially modulated by sexual steroids, suggesting that the mechanisms controlling the two behaviors are different even though they are often associated.

Animals↗
PubMed1979

Neuroendocrine effects of apomorphine: characterization of response patterns and application to schizophrenia research.

Apomorphine, a direct-acting dopamine agonist, stimulates release of growth hormone (hGH) and suppresses release of prolactin (PRL) from the anterior pituitary. Previous studies comparing the magnitude of these responses in schizophrenics and controls suggest that many acute (and some chronic) schizophrenics have exaggerated hGH responses; many chronic schizophrenics (and patients with tardive dyskinesia) have blunted hGH responses to apomorphine, and possibly blunted PRL responses. The present studies extend and confirm these findings in chronic schizophrenics; in addition, several studies were undertaken to further characterize these apomorphine-induced endocrine responses. Studies in which apomorphine was given on 2 or 3 separate occasions to each of five subjects indicate that the hGH response is a highly reproducible individual index, but PRL suppression is a less satisfactory measure. hGH responses to apomorphine were consistently antagonized by pretreatment with haloperidol, supporting the concept that the hGH-releasing effect of apomorphine is mediated by its action on dopamine receptors. Cyproheptadine pretreatment was associated with erratic increases or decreases in the hGH response to apomorphine, but did not alter PRL levels or apomorphine-induced PRL suppression. The relationship of these findings to biological hypotheses of schizophrenia and to neuroleptic-induced receptor changes is discussed.

Adult↗
PubMed2004

Other formulations and future considerations for apomorphine for subcutaneous injection therapy.

This manuscript reviews apomorphine administration in formulations other than intermittent bolus injection, and comments on other potential uses for this unique compound. Continuous sc apomorphine therapy has been shown to alter peak-dose dyskinesia thresholds in advancing patients, and in some instances may replace all other anti-parkinson therapies. In general continuous infusion of sc apomorphine at a rate of 4 mg/h is well tolerated, and has been postulated to be equivalent to approximately 600 mg levodopa/day. This therapy is associated with skin complications, particularly nodule formation, and focal panniculitis is seen in more than 50% of subjects. Optimal dosages for intranasal apomorphine range from 2 to 5 mg per inhalation with benefit seen at 7.5 minutes and duration of effect of 45 to 55 minutes. Side effects included nasal irritation, vestibulitis, dyskinesias, yawning, and nausea. Comparison of 3 mg sc and 30 mg sublingual apomorphine in 9 Parkinson's disease subjects in a blinded cross-over trial found that the time to peak benefit was beyond 40 minutes with sl apomorphine, compared to 21 minutes in the sc preparation. Chronic use of the sublingual formulation was associated with severe stomatitis in half the subjects, and markedly limited the treatment. Rectal administration of apomorphine has been evaluated in limited, usually post-operative settings. Administration of a 200 mg apomorphine rectal suppository resulted in an average time to benefit of 32 minutes with an average duration of 195 minutes. Sedation, nausea and faintness were reported as side effects. Although the diagnostic confirmation potential of this agent has been questioned, the drug may have an important role in evaluating the potential for benefit in the deep brain stimulation surgical setting.

Antiparkinson Agents↗
PubMed1991

Sublingual apomorphine solution in Parkinson's disease.

OBJECTIVE: To compare the effects of single doses of oral levodopa, subcutaneous apomorphine and sublingual apomorphine. DESIGN: Single-blind placebo-controlled comparative study. SETTING: Subjects were admitted as day patients to the neurology ward. PATIENTS: Five patients with idiopathic Parkinson's disease and "end of dose deterioration" entered and completed the study. INTERVENTIONS: Patients were given domperidone (20 mg by mouth three times a day) to prevent nausea and apomorphine (1-3 mg by subcutaneous injection), apomorphine in glycerol (10-30 mg sublingually) or their usual levodopa regimen. MAIN OUTCOME MEASURES: Efficacy, time to onset of effect and duration of effect of oral levodopa, subcutaneous apomorphine and sublingual apomorphine. Tremor amplitude and timed pegboard and gait tasks were used as objective indices of clinical state. RESULTS: Maximal efficacy of the three treatments was comparable (P = 0.28-0.99). Mean latency to onset of effect of both formulations of apomorphine was less than that of levodopa (P = 0.022-0.048) but so was the duration of effect (P = 0.044-0.049). CONCLUSIONS: Sublingual apomorphine may be a convenient means of rapidly terminating "off" periods associated with long term levodopa therapy.

Administration, Oral↗
PubMed1999

The effect of sildenafil on apomorphine-evoked increases in intracavernous pressure in the awake rat.

PURPOSE: The aim of this study was to develop a quantitative, awake animal model to investigate the effect of sildenafil on centrally-evoked erectile activity. METHODS: Intracavernous pressures were recorded in awake, male Sprague Dawley rats after administration of apomorphine (100 or 250 microg./kg. subcutaneously). Sildenafil (100 microg./kg. intravenously) was then given 10 min. after a second dose of apomorphine. The time to first response, duration of response, and peak intracavernous pressure and area under the response, were measured before and after sildenafil. RESULTS: Apomorphine produced rhythmic increases in intracavernous pressure. The pressure increase consisted of two components. The amplitude of the first, tonic response was 58 +/- 3 mm. Hg, and a superimposed, burst-like increase in pressure elevated this further to 81 +/- 6 mm. Hg. Bilateral transection of the pudendal nerves abolished the burstlike pressure changes; bilateral transection of the cavernous nerves prevented both responses. The duration of the apomorphine-induced increase in intracavernous pressure was significantly (p = 0.003) prolonged by sildenafil (100 microg./kg.) from 37 +/- 4 to 62 +/- 11 s (n = 6). The overall intracavernous pressure response to apomorphine (100 microg./kg.), measured as the area under the curve, was significantly (p = 0.003) increased by sildenafil (100 microg./kg.) from 67 +/- 8 to 142 +/- 31 units (n = 6). N-nitro-L-arginine methyl ester (40 mg./kg. intravenously) prevented the apomorphine-induced responses. CONCLUSIONS: Monitoring intracavernous pressures in the awake rat represents a simple model to evaluate the effect of drugs on erectile function. Using this model we have shown that apomorphine elicits a rise in intracavernous pressure that can be prolonged by sildenafil. These results suggest that there may be a role for the combination of apomorphine and sildenafil in the management of erectile dysfunction.

Animals↗
PubMed1991

Effects of apomorphine on heart rate during simultaneous administration of sulpiride: a challenge of the composed concentration-effect model.

Apomorphine elicits opposite concentration-dependent effects on the heart rate in rat bradycardia at low concentrations and tachycardia at higher ones. This has been modeled with a composed sigmoid Emax equation. To challenge this model, a selective antagonist, sulpiride, was administered simultaneously with apomorphine. Four short intravenous infusions of apomorphine, at different rates, were administered to rats, while a steady state concentration of sulpiride was maintained by intravenous infusion. Another group of rats was infused with apomorphine at the same rates of infusion as in the above groups, together with saline. In this latter group a biphasic concentration-response relationship was observed, while in the group receiving sulpiride and apomorphine no bradycardia was detected. A sigmoid Emax model with one term describing bradycardia and one tachycardia was used for the saline plus apomorphine data. For the sulpiride plus apomorphine data a single-term sigmoid Emax model was used. The maximal induced tachycardia was found to be the same in both groups. The tachycardia occurred at lower concentrations in the sulpiride group, probably as a result of an antagonist-induced shift of the bradycardia towards higher concentrations. The obtained results show that a composite concentration-effect curve of apomorphine has experimental validity and that it is possible to separate its pharmacodynamic characteristics on heart rate into its components, bradycardia and tachycardia, by sulpiride.

Animals↗
PubMed1985

Studies on the cardiovascular actions of apomorphine in dogs: central versus peripheral mechanisms and role of the adrenal medulla.

The effects of apomorphine on blood pressure and heart rate were studied in normotensive chloralose anaesthetized dogs. Intravenous apomorphine (200 micrograms/kg) induced both a marked decrease of blood pressure and an increase in heart rate. These two cardiovascular responses to intravenous apomorphine were suppressed by haloperidol (1 mg/kg i.v.) or phentolamine (1 mg/kg i.v.). In contrast, pretreatment with atropine (1 mg/kg i.v.) only abolished the chronotropic (but not the hypotensive) response to apomorphine. Intravenous (500 micrograms/kg) but not intracisternal (50 micrograms/kg) domperidone suppressed the hypotensive responses elicited by intravenous or intracisternal apomorphine. In contrast, domperidone, injected either by intravenous or intracisternal route, abolished apomorphine-induced tachycardia. In adrenal demedullated dogs, the hypotensive response to apomorphine was abolished. These results suggest that the hypotensive response to apomorphine in normotensive dogs is mainly mediated by activation of peripheral dopaminergic mechanisms. The drug decreases blood pressure through stimulation of dopaminergic receptors located on sympathetic nerve terminals and on the adrenal medulla leading to a decrease of the release of catecholamines.

Adrenal Medulla↗
PubMedDate not supplied

The responsiveness of the endogenous inhibitor of cAMP-dependent protein kinase to apomorphine in rat striatum after prolonged treatment with nomifensin.

Apomorphine produced biphasic changes in the activity of an endogenous, specific inhibitor of cAMP-dependent protein kinase (type I inhibitor). Small doses of apomorphine (50-100 micrograms/kg) induced an increase while high doses (1-10 mg/kg) produced a dose-dependent decrease of the type I inhibitor activity in the striatum of control rats. Prolonged treatment with nomifensin markedly reduced the response of the type I inhibitor both to low and high doses of apomorphine and shifted the dose-response curves to the right. The apomorphine-induced increase of the type I inhibitor activity in nomifensin-pretreated rats was blocked by aminophylline and by small, presynaptically active doses of haloperidol. This suggests that small doses of apomorphine stimulate presynaptic D2 receptor. The apomorphine-induced decrease of the type I inhibitor activity in nomifensin pretreated animals was enhanced by aminophylline and by presynaptically active dose of haloperidol. In contrast, this action of apomorphine was blocked by high, postsynaptically active, dose of haloperidol. It suggested postsynaptic site of action of high doses of apomorphine. Prolonged pretreatment with nomifensin resulted in subsensitivity of both presynaptic D2 and postsynaptic D1 receptors.

Aminophylline↗