By using commercially available software it is readily possible to design electronic circuits and to analyze them. By introducing the concept of equivalent quantities a simulation of various ...physiological phenomena is possible. This includes the steady state as well as various complex transient phenomena. This paper describes the use of an equivalent electronic circuit in simulating the cardiovascular system. It allows a stepwise upgrading. The first step is a one-ventricle circuit similar to the Starling heart-lung preparation. The final step is an equivalent circuit allowing simulation of various normal as well as pathological states (e.g. effects of heart rate, negative intrathoracic pressure, exercise, hemorrhage, heart failure, and hypertension). The degree of disturbance can be set by adjusting the value of single components. Following this, the optimal type of compensation (e.g. the increase in blood volume in failure of the right ventricle; systemic venoconstriction in failure of the left ventricle) of the basic disturbance can be searched for, activated and the consequences studied. The described approach has been found a useful tool in teaching physiology and pathophysiology for postgraduate medical students.
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Previous experiments have suggested a potential atypical antipsychotic activity of the ergoline derivative LEK‐8829. In vitro experiments showed a high affinity to 5‐HT1A, 5‐HT2 and D2 receptors ...(the ratio of pKi values 5‐HT2/D2 = 1.11) and a moderate affinity to D1 receptors. In vivo experiments showed antagonism of dopamine and 5‐hydroxytryptamine (5‐HT) receptor‐linked behaviours.
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In the present study, the rats with unilateral dopaminergic deafferentation of the striatum, induced by the lesion of the median forebrain bundle with 6‐hydroxydopamine (6‐OHDA), were used to determine the effects of LEK‐8829 on turning behaviour and on striatal c‐fos mRNA levels.
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The administration of LEK‐8829 induced a long lasting contralateral turning behaviour that was dose‐dependent. It was found that the specific D1 receptor antagonist SCH‐23390 but not the D2 receptor antagonist haloperidol or 5‐HT1A antagonist pindolol, dose‐dependently inhibited the turning behaviour induced by LEK–8829.
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In an attempt to clarify the D1:D2 receptor interactions involved in the action of LEK‐8829 in the 6‐OHDA model, we used in situ hybridization histochemistry to compare the effect of SCH‐23390 pretreatment on striatal c‐fos mRNA expression induced either by LEK‐8829 or by the typical antipsychotic haloperidol.
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LEK‐8829 induced a bilateral striatal c‐fos mRNA expression that was significantly higher in the denervated striatum as compared to the intact striatum and was completely blocked on both sides by pretreatment with SCH‐23390. In contrast, haloperidol‐induced striatal c‐fos mRNA expression was limited to the innervated striatum and was not blocked by SCH‐23390.
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Our data demonstrate an intrinsic activity of LEK‐8829 on D1 receptors that is potentiated in the dopamine‐depleted striatum. We conclude, therefore, that the putative atypical antipsychotic LEK‐8829 may prove useful as an experimental tool for the study of D1:D2 receptor interactions and could have beneficial effects in the treatment of drug‐induced psychosis in patients with Parkinson's disease.
The pharmacological properties of 9,10-didehydro-N-methyl-N-(2-propynyl)-6-methyl-8 beta-aminomethylergoline (LEK-8829) and 9,10-didehydro-N-methyl-N-(2-propynyl)-2-bromo-6-methylergoline ...-8-beta-carboxamide (LEK-8841), new ergoline derivatives, were compared with those of haloperidol and clozapine by in vitro radioligand displacement assays, various behavioral tests and blood pressure measurements. Both ergolines displayed low affinity for rat striatal 3H-SCH23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pin e)- labeled dopamine (D)1 binding sites and high affinity for striatal 3H-spiperone-labeled D2 and cortical 3H-ketanserin-labeled serotonin-2 (5-HT2) sites. The ratio of pKi values 5-HT2/D2 was 1.11 for LEK-8829 (close to that of clozapine, 1.13) and 0.98 for LEK-8841 (close to that of haloperidol, 0.95). All compounds inhibited apomorphine-induced locomotor activity in rats, apomorphine-induced climbing behavior in mice and 5-hydroxytryptophan-induced head twitches in mice and induced catalepsy in rats and in mice. LEK-8829 and clozapine, but not LEK-8841 and haloperidol, showed a certain degree of mesolimbic selectivity, i.e., they caused more potent inhibition of apomorphine-induced locomotion compared with the induction of catalepsy in rats. In the case of LEK-8829, nonspecific effects that presumably predict a side effect profile, such as potentiation of pentobarbital-induced anesthesia in mice (sedation), antagonism of oxotremorine-induced tremors in mice (anticholinergic activity), spontaneous locomotor activity in mice and norepinephrine-induced lethality in rats (sedation and hypotension), were relatively weak compared with the activities described earlier. In contrast, LEK-8841 showed nonspecific effects at the similar dose levels as dopamine and 5-HT antagonistic effects. The results of direct measurements of the influences of both compounds on blood pressure agreed with the previously mentioned findings, i.e., LEK-8829 was relatively less hypotensive than LEK-8841 was. It is suggested that LEK-8829 might be an efficient antipsychotic with a reduced propensity to cause sedative, anticholinergic and hypotensive side effects. A certain degree of mesolimbic selectivity also points toward the possibility of a reduced propensity to cause extrapyramidal symptoms. In contrast, in regard to side effects (including extrapyramidal symptoms), the profile of LEK-8841 is less promising.
Parkinsonism, a common unwanted side effect of typical antipsychotic (neuroleptic) drugs, is induced by the blockade of striatal dopamine D2 receptors. In rats with hemi-parkinsonism induced by ...unilateral lesion of dopaminergic nigrostriatal neurons with 6-hydroxydopamine, D2 antagonists inhibit contralateral turning induced by D2 agonists and augment the levels of neurotensin mRNA in dopaminergically intact striatum. By contrast, D1 agonists induce contralateral turning and augment neurotensin mRNA levels in dopamine-depleted striatum. These effects could be inhibited by D1 but not by D2 antagonists. Here we used a hemi-parkinsonian model to investigate the effects of putative D1 agonist/D2 antagonist LEK-8829 (9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8-aminomethylergoline bimaleinate), an experimental antipsychotic, on turning behavior and the expression of striatal neurotensin, preprotachykinin and neurotransmitter-induced early gene protein 4 (ania-4) mRNAs. We found that LEK-8829 inhibited contralateral turning induced by D2 agonist quinpirole, but only if the rats were cotreated with D1 antagonist SCH-23390. In situ hybridization showed that LEK-8829 induced the expression of neurotensin and ania-4 mRNAs in dopamine-intact striatum that could be completely blocked only by the combined treatment with SCH-23390 and quinpirole. In addition, LEK-8829 augmented the expression of neurotensin, preprotachykinin and ania-4 mRNAs in dopamine-depleted striatum that could be completely blocked by SCH-23390. This study clearly demonstrates that in hemi-parkinsonian rats D1 agonistic activity of LEK-8829 confers its anti-parkinsonian drug-like properties and modulates its neuroleptic drug-like properties, which are dependent on the blockade of dopamine D2 receptors. These findings imply that atypical antipsychotics with D1 intrinsic activity might have a reduced propensity for the induction of extrapyramidal syndrome.
When applied to rats (intraperitoneally) immediately after subcutaneous injection of soman (120 micrograms/kg) HI-6 (100 mg/kg) protected about 40% of the activity of acetylcholinesterase (AChE) in ...the motor end plate region of the diaphragm but did not protect AChE in the brain. However, a partial protection of AChE in brain against inhibition by soman was obtained in anaesthetized, atropinized rats by the oxime injected into the cerebral ventricle 5 min before parenteral exposure to soman. The AChE activity in brain of rats pretreated with HI-6, analyzed 60 min after the injection of soman was between 10 and 19%, while that in non-protected animals did not exceed 1% of the control. The degree of protection of AChE in brain was dose-dependent. Large doses of HI-6 (greater than or equal to 100 micrograms) were tolerated by animals because of the pentobarbital anaesthesia which counteracted the lethal action of HI-6. The rate of "aging" of AChE in brain inhibited by soman was analyzed by intracerebroventricular injection of 200 micrograms of HI-6 at different time intervals after the subcutaneous injection of soman. A statistically-significant reactivation of inhibited AChE activity in brain was demonstrated when HI-6 was applied up to 20 min after soman. The protection and reactivation by HI-6 of both AChE in brain and AChE in muscle end plates in poisoning with soman appear to be quite similar.
It has been reported recently that some oximes reactivating acetylcholinesterase (AChE) exhibit concomitant ganglion-blocking effects which presumably could contribute independently to their powerful ...antidotal action in organophosphate inhibitor (OPI) poisoning, thus mimicking some unrelated substances which are effective antidotes without reactivating AChE. This raises the question whether OPI-induced muscle lesions, like some other symptoms could also be attenuated by oximes and other antidotes in the absence of AChE reactivation. To test this possibility, the oxime HI-6 was applied at increasing time intervals after the injection of soman until and beyond the point when soman-AChE complex becomes completely "aged" and not capable of reactivation. As the examples of OPI antidotes which do not reactivate AChE, the muscarinic antagonist atropine and the ganglion-blocking agent hexamethonium were also tested on possible attenuation of muscle lesions. The proportions of fibers with lesions, AChE inhibition and muscle fasciculations in experimental groups relative to the controls treated with soman only were evaluated. The results show that HI-6 can attenuate lesions only if AChE is partially reactivated and muscle fasciculations are permanently eliminated. However, atropine does not affect either AChE inhibition or muscle fasciculations and is also ineffective in counteracting the lesions in spite of its potency as an effective general antidote. Hexamethonium also does not affect AChE inhibition, but abolishes fasciculations and effectively attenuates muscle lesions. The latter findings reveal the existence of lesion-protecting mechanisms unrelated to AChE reactivation, which if further elucidated might become potentially relevant for additional treatment in OPI poisoning.
Synaptotagmins (Syts) I and IV are synaptic proteins involved in the regulation of neurosecretion. Dopaminergic drugs have been shown to modulate their expression. Here we investigate whether ...dopaminergic regulation of syt I and syt IV expression could play a role in the hypersensitive striatum of rats with unilateral lesions of dopaminergic nigrostriatal neurons with 6-hydroxydopamine. We show that chronic dopaminergic denervation resulted in a small down-regulation of striatal syt I mRNA, whereas acute treatment with SKF-82958, a dopamine D1 receptor agonist, induced a massive syt IV mRNA upregulation in the striatum on the lesioned side. We conclude that chronic lack of dopamine and treatment with dopamine D1 receptor agonists alter the synaptic plasticity in dopamine depleted basal ganglia.
Botulinum toxin type A (BTx), which blocks quantal and partially reduces spontaneous nonquantal acetylcholine (ACh) release at neuromuscular junctions, was tested for its possible attenuating effect ...on diisopropylphosphorofluoridate (DFP)-induced muscle lesions. The extent of muscle lesion in extensor digitorum longus and soleus muscle of DFP injected rats with and without BTx pretreatment was evaluated using light and electron microscopic procedures. In parallel experiments, acetylcholinesterase (AChE) activity was measured and the functional state of muscles in experimental groups was determined by electrophysiological methods. The results show that pretreatment with BTx almost completely protects the muscles from DFP-induced spontaneous activity and lesions in spite of critically inhibited synaptic AChE. These results are consistent with the conclusion that the effect is not mediated by direct action of organophosphate on muscle, but by the accumulation of ACh resulting in muscle hyperactivity. Therefore, it is concluded that in conditions of acutely inhibited synaptic AChE, the quantal release of ACh is essential for lesion induction, whereas the spontaneous nonquantal ACh release, which is only partially affected in BTx-blocked nerve endings, seems not to be involved.
LEK-8829 9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8- aminomethylergoline bimaleinate is an antagonist of dopamine D2 receptors and serotonin (5-HT)2 and 5-HT1A receptors in intact animals and a ...D1 receptor agonist in dopamine-depleted animals. In the present study, we used rats with unilateral striatal lesions with ibotenic acid (IA) to investigate the dopamine receptor activities of LEK-8829 in a model with innervated dopamine receptors. The IA-lesioned rats circled ipsilaterally when challenged with apomorphine, the mixed agonist on D1/D2 receptors. LEK-8829 induced a dose-dependent contralateral turning that was blocked by D1 receptor antagonist SCH-23390. The treatment with D1 receptor agonist SKF-82958 induced ipsilateral turning, whereas the treatment with D2 receptor antagonist haloperidol induced contralateral posture. The combined treatment with SKF-82958 and haloperidol resulted in a weak contralateral turning, indicating the possible receptor mechanism of contralateral turning induced by LEK-8829. Bromocriptine induced a weak ipsilateral turning that was blocked by haloperidol. The ipsilateral turning induced by bromocriptine was significantly potentiated by the coadministration of a low dose but not by a high dose of LEK-8829. The potentiation of turning was blocked either by SCH-23390 or by haloperidol. The potentiation of ipsilateral turning suggests the costimulation of D2 and D1 receptors by bromocriptine and LEK-8829, respectively, whereas the lack of potentiation by the highest dose of LEK-8829 may be explained by the opposing activity of LEK-8829 and bromocriptine at D2 receptors. We propose that the D2 and 5HT2 receptor-blocking and D1 receptor-stimulating profile of LEK-8829 is promising for the treatment of negative symptoms of schizophrenia.
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