[Electrophysiologic effects of plasminogen activators and plasmin].
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Animals↗
Biomedical subjects
L Pichler
Publications and source records attributed to L Pichler.
Locomotor behaviour of selective dopamine agonists in mice: is endogenous dopamine the only catecholamine involved?
The purpose of the study was to determine the effect alone and in combination of the selective dopamine (DA) agonists SKF 38393 (D1-) and B-HT 920 (D2-) on the locomotor activity of reserpine pretreated mice (5 mg kg-1 i.p.). After 4 h, reserpine-B-HT 920 (up to 20 mg kg-1 s.c.) did not induce locomotor activity whereas SKF 38393 was markedly effective at high doses (greater than or equal to 30 mg kg-1 s.c.). In contrast, at 24 h, reserpine-B-HT 920 (0.2-6 mg kg-1 s.c.) elicited considerable locomotor activity and SKF 38393 (1-100 mg kg-1 s.c.) was effective at lower doses when compared with the corresponding 4 h reserpine experiments. When, however, these animals additionally received alpha-methyl-p-tyrosine (alpha MPT; 300 mg kg-1 i.p., at 4 h before the DA agonists) neither B-HT 920 (0.2-20 mg kg-1 s.c.) nor SKF 38393 (1-100 mg kg-1 s.c.) had an effect of their own. When B-HT 920 was tested in the presence of a fixed-dose of SKF 38393 (10 or 3 mg kg-1 s.c., combination experiments) B-HT 920 (0.6-20 mg kg-1 s.c.) induced considerable locomotor activity at 4 h post reserpine. At 24 h post reserpine the dose-response curve of B-HT 920 (0.06-20 20 mg kg-1 s.c.) was shifted to the left and the maximum effect was greatly increased. When additional alpha MPT was given, the dose response curve was the same but the maximum effect was markedly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Action and interaction of two alpha 1-adrenoceptor agonists, methoxamine and St 587, on the rabbit's blood pressure and EEG.
In rabbits methoxamine reversed the vasopressor effect of St 587 and abolished the EEG synchronizing action of St 587. The interaction on the blood pressure could be ascribed either to the different chemical structures of St 587 and methoxamine or to partial agonistic properties of St 587. The interaction on the EEG appears to be more complex.
Animals↗
The dopamine autoreceptor agonist, B-HT 920, preferentially reduces brain dopamine release in vivo: biochemical indices of brain dopamine, noradrenaline and serotonin in ventriculocisternal perfusates in the cat.
B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine), a candidate for selective dopamine (DA) autoreceptor agonist activity, was tested for its interactions with biochemical parameters of brain dopaminergic, noradrenergic and serotoninergic systems as measured in ventriculocisternal perfusates of chloralose-anaesthetized cats. DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA) and 5-hydroxyindolic acid (5-HIAA) were measured in samples of 30 min collection periods by high-pressure liquid chromatography with electrochemical detection. B-HT 920, in the dose range of 0.03-1 mg/kg i.v., promptly inhibited the efflux of DA and DOPAC in a dose-dependent manner. The 1 mg/kg dose of B-HT 920 reduced the DA levels below 25% of control levels for the whole length of the experiments. The HVA levels were reduced less and in a protracted manner. Only the highest dose of B-HT 920 tested (1 mg/kg) had a significant effect on the level of NA (marked, prompt reduction) and 5-HIAA (delayed, moderate reduction), reflecting its well known alpha 2-adrenoceptor agonist property. The effects of B-HT 920 on the dopaminergic indices were DA receptor-mediated as they were reversed by a low dose (0.05 mg/kg i.v.) of haloperidol. In contrast, the alpha 2-adrenoceptor blocking drug, idazoxan, 4 mg/kg i.v., while it reversed the NA and 5-HIAA reductions did not modify the effect of B-HT 920 on DA, DOPAC and HVA. Thus B-HT 920, in the dose range between 0.03-0.1 mg/kg, selectively affected brain dopaminergic parameters. Our experiments demonstrated that B-HT 920 causes an effective, long lasting and selective suppression of extracellular brain DA levels in vivo. B-HT 920 represents a promising compound for clinical use in pathological conditions known to be ameliorated by a reduction of brain DA activity, such as Huntington's disease, mania and schizophrenia.
3,4-Dihydroxyphenylacetic Acid↗
Synchronizing effect of the alpha 1-adrenoceptor agonist 2-(2-chloro-5-trifluoromethylphenylimino)imidazolidine on rabbit electroencephalogram.
The selective alpha 1-adrenoceptor agonist St 587 (2-(2-chloro-5-trifluoromethylphenylimino)imidazolidine) was tested in conscious rabbits in the dose range of 0.125 to 8 mg/kg cumulatively i.v. In cardiovascular experiments St 587 increased mean arterial blood pressure and decreased heart rate in a dose dependent manner. In neuropharmacological experiments St 587 induced a biphasic EEG effect, an EEG synchronization preceded by a short period of cortical arousal. The duration of both EEG phenomena increased with increasing doses. There was no correlation between rise in blood pressure and EEG arousal reaction as periods of precentral spindling appeared also during maximal increase in blood pressure. Both, EEG synchronization and arousal reaction could be antagonized by the alpha 1-adrenoceptor antagonist prazosin, 1-2 mg/kg i.v. From these experiments it is concluded that the main effect of the alpha 1-adrenoceptor agonist St 587 in rabbits is EEG synchronization, i.e. sedation. Furthermore a barbiturate antagonism by high doses of St 587 was shown and this is explained by the initial arousal reaction as observed after injection of St 587.
Animals↗
The dopamine autoreceptor agonist B-HT 920 inhibits in vivo dopamine release into the cerebroventricular system of cats.
In anesthetized cats the dopamine autoreceptor agonist B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine), 1 mg/kg i.v., greatly decreased the amount of dopamine in cerebroventricular perfusates. This effect was antagonized by a low dose (50 micrograms/kg i.v.) of haloperidol, but not by the alpha 2-adrenoceptor blocker idazoxan. Our observations provide evidence that B-HT 920 inhibits brain dopamine release in vivo and may be therapeutically valuable in diseases presumed to be accompanied by a predominance of brain dopamine activity, such as Huntington's disease, mania and schizophrenia.
Adrenergic alpha-Agonists↗
The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment.
B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepine), an agonist at alpha 2-adrenoceptors and at dopamine autoreceptors, was tested with respect to stimulation of postsynaptic brain dopamine receptors in mice, rats and rhesus monkeys. In mice B-HT 920 (0.2-20 mg/kg s.c.) injected 4 h after reserpine did not stimulate locomotor activity; this was in contrast to apomorphine (0.1-10 mg/kg s.c.) which elicited locomotor activity in a dose-dependent manner. However, B-HT 920 was effective in inducing locomotor activity when injected 12, 24 and 48 h after reserpine. This effect was dose-dependent and increased with the duration of reserpine pretreatment. In naive rats, B-HT 920 (0.02-2.0 mg/kg s.c.) only decreased exploratory activity and did not elicit stereotyped activity in doses up to 4 mg/kg s.c. This was in contrast to the stereotypy-inducing effect of apomorphine (2.0 and 4.0 mg/kg s.c.). In rats with unilateral striatal ibotenic acid lesion, B-HT 920 (0.2-2.0 mg/kg s.c.) was ineffective in producing significant ipsilateral rotation, whereas apomorphine (0.5-10.0 mg/kg s.c.) was very potent in this model. In rats with unilateral 6-OH-dopamine lesions of the medial forebrain bundle B-HT 920 elicited strong contralateral rotation in a dose-dependent manner (0.02-1.0 mg/kg s.c.). In this model B-HT 920 was equi-effective but long acting when compared with apomorphine. The contralateral rotation produced by B-HT 920 was antagonized by the D2-antagonist sulpiride but not by the D1-antagonist SCH 23390. In rhesus monkeys with severe parkinson-like symptoms induced by MPTP, B-HT 920 in doses of 10 micrograms/kg i.m. and higher restored normal behavior, resulting in complete relief of parkinson symptoms in all animals with 100 micrograms/kg i.m. It is concluded that the property of B-HT 920 to stimulate the 'denervated' supersensitive (reserpine, 6-OH-dopamine, MPTP) but not the normosensitive postsynaptic dopamine receptor in the striatum may represent a novel principle for a specific approach to dopamine substitution treatment of Parkinson's disease.
Animals↗
Possible function of alpha 1-adrenoceptors in the CNS in anaesthetized and conscious animals.
The influence of St 587 (2-(2-chloro-5-trifluoromethylphenylimino)imidazolidine), a selective alpha 1-adrenoceptor agonist which easily penetrates the blood-brain barrier, was tested on behavior and cardiovascular functions, respectively. The substance (up to 10 mg/kg subcutaneously (s.c.)) did not increase the exploratory activity of naive mice. The hexobarbitone 'sleeping' time in mice was reduced in a dose-dependent manner (St 587 ED50 = 14.4 mg/kg s.c.). Haloperidol 10 mg/kg s.c. induced catalepsy which was antagonized by St 587 in a dose-dependent manner (ED50 = 2.7 mg/kg i.p.). Conversely, the alpha 1-adrenoceptor-blocking agents prazosin and corynanthine elicited catalepsy in mice which had been treated with a subthreshold dose (2 mg/kg s.c.) of haloperidol; the ED50 values of the antagonists were 0.26 and 4.7 mg/kg i.p., respectively. In anaesthetized cats blood pressure and heart rate were not affected by 100 micrograms/kg St 587 injected into the left vertebral artery. In conscious dogs with beta-adrenoceptors blocked, the drug was without effect (100 micrograms/kg intracisternally) on vagally mediated reflex bradycardia, as evoked by intravenous noradrenaline injection. As a positive control the alpha 2-adrenoceptor agonist B-HT 920 which is equipotent to St 587 with respect to peripheral vasopressor effects in rats was injected with 10 micrograms/kg intracisternally and facilitated the reflex bradycardia. It is concluded that alpha 1-adrenoceptors within the brain mediate behavioral activation in states of CNS depression but remain without effect on cardiovascular centers.
Anesthesia↗
Alpha 2-adrenoceptor blocking properties of the alpha 1-selective agonist 2-(2-chloro-5-trifluoromethylphenylimino)imidazolidine (St 587).
The selective alpha 1-adrenoceptor agonist 2-(2-chloro-5-trifluoromethylphenylimino)imidazolidine (St 587) was tested with respect to putative alpha 2-adrenoceptor blocking properties. In these studies 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine (B-HT 920) was used as a selective alpha 2-adrenoceptor agonist. At peripheral presynaptic sites St 587 (1 mg/kg i.v.) significantly antagonized the inhibitory effect of B-HT 920 (3-30 micrograms/kg i.v.) on electrically induced tachycardia in pithed rats. To study influences on central sympathoinhibition, urethane anaesthetized, vagotomized rats were used. Parameter measured was heart rate and this was decreased by B-HT 920. St 587 antagonized this effect in the range 1-10 mg/kg s.c. in a dose-dependent manner. These vagotomized rats were pretreated with prazosin, thus a central stimulation of alpha 1-adrenoceptors by St 587 was excluded. In anaesthetized dogs with beta-adrenoceptors blocked 10 micrograms/kg B-HT 920 intracisternally promoted a vagally mediated reflex bradycardia as elicited by angiotensin. St 587 given 20 min later with 100 micrograms/kg intracisternally almost completely abolished this effect. In mice, the exploratory activity was greatly diminished by treatment with the alpha 2-adrenoceptor agonists B-HT 920 (200 micrograms/kg s.c.) or azepexole (20 mg/kg s.c.) and this effect was partly antagonized by St 587 (0.1 or 1 mg/kg i.p.). In behavioral experiments dogs treated with St 587 (0.3-10 mg/kg i.v.) showed signs of irritation, especially in higher doses. Dogs treated with B-HT 920 (0.3 mg/kg i.v.) fell into a narcotic state, dogs treated in addition with St 587 (0.3-3 mg/kg i.v.) remained conscious but were remarkably sedated.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-Agonists↗
B-HT 958--an antagonist at alpha 2-adrenoceptors and an agonist at dopamine autoreceptors in the brain.
B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo[5,4-d]az epine), a compound chemically related to clonidine-like drugs of the azepine type, was described previously as a mixed agonist-antagonist at peripheral alpha 2-adrenoceptor sites. In the present experiments the actions of B-HT 958 on brain noradrenergic and dopaminergic mechanisms were examined using behavioural, pharmacological and biochemical methods. (i) In the dog, intracisternally injected B-HT 958 (300 micrograms/kg) abolished the reflex bradycardia facilitated by the alpha 2-agonist B-HT 920 (10 micrograms/kg i.ci.). (ii) In the whole mouse brain as well as in the rat hypothalamus and neocortex, but not in the hippocampus, amygdala and nucleus accumbens B-HT 958 (5-20 mg/kg s.c.) accelerated the alpha-methyltyrosine (alpha-MT)-induced disappearance of noradrenaline. (iii) B-HT 958 decreased in a dose-dependent manner the exploratory activity of mice (ED50: 6.3 mg/kg s.c.) and slightly enhanced the motor activity of reserpine-treated mice only in high doses. (iv) B-HT 958 (20 mg/kg s.c.) lowered the level of homovanillic acid in the striatum and nucleus accumbens and dose dependently (1-20 mg/kg) slowed the alpha-MT-induced disappearance of dopamine in these 2 brain regions of the rat as well as in the whole mouse brain. (v) The gamma-butyrolactone-induced increase in DOPA levels was effectively antagonized by B-HT 958 (1 and 5 mg/kg s.c.) in the rat striatum and nucleus accumbens. These behavioural, pharmacological and biochemical observations indicate that B-HT 958 possesses central alpha-adrenoceptor blocking activity and exerts a strong agonistic effect on brain dopamine autoreceptors.
Adrenergic alpha-Antagonists↗
Cardiovascular effects of B-HT 958, an alpha-adrenoceptor agonist with a high pre/postsynaptic activity ratio.
B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo[5,4-d]az epine), chemically related to clonidine-like drugs of the azepine type, was described previously as a partial alpha 2-adrenoceptor agonist which acted presynaptically mainly as agonist and postsynaptically as antagonist. Following i.v. infusion in anaesthetized cats, 3 mg/kg of B-HT 958 lowered blood pressure, heart rate, cardiac output and total peripheral vascular resistance. A small central nervous component was indicated, since 100 micrograms/kg injected into the vertebral artery was equipotent to 300 micrograms/kg i.v. in lowering blood pressure and heart rate. The drug (1 mg/kg i.v.) decreased the discharge rate of the preganglionic sympathetic splanchnic nerve, but in contrast to the effect of clonidine this could not be demonstrated in decerebrate cats. As blood pressure and heart rate were decreased by B-HT 958 in decerebrate cats, the main site of action was assumed to be peripheral. Also in contrast to clonidine, B-HT 958 did not induce vagal baroreflex bradycardia in anaesthetized dogs with blocked beta-adrenoceptors following intracisternal (30 micrograms/kg as well as 3 mg/kg) injection. In anaesthetized rats the decrease in blood pressure and heart rate caused by 1 mg/kg B-HT 958 i.v. was antagonized by 0.5 mg/kg piperoxan i.v. It is suggested that the cardiovascular effects of B-HT 958 depend on its high selectivity for alpha 2-adrenoceptors and are due to its agonist action presynaptically on peripheral adrenergic nerve terminals.
Adrenergic alpha-Agonists↗
alpha 1/alpha 2 Selectivity ratio in a series of agonists and their relation to pre/postsynaptic activity ratios.
beta-Blocked pithed rats were used to obtained dose-response curves (blood-pressure increase) for 13 various alpha-adrenoceptor agonists of clinical and theoretical interest, in the absence and in the presence of the selective antagonists rauwolscine (alpha 2) and prazosin (alpha 1). Antagonist doses which shifted the dose-response curves for an agonist 10-fold to the right along the abscissa were then calculated (D10rauwolscine = D10R; D10prazosin = D10P). The ratio D10R/D10P is considered to be a quantitative estimation of an agonist's alpha 1/alpha 2 selectivity ratio. A correlation with post/presynaptic activity ratios is presented.
Adrenergic alpha-Agonists↗
Presynaptic activity of the imidazolidine derivative ST 587, a highly selective alpha 1-adrenoceptor agonist.
St 587 increased the blood pressure of pithed rats. When the antagonists prazosin (alpha 1) and rauwolscine (alpha 2) were used the drug was shown to be a more selective alpha 1-adrenoceptor agonist than methoxamine. St 587 inhibited the tachycardia elicited by sympathetic stimulation in pithed rats. This effect was presynaptic and due to stimulation of alpha 1-adrenoceptors, as revealed by the different antagonism exerted by prazosin and yohimbine (alpha 2), respectively. The existence of presynaptic alpha 1-adrenoceptors is discussed.
Adrenergic alpha-Agonists↗
B-HT 958, a new alpha-adrenoceptor agonist with a high pre/postsynaptic activity ratio.
B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo [5,4-d] azepine) was a potent agonist at presynaptic and a less potent agonist at postsynaptic alpha-adrenoceptor sites. Presynaptically this was shown in pithed rats by the inhibition of tachycardia evoked by sympathetic nerve stimulation (0.2 Hz). The 50% inhibitory dose (ID50) was 0.3 mg/kg i.v. Moreover in isolated perfused cat hearts, the drug inhibited the tachycardia and the outflow of noradrenaline induced by sympathetic nerve impulses. These effects of B-HT 958 were antagonized by phentolamine or yohimbine. At postsynaptic sites high doses of B-HT 958 increased the blood pressure of decentralized rats. The dose which increased pressure by 30 mm Hg (PD 30) was 46.3 mg/kg i.v. This effect was antagonized by rauwolscine 5 mg/kg i.v. After pretreatment with reserpine (7.5 mg/kg i.p., 18 h) B-HT 958 proved much more potent (PD 30 = 0.6 mg/kg i.v.) and its effect was strongly antagonized by yohimbine but hardly by prazosin. The dose of yohimbine which shifted the dose-response curve of B-HT 958 by the factor of 10 (D10) to the right was 1.8 mg/kg iv., the corresponding dose of prazosin was 1,900 mg/kg i.v. (extrapolated). B-HT 958 showed also alpha-adrenoceptor blocking properties. This was demonstrated presynaptically in pithed rats by the drug-induced augmentation of tachycardia elicited by electrical stimulation at high frequency (6.4 Hz). At postsynaptic sites B-HT 958 antagonized the blood pressure increase-caused by B-HT 920 (alpha 2; D10 = 1.1 mg/kg i.v.) but not that caused by methoxamine (alpha1). It is concluded that B-HT 958 is a partial agonist at peripheral alpha 2-adrenoceptors. In doses of about 1 mg/kg and with low frequency sympathetic stimulation (less than 6.4 Hz) it acts presynaptically as agonist; in this dose the drug acts postsynaptically mainly as antagonist.
Adrenergic alpha-Agonists↗
alpha-Adrenoceptor subtypes in cardiovascular regulation.
A great deal of experimental observations at alpha-adrenoceptors may be explained if two points are considered: (1) the alpha 1-/adrenoceptor ratio (selectivity ratio) of a given drug and (2) the ratio of alpha 1-/adrenoceptors in the target organ or tissue. The alpha 1-/alpha 2-selectivity ratio for 10 agonists was determined in pithed rats by their hypertensive effect in the presence or absence of the antagonists rauwolscine or prazosin, respectively. Treatment with a beta-blocking agent made it possible to test drugs with additional beta-adrenergic potencies (phenylethylamines). Methoxamine exerted the highest alpha 1-/alpha 2-selectivity ratio, the azepine derivative B-HT 920 the lowest ratio, i.e., the highest selectivity for alpha 2-adrenoceptors. Using the two selective agonists methoxamine and B-HT 920, respectively, the alpha 1-/alpha 2-adrenoceptor ratio (importance) in several target systems was estimated (determination of equieffective doses). Results indicated the prevalence of alpha 1-adrenoceptors in the nictitating membrane, and the equal importance of both subtypes at peripheral postsynaptic vascular sites in rats, as well as in cats. At presynaptic sites (cardiac nerve, rats), alpha 2-adrenoceptors are prevalent. A comparison of equieffective doses of B-HT 920 and clonidine in cats indicated the alpha 2-nature of the central adrenoceptors which mediate hypotension.
Adrenergic alpha-Agonists↗
Effect of alinidine (St 567) on sympathetic and vagal activities.
A depressor effect on spontaneous preganglionic sympathetic discharge rate could be shown in anaesthetized, debuffered cats after i.v.-injection of 2.5 mg/kg alinidine. This effect developed gradually and did not parallel the marked bradycardia which was of prompt onset. In anaesthetized dogs with beta-adrenoceptors blocked, alinidine (2.5 mg/kg i.v. or 0.5 mg/kg intracisternally) proved to be without effect on vagally mediated reflex bradycardia. This reaction pattern (inhibition of sympathetic discharges, no effect on vagal baroreflex activity) differentiates alinidine from clonidine-like substances, which are known to decrease sympathetic tone and to increase vagally mediated reflex bradycardia.
Adrenergic beta-Antagonists↗
alpha 2-Adrenoceptor agonistic effect of B-HT 920 in isolated perfused hindquarters of rats.
In isolated perfused hindquarters of rats pretreated with reserpine the alpha 2-adrenoceptor selective agonist B-HT 920 decreased the flow dose-dependently. This effect was strongly antagonized by yohimbine and less by prazosin, and the reverse potency was demonstrated for methoxamine. With increasing concentrations of B-HT 920, a half maximal effect was achieved with 10(-6.64) M. This value is discussed wih respect to the antagonistic potency of B-HT 920 at alpha 1-adrenoceptors with a pA2 of 4.9.
Adrenergic alpha-Agonists↗
alpha 1-adrenoceptor blockade by alpha 2-adrenoceptor agonists in the isolated perfused hindquarter of rats.
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Adrenergic alpha-Agonists↗