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Biomedical subjects

A de Jonge

Publications and source records attributed to A de Jonge.

At least 55 records · Page 3Linked to original sources
PubMed1982

Differential effects of selective alpha 1- and alpha 2-adrenoceptor agonists on intraocular pressure in the conscious rabbit.

In the present study the influence of topically applied selective alpha 1- and alpha 2-adrenoceptor agonists on intraocular pressure and the diameter of the pupil was investigated in conscious rabbits. Selective stimulation of the alpha 1-subtype of receptors induced an elevation in intraocular pressure, accompanied by mydriasis, whereas stimulation of the alpha 2-subtype caused a marked and dose-dependent ocular hypotensive response, which could be blocked by the selective alpha 2-adrenoceptor antagonist yohimbine. After application of the non-selective alpha-adrenoceptor agonist clonidine the alpha 2-adrenoceptor mediated decrease in IOP is probably counteracted by a pressor effect due to the stimulation of alpha 1-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1982

Central and peripheral alpha-adrenoceptors.

The recent interest in the characterization and functional, role of alpha-adrenoceptors has prompted us to study the following different, although interdigitated, lines of research: (a) The functional role of calcium ions in the process of vasoconstriction, induced by alpha 2-adrenoceptor stimulation. We have shown in various animal species that the vasoconstriction induced by alpha 2-adrenoceptor stimulation with specific agonists is impaired by various organic and inorganic calcium antagonists. This finding suggests that the influx of extracellular calcium is required in order to enable the occurrence of vasoconstriction, mediated by the stimulation of vascular alpha 2-adrenoceptors. (b) The functional role of cardiac presynaptic alpha 2-adrenoceptors in the bradycardiac effect of clonidine and related congeners. In the pentobarbitone-anaesthetized rat, the stimulation of cardiac presynaptic alpha 2-adrenoceptors appears to be a highly relevant mechanism, which in combination with the facilitation of the vagal reflex bradycardia explains the bradycardiac action of clonidine and related drugs. (c) The possible extrasynaptic location of postsynaptic alpha 2- and beta 2-adrenoceptors in vascular smooth muscle. A comparison of the influence of the blocking potency of selective alpha 1- and alpha 2-adrenoceptor antagonists on the vasoconstrictor and tachycardia effects of catecholamines, either released endogenously or injected via an exogenous route, has suggested that the alpha 2- and beta 2-adrenoceptors are probably located at extrasynaptic sites, whereas the alpha 1-adrenoceptors are rather situated within the synapse. (d) The characterization of alpha-adrenoceptors involved in the central hypotensive and sedative activities of clonidine. Experiments with selective alpha-adrenoceptors blocking agents have revealed that the central alpha-adrenoceptors involved in the hypotensive and sedative effects of clonidine are most likely to correspond to the alpha 2-subtype.

Adrenergic alpha-Agonists↗
PubMed1981

Discrimination between peripheral and central alpha-adrenergic effects using meta-substituted imidazolidines.

meta-Substituted 2-chlorophenyl(imino)imidazolidines of the clonidine-type (2,3- and 2,5-substituted derivatives) were used in attempts to discriminate between alpha-adrenergic effects (central hypotensive and peripheral hypertensive activities) in rats. The central hypotensive activity of four pairs of substitution isomers was expressed as a pC20, calculated from log dose-response curves after i.v. administration of the compounds to anaesthetized, normotensive rats. Peripheral hypertensive potency was evaluated in pithed normotensive rats following i.v. injections and quantified by means of pC60. The partition coefficients of the drugs were determined in an octanol/aqueous buffer (pH 7.4, 37 degrees C) system as a measure of lipophilic behaviour. The pressor activities in rats were comparable within each pair of substitution isomers whereas the depressor potencies differed greatly, although the representatives within each pair displayed similar lipophilicity. Regression analysis showed that the central hypotensive activity was governed by the steric bulk of the 5-substituent. On the other hand, this feature did not affect the peripheral hypertensive potency. The discrepancy between central and peripheral alpha-adrenergic activities found for 2,5-substituted imidazolidines is discussed in connection with the selectivity of these compounds for alpha 1 and alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1981

Organic and inorganic calcium antagonists reduce vasoconstriction in vivo mediated by postsynaptic alpha 2-adrenoceptors.

The influence of various calcium antagonists and divalent metal cations on the pressor responses induced by the selective alpha 1-adrenoceptor agonist methoxamine and the selective alpha 2-adrenoceptor stimulating agent B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]-azepine) was studied in pithed rats. 1. The calcium antagonists verapamil, D 600 and nifedipine, when given intraarterially (i.a.) in doses up to 1 mg/kg did not influence the pressor effects of methoxamine. Only higher amounts of these calcium antagonistic drugs (1 - 3 mg/kg i.a.) somewhat reduced this pressor response. 2. The vasoconstriction due to B-HT 920, as reflected by the increase in diastolic pressure, was markedly inhibited by verapamil, D 600 and nifedipine in a dose-dependent manner. In low doses a parallel displacement to the right was observed, whereas in higher amounts the shift was non-parallel. 3. The divalent cations MN2+, Ni2+ and Co2+ (0.05 - 0.15 mmol/kg i.a.) hardly affected the pressor effect of methoxamine, whereas B-HT 920-induced vasoconstriction was highly sensitive to these metal ions. La3+ and Mg2+ were ineffective. 4. The calcium antagonists verapamil, D 600 and nifedipine displayed only minor affinities for [3H]prazosin (alpha 1) as well as [3H]clonidine (alpha 2) binding sites of rat brain membranes. 5. It is concluded that an influx of extracellular Ca2+ is necessary for the vasoconstriction in vivo initiated by stimulation of vascular postsynaptic alpha 2-adrenoceptors. On the other hand, vasopressor responses to alpha 1-adrenoceptor stimulation are not directly dependent on a transmembrane influx of calcium ions.

Adrenergic alpha-Agonists↗
PubMed1981

The effect of selective alpha 1- and alpha 2-adrenoceptor stimulation on intraocular pressure in the conscious rabbit.

The influence of topically applied selective alpha 1-and alpha 2-adrenoceptor agonists on intraocular pressure and the diameter of the pupil was investigated in conscious rabbits. Selective stimulation of the alpha 1-subtype of receptors induced an elevation in intraocular pressure, accompanied by mydriasis, whereas stimulation of the alpha 2-subtype caused a marked and dose-dependent ocular hypotensive response, which was blocked by the selective alpha 2-adrenoceptor antagonist yohimbine. alpha 2-Agonists induced neither macroscopic ocular side effects, nor an effect on the pupil size. Possibly, the subclass of alpha 2-adrenoceptor stimulating drugs represents a group of new antiglaucomatous agents.

Adrenergic alpha-Agonists↗
PubMed1981

Characterization of alpha-adrenoceptor populations. Quantitative relationships between cardiovascular effects initiated at central and peripheral alpha-adrenoceptors.

The agonist selectivities of central (medullary) and peripheral (vascular) alpha-adrenoceptors were compared in order to investigate a possible similarity among these two alpha-adrenoceptor populations. Linear regression equations were derived between the alpha-adrenergic potencies, mediated by these two types of alpha-adrenoceptors for 21 structurally dissimilar alpha-adrenoceptor agonists. Hypotensive potency after intravenous administration to anesthetized, normotensive rats was determined as a measure of central alpha-adrenergic activity and expressed as pC25, obtained from log dose-response curves. Peripheral alpha-adrenergic potency was quantified by means of the hypertensive effect elicited in pithed, normotensive rats after intravenous injections, yielding pC60 as the biological variable. A most significant linear relationship was generated between central hypotensive activity (pC25) and peripheral hypertensive potency (pC60), provided that log P' (octanol/buffer; pH 7.4, 37 degrees C) was included into the regression in a parabolic form. This result indicates that the central (medullary) alpha-adrenoceptors and the peripheral (vascular) alpha-adrenoceptor sites, which are excited by the drugs in question, make identical demands upon their agonists. The difference in accessibility to these peripheral and central alpha-adrenoceptor populations is adequately accounted for by a parabolic description in log P'. The apparent contradiction of this finding with the suggestion that central, hypotensive alpha-adrenoceptors are of the alpha 2 type and peripheral, vascular alpha-adrenoceptors belong to the alpha 1 subpopulation is discussed. The recent identification of an additional subclass of postsynaptic, vascular alpha 2-adrenoceptors and the lack of pronounced differential stimulating activity of the agonists at peripheral alpha-adrenoceptors may explain the present findings and clarify the paradox.

Animals↗
PubMed1978

Properties of immobilized fig alpha-galactosidase and effect on ceramide-3 content of plasma from patients with Fabry's disease.

The possibility of lowering the level of ceramide-3 (galactosyl-alpha(1 leads to 4)-galactosyl-beta(1 leads to 4)-glucosyl-beta(1 leads to 1)-ceramide) in the plasma of patients with Fabry's disease was investigated. An immobilized alpha-galactosidase (alpha-D-galactoside galactohydrolase, EC 3.2.1.22) was prepared by coupling purified fig alpha-galactosidase to Sepharose 4B. The pH optimum for the hydrolysis of the artificial substrate p-nitro-phenyl-alpha-D-galactopyranoside was shifted by approx. 0.5--1.0 pH unit to higher pH values upon coupling of the enzyme to Sepharose 4B. The immobilized enzyme was more stable than the native enzyme to incubation at 60 degrees C. The immobilized enzyme was able to hydrolyse ceramide-3 either at pH 4.5 or at pH 7.4 in an artificial system in which sodium taurocholate was used to solubilize the substrate. In contrast, when the immobilized enzyme was incubated with normal plasma or plasma from a patient with Fabry's disease, in which elevated levels of ceramide-3 occur, no hydrolysis of the glycosphingo-lipid could be detected. The results suggest that lowering of level of ceramide-3 in plasma from patients with Fabry's disease by enzymic means is not feasible.

Drug Stability↗
PubMedDate not supplied

Influence of nifedipine on functional responses in vivo initiated at alpha 2-adrenoceptors.

The pressor effects of intravenous B-HT 920 in pithed cats were sensitive to antagonism by yohimbine (1 mg/kg i.v.), but not by prazosin (1 mg/kg i.v.). In contrast, prazosin profoundly affected the vasoconstriction caused by intravenous (-)-phenylephrine, whereas yohimbine only slightly influenced this response. These results confirm and extend earlier observations which favor a distinct subclassification of vascular postsynaptic alpha-adrenoceptors into alpha 1- and alpha 2-subtypes. Vasoconstriction in pithed cats by B-HT 920 was markedly antagonized by low doses (30 and 100 micrograms/kg) of nifedipine in a noncompetitive manner. The hypertensive responses to (-)-phenylephrine were moderately attenuated in a competitive fashion. These findings are consistent with the concept that extracellular calcium ions are indispensable for linking vascular alpha 2-adrenoceptor activation to vasoconstriction in vivo. Nifedipine (up to 1 mg/kg i.v.) neither interfered with the tachycardia induced by electrical stimulation in pithed normotensive rats nor influenced the inhibitory effect of B-HT 920. Clonidine's (0.3 mg/kg i.p.) prolongation of the hexobarbitone-induced loss of the righting reflex in mice was unchanged after nifedipine administration (up to 1 mg/kg i.p.). The central hypotensive action of clonidine in anesthetized cats (1 microgram/kg via vertebral artery) and in anesthetized normotensive rats (3-30 micrograms/kg i.c.v.) was reduced by nifedipine (30 and 100 micrograms/kg i.v. or i.c.v.). The results show a differential influence of nifedipine on functional responses in vivo caused by stimulation of pre- and postsynaptic alpha 2-adrenoceptors. In contrast to its inability to inhibit alpha 2-adrenoceptor-mediated effects at presynaptic sites, this calcium entry blocker impairs postsynaptic alpha 2-adrenoceptor-induced responses.

Animals↗