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Biomedical subjects

M C Koss

Publications and source records attributed to M C Koss.

At least 91 records · Page 5Linked to original sources
PubMed1983

Alpha-methyl-DOPA induced mydriasis in the cat. Relationship between pupillary response and the oculomotor perfusate concentration of methyldopa and its metabolites.

In pentobarbital anaesthetized cats, intravenous administration of 30 mg/kg, alpha-methyl-DOPA produced mydriasis that reached a maximum plateau in 2--2.5 h. The oculomotor nucleus was perfused with saline using a push-pull cannula system chronically implanted over the nucleus. Perfusate samples were collected and subsequently analyzed by liquid chromatography with electrochemical detection (LC-EC). Alpha-methyl-DOPA administration resulted in a gradual build up of alpha-methyl-noradrenaline to approximately 32 mumoles over the 3 h sampling period. In contrast, the concentration of alpha-methyl-dopamine was below the detection level for the first 90 min with peak levels of less than 6 mumoles after 3 h. A linear regression analysis demonstrated a negative correlation (R = 0.90) between the pupil size and the perfusate concentration of alpha-methyl-DOPA and a positive correlation for both alpha-methyl-dopamine and alpha-methyl-noradrenaline (R = 0.88 and 0.94 respectively). Pretreatment with the DOPA-decarboxylate inhibitor, 3-hydroxy-benzyl-hydrazine (NSD-1015; 25 mg/kg, i.p.) completely blocked the mydriatic response to alpha-methyl-DOPA, with neither alpha-methyl-dopamine nor alpha-methyl-noradrenaline reaching detectable levels in the oculomotor perfusate. After treatment with the dopamine-beta-hydroxylase inhibitor, bis (4-methyl-homopiperazinyl thiocarbonyl) disulfide (FLA-63; 2.5 mg/kg, i.p.) there was a significant accumulation of alpha-methyl-dopamine when compared to that obtained in the alpha-methyl-DOPA controls but with no apparent alpha-methyl-dopamine related pupillary dilation. However, the correlation between alpha-methyl-noradrenaline concentration and the increase in the diameter of the pupil was maintained.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Studies on the mechanism of methyl-dopa-induced mydriasis in the cat.

Alpha-methyl-Dopa (10-100 mg/kg, i.v.) produced a dose-dependent mydriasis in cats anaesthetized with pentobarbital (30 mg/kg, i.p.). The onset was gradual, reaching a maximum plateau in 2-2.5 h. Intracerebroventricular administration of 1 or 3 mg of alpha-methyl Dopa (MD) also produced pupillary dilation with a similar time course. These dosages were without effect when given intravenously. Pretreatment with the alpha 2-adrenoceptor antagonist, yohimbine (0.5 mg/kg i.v.), blocked the pupillary response to MD. The alpha 1-adrenoceptor antagonist, prazosin (1.0 mg/kg. i.p.), was ineffective. Selective enzymatic blockade with 3-hydroxy-benzyl-hydrazine (NSD-1015; 25 mg/kg, i.p.), a Dopa-decarboxylase enzyme inhibitor, as well as with bis (4-methyl-homopiperazinyl-thiocarbonyl) disulfide (FLA-63; 2.5 mg/kg, i.p.), a dopamine-beta-hydroxylase blocker, prevented the mydriatic effect of MD. These results support the hypothesis that MD produces a clonidine-like, CNS mediated mydriasis in the cat, primarily by action of its metabolite alpha-methyl-noradrenaline acting on alpha 2-adrenoceptors.

Animals↗
PubMed1982

A quantitative assessment of CNS sympatho-inhibition produced by psychotropic drugs.

As one index of sympathetic reactivity, electrodermal responses (EDR) were evoked from central (hypothalamic) and peripheral (ulnar nerve) sites in pentobarbital-anesthetized cats. When compared with intravenous chlorpromazine (ED50 approximately 1.0 mg/kg), only thioridazine, trifluoperazine, and pimozide were less potent than chlorpromazine in reducing the amplitude of these centrally-evoked sympathetic-cholinergic responses. Perphenazine and methotrimeprazine (a non-neuroleptic phenothiazine) were about twice as potent as chlorpromazine. Haloperidol and triflupromazine were about 5 times as potent and chlorprothixine was more than 10 times as potent. None of these agents reduced the peripherally-evoked electrodermal response, indicating a CNS mode of action. Diazepam was without effect at either site. In addition, pretreatment with yohimbine (0.5 mg/kg. i.v.) did not significantly alter the ED50 for any of the above drugs. These results demonstrate that all of the phenothiazines and non-phenothiazine neuroleptics tested produce a dose-dependent central sympatho-inhibition and that diazepam does not. The results also suggest that there is no significant correlation between central sympatho-inhibition and the antipsychotic potency of these compounds and that their depression of central sympathetic outflow is independent of alpha-adrenergic mechanisms in the CNS.

Animals↗
PubMed1981

Analysis of pupillary dilation produced by analogs of clonidine.

Pupillary responses to intravenous administration of clonidine and five congeneric derivatives of clonidine were observed in anesthetized cats. All of the agents tested produced a dose-dependent mydriasis of long duration. The order of potency for these compounds was clonidine (St-155) greater than St.375 greater than St-606 greater than St-608 greater than St-91. Pretreatment with yohimbine hydrochloride (0.5 mg/kg i.v.) shifted the dose-response curve for all of the compounds tested to the right. A CNS inhibition of parasympathetic nerve activity was demonstrated for clonidine and St-375 by means of direct recordings from the postganglionic ciliary nerves. An effect of high doses of St-91 on nerve activity was also observed. These results suggest that all the analogs of clonidine tested (with the possible exception of St-91) act like clonidine to produce mydriasis by a central alpha-adrenergic inhibition of parasympathetic outflow to the eye.

Animals↗
PubMed1980

Stimulant action of thyrotropin-releasing hormone on ciliary nerve activity.

Thyrotropin-releasing hormone (TRH) was found to cause a dose-dependent stimulation of tonic ciliary nerve activity when administered intravenously to chloralose anesthetized cats. This increase in nerve activity appeared to be independent of the excitatory light reflex. TRH also produced a dose-dependent pressor effect in these preparations. These findings suggest that TRH may play a role as a neurotransmitter or neuromodulator with regard to central parasympathetic outflow to the eye.

Animals↗
PubMed1980

Methyldopa produces central inhibition of parasympathetic activity in the cat.

alpha-Methyldopa (10-100 mg/kg i.v.) produced a dose-dependent pupillary dilation in anaesthetized cats which was antagonized by subsequent administration of yohimbine hydrochloride (0.5 mg/kg i.v.). The peak effects were observed approximately 2-3 h after injection. This alpha-methyldopa-induced mydriasis was present only when the parasympathetic innervation to the iris was intact. Prior treatment with yohimbine (0.5 mg/kg i.v.) 30 min before alpha-methyldopa also antagonized the mydriatic effect, whereas pretreatment with phenoxybenzamine (2.5 mg/kg i.v.) did not. In contrast, phenoxybenzamine, but not yohimbine, effectively antagonized the pupillary dilation produced by adrenaline (0.3-10.0 microgram/kg i.v.). These results suggest that alpha-methyldopa produces mydriasis in the cat by means of CNS inhibition of tonic outflow from the oculomotor nucleus and that an alpha-adrenergic inhibitory mechanism may be involved. This conclusion is supported further by experiments in which direct measurements of ciliary nerve activity were made.

Animals↗
PubMed1980

Studies on the mechanism of amphetamine mydriasis in the cat.

This study was undertaken in order to determine the relative extent to which amphetamine-induced mydriasis is of central nervous system (CNS) or of peripheral origin. Anesthetized cats were administered cumulative dosages of amphetamine given either intravenously (0.05-3.2 mg/kg) or directly into the third ventricle of the brain (500 micrograms i.c.v.). Pupillary dilation and ciliary nerve activity were monitored. In cats with only parasympathetic tone to the iris intact, i.v. amphetamine produced a dose-dependent mydriasis and decrease of ciliary nerve activity. Treatment with yohimbine (0.5 mg/kg i.v.), before amphetamine administration, blocked the amphetamine-induced reduction of parasympathetic nerve activity and partially antagonized the pupillary dilation. Both yohimbine pretreatment and CNS monoamine depletion (with reserpine 5 mg/kg i.p. and alpha-methyl-p-tyrosine 2 x 300 mg/kg i.p.) prevented the mydriatic and ciliary nerve activity lowering effects of i.c.v. amphetamine. These results suggest that amphetamine produces mydriasis in the cat primarily by means of CNS inhibition of tonic outflow from the oculomotor nucleus and to only a minor extent by acting as a peripheral sympathomimetic. This conclusion is consistent with the hypothesis that release of norepinephrine within the CNS inhibits tonic parasympathetic outflow to the iris.

Animals↗
PubMed1979

Effects of clonidine and chlorpromazine on a sympathetic-cholinergic reflex.

Intravenous administration of clonidine and chlorpromazine resulted in a dose-dependent inhibition of the amplitude of reflexly evoked electrodermal responses in intact and spinal cats. Yohimbine pretreatment (0.5 mg/kg, i.v.) antagonized the effects of clonidine but not chlorpromazine in both preparations. These findings confirm and expand previous observations that both clonidine and chlorpromazine inhibit the amplitude of centrally evoked responses in this sympathetic-cholinergic system. In addition, both drugs appeared to have a spinal site of action. The antagonism of the effects of clonidine by yohimbine suggests that the mechanism of the action of clonidine may be a result of activation of central inhibitory alpha-adrenergic receptors. The failure of yohimbine to antagonize the effects of chlorpromazine suggests that clonidine and chlorpromazine may depress these sympathetic reflexes by different mechanisms.

Animals↗
PubMed1979

Clonidine mydriasis in the rat.

Pupillary responses to clonidine (3--100 micrograms/kg, i.v.) and epinephrine (1--30 micrograms/kg, i.v.) were observed in anesthetized rats. Clonidine caused a dose-dependent mydriasis which was effectively antagonized by pretreatment with yohimbine (1.5 mg/kg, i.v.). Pretreatment with phentolamine (5 mg/kg, i.v.) was less effective in antagonizing this clonidine-induced mydriasis. Phenoxybenzamine (2 mg/kg, i.v.) was almost without effect. In contrast, both phentolamine and phenoxybenzamine blocked the pupillary dilation produced by epinephrine while yohimbine pretreatment resulted in no antagonism of epinephrine-induced mydriasis. These results suggest that clonidine-induced mydriasis in the rat is mediated by a central adrenergic inhibitory mechanism.

Adrenergic alpha-Antagonists↗
PubMed1979

Topical clonidine produces mydriasis by a central nervous system action.

One drop of clonidine solution (0.125, 0.25 or 0.5%) was administered topically to one eye in cats anesthetized with pentobarbital in which the vagosympathetic nerves had been sectioned. Clonidine caused a simultaneous dose-related mydriasis in both eyes along with a decrease in heart rate. The peak effects were observed in about 20--30 min. Topical administration of clonidine (0.5%) produced no effect on the parasympathectomized, eserinized iris but did dilate the opposite pupil. Epinephrine (0.1--30 microgram, i.a.) produced equal pupillary dilation in both eyes. In addition, topical clonidine caused a dramatic decrease in postganglionic ciliary nerve activity. All of the effects of clonidine were antagonized by yohimbine (0.5 mg/kg, i.v.). These results demonstrate that topical administration of clonidine causes my driasis in the cat and that this effect is mediated totally by means of CNS inhibition of parasympathetic tone to the iris.

Administration, Topical↗
PubMed1979

Evidence for a central postsynaptic action of clonidine.

Intravenous administration of clonidine (1--100 micrograms/kg) produces a dose-dependent mydriasis in cats by inhibition of parasympathetic tone to the iris. The magnitude of CNS-induced pupillary dilation was similar in both normal anaesthetized cats and in anaesthetized preparations pretreated with reserpine (5 mg/kg i.p.) and alpha-methyl-p-tyrosine (2 x 300 mg/kg i.p.). Pretreatment reduced the concentrations of noradrenaline, dopamine and serotonin to less than 3% of that control levels in most parts of the CNS in which these amines were measured. Clonidine produced bradycardia in control animals but not in pretreated cats. In amine depleted animals in which only one eye was innervated by the ciliary nerves (parasympathetic), clonidine produced mydriasis only on the innervated side. These experiments confirm our previous observations that clonidine produces mydriasis in the cat by means of inhibition of parasympathetic tone to the iris. It is concluded that if clonidine produces this effect by stimulating noradrenergic, dopaminergic or serotonergic receptors, then clonidine exerts its centrally-induced mydriatic effect by acting on post-synaptic mechanisms.

Animals↗
PubMed1977

Effect of clonidine and chlorpromazine on centrally evoked electrodermal responses and their interaction with yohimbine.

Both clonidine and chlorpromazine reduced the amplitude of electrodermal responses (EDR) evoked by stimulation of the hypothalamus at a constant submaximal frequency (10-16 Hz). The ED50 for clonidine was approximately 5 mug/kg and that for chlorpromazine was about 1 mg/kg. Yohimbine pretreatment (0.5 mg/kg, i.v.) antagonized the effects of clonidine but did not alter the effectiveness of clorpromazine in inhibiting these responses. Yohimbine alone was without effect on these sympathetic-cholinergic responses. These results suggest that clonidine and chlorpromazine deress central sympathetic reactivity by different mechanisms.

Animals↗
PubMed1976

Epinephrine inhibition of the electrodermal response in the cat.

Intravenous administration of epinephrine results in a dose-dependent inhibition of the peripherally evoked electrodermal response (EDR) in the cat. The magnitude of this depression of the EDR was greater when the responses were evoked by a single shock than by a train of shocks (10-12 Hz). The observation that this epinephrine-induced inhibition is antagonized by phentolamine suggests that an alpha-adrenergic mechanism is involved. It is unlikely that this effect is due primarily to the vascular actions of epinephrine because the inhibition of the EDR was much more prolonged than was the pressor action. Angiotensin was ineffective in inhibiting these responses.

Angiotensin II↗
PubMed1976

Characteristics of the electrodermal response. A model for analysis of central sympathetic reactivity.

Electrodermal responses (EDR) of the sympathetic-cholinergic sudomotor system were elicited in anaesthetized cats. Responses were evoked centrally from hypothalamic, medullary and spinal loci, by stimulation of the pre- and postganglionic peripheral nerves, and reflexly following stimulation of an afferent nerve. The response was found to be dependent upon innervation of both the median and ulnar nerves (approximately 40 and 60% respectively). Both the centrally and peripherally evoked responses were frequency-dependent when a maximal current was used. The EDR evoked peripherally or from the cervical cord reached its maximal amplitude at 10-16 Hz whereas the EDR evoked from the hypothalamus and medulla did not reach its maximal amplitude until 48-64 Hz. These responses are relatively independent of blood flow in that complete occlusion of the peripheral blood supply did not greatly alter the amplitude of centrally evoked responses. The results suggest that this sympathetic-cholinergic system may be a useful model system with which to study the actions of various adrenergic agents on the reactivity of central structures which regulate sympathetic nervous activity.

Animals↗
PubMed1976

The electrodermal response as a model for central sympathetic reactivity: the action of clonidine.

Electrodermal responses (EDR) were evoked centrally by stimulation of reactive loci in the posterior hypothalamus and peripherally by stimulation of the distal portion of the sectioned median or ulnar nerve. Moderate doses of clonidine (3-30 mug/kg, i.v.) reduced the amplitude of the centrally evoked EDR while having no effect on the peripherally evoked responses. This central action of clonidine occurred concomitantly with the clonidine-induced bradycardia and hypotension. Administration of clonidine shifted the centrally evoked EDR frequency-response curve to the right in a dose related manner at 3, 10 and 30 mu/kg, i.v. 1 mug/kg was without effect on these responses. This central depressant action of clonidine was partially reversed following administration of yohimbine (0.5-1.0 mug/kg, i.v.). These results suggest that clonidine inhibits central reactivity in this sympathetic-cholinergic system in a manner analogous to its action on other sympathetic systems, and that a central adrenergic inhibitory mechanism may be involved.

Animals↗
PubMed1976

Studies on the site of action of clonidine utilizing a sympathetic-cholinergic system.

Clonidine (30 mug/kg, i.v.) reduced centrally evoked electrodermal responses (EDR) following stimulation of reactive loci in the hypothalamus and medulla. The responses were most depressed following low frequency stimulation. Similar results were observed on the EDR evoked by stimulation of the cervical cord in the spinal cat. Little effect was seen following peripheral nerve stimulation. These results demonstrate that clonidine depresses the reactivity of this sympathetic-cholinergic system at all central levels including the cervical cord.

Animals↗