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Biomedical subjects

W Kobinger

Publications and source records attributed to W Kobinger.

At least 55 records · Page 3Linked to original sources
PubMed1980

Chemistry, pharmacology, and structure-activity relationships with a new type of imidazolines exerting a specific bradycardic action at a cardiac site.

The reaction of alkyl halides with 2-(arylimino)imidazolidines (I) leads to imidazoline derivatives II, in which the side chain is situated at the bridge nitrogen atom between the phenyl group and the imidazoline ring. The new imidazolines (II) exert a specific bradycardic action at a cardiac site. Syntheses and pharmacology are shown and structure-activity relationships discussed. The results reveal that the imidazoline derivatives (II) represent a class of compounds with a novel type of cardiac action.

Animals↗
PubMed1980

Central cardiovascular alpha-adrenoceptors. Relation to peripheral receptors.

Clonidine and related drugs cause a specific pattern of cardiovascular depression by an agonistic effect on alpha-adrenoceptors within the central nervous system (CNS). For further characterization of the central adrenoceptors, the actions of three substances of the "clonidine-type" derived from two different chemical groups were studied at peripheral vascular sites. Clonidine and two azepin derivatives had very weak vasoconstrictor activity in isolated perfused rat hindquarters. Signs of desensitization were observed when these drugs were administered repeatedly. However, these compounds exerted antagonism against the vasoconstricting effect of noradrenaline. The ranking order of these drugs in their antagonistic potency was the same as with their central cardiovascular depressor potency. In spinal rats, the three compounds raised blood pressure due to their alpha-adrenoceptor stimulation. The ranking order was the same for the pressor potency as for their central cardiovascular depressor potency. It is concluded that in isolated preparations the agonistic activity of clonidine-like substances on postsynaptic alpha-adrenoceptors might not be representative for their CNS effect.

Animals↗
PubMed1978

Differentiation of drugs acting centrally upon the cardiovascular system by means of sympathetic and vagal responses.

The response pattern of the autonomic nervous system was investigated after central administration (intra-cisternal, vertebral artery) of amphetamine, morphine, fentanyl, dextromoramide and the substance R 28935, chemically related to the neuroleptic agent pimozide. Effects on the sympathetic system were measured by recording electrical discharges of fibres of the (preganglionic) major splanchnic nerve in anaesthetized cats; those on the vagal system by recording the heart rate in anaesthetized dogs under beta-adrenoceptor blockade; the baroreceptor reflex was elicited by the blood pressure increase of i.v. injected angiotensin. All substances decreased the spontaneous discharge rate of the splanchnic nerve. Amphetamine facilitated the vagally mediated reflex bradycardia and this was antagonized by the alpha-adrenoceptor blocking agent piperoxan. Amphetamine did not affect the resting heart rate, as has already been shown for clonidine and related substances. The narcotic analgesics lowered the resting heart rate but did not facilitate the baroreceptor reflex response. R 28935 neither influenced resting heart rate nor the baroreceptor reflex response in beta-blocked dogs. On the basis of the vagal response pattern it was therefore possible to distinguish between 3 groups of central hypotensive drugs.

Amphetamine↗
PubMed1977

[New concepts on central regulation of the blood pressure. Mode of action of clonidine and alpha-methyl DOPA (author's transl)].

A review is presented of several reports which strongly indicate that the reaction pattern of "cardiovascular depression" (decrease in blood pressure, heart rate and cardiac output) is triggered off by the stimulation of alpha-adrenoceptors in the brain. The efferent information is mediated by an inhibition of the sympathetic and by an activation of the cardiac vagal system. The central alpha-adrenoceptors, which are localized within the medulla, are stimulated by the antihypertensive agents clonidine and alpha-methyl-DOPA, and also by central administration of other sympathomimetic drugs such as naphazoline, oxymetazoline, amphetamine and others. It can be assumed that these drugs mimic the action of endogenous nor-adrenaline, which is present in considerable amounts in the brain stem, and which might, under physiological conditions, mediate the pattern of cardiovascular depression.

Animals↗
PubMed1976

RA 642, a pyrimido-pyrimidine-derivative with vasodilating and hypertensive potency.

2,2'-[(4,8-bis(diethylamino)-pyrimido[5,4-d]-pyrimidine-2,6-diyl)di-(2-methoxyethyl)imino]diethanol), RA 642, combines hypertensive and vasodilating effects. In anaesthetized animals arterial blood pressure was increased by i.v. doses of 0.25-4 mg/kg in cats and 0.025-0.25 mg/kg in dogs. In conscious dogs, 25 mm increase of mean blood pressure was achieved with 0.2 mg/kg i.v. and 18.8 mg/kg p.o. Cerebral blood flow was enhanced and calculated cerebral vascular resistance was reduced by RA 642. Total peripheral resistance was diminished by 0.25-1.0 mg/kg i.v. A vasodilatation of femoral and coronary vessels was shown after intraarterial injection. This effect as well as a BaCl2-antagonism in the isolation ileum is explained by a papaverine-like relaxant effect on smooth muscle. Activity on peripheral adrenergic receptors was excluded. Hypertension was abolished in spinalized cats, indicating a central mechanism of this effect.

Animals↗
PubMed1976

Stimulation of sympathetic cardiovascular centres by RA 642, a new pyrimido-pyrimidine derivative.

RA 642, 2,2'-[14,8-bis(diethylamino)-pyrimido[5,4-d] pyrimidine-2,6-diyl)di-(2-methoxyethyl)-imino]diethanol, has formerly been described to hypertensive when administered systemically. In the present experiments injection of 50 mug/kg RA 642 into the vertebral artery (i.a. vert.) of the cat exerted hypertension, while the same dose given intravenously (i.v.) elicited no effect. Since the drug was still effective in cats of which the brain was removed rostrad of the myelencephalon but not in spinal animals, its site of action was concluded to be in cardiovascular centres of the medulla oblongata. An i.a. vert. injection increased total peripheral resistance of the vasculature. The electrical discharge rate in preganglionic cervical sympathetic nerve fibres increased in parallel to the arterial blood pressure following the i.v. injection of 1 mg/kg of the substance. 1 mg/kg RA 642 i.v. decreased the reflex bradycardia elicited by the i.v. injection of angiotensin in dogs pretreated with a beta-adrenoceptor blocking drug to study the vagal effector reactions of the baroreceptor reflex, and treated with clonidine to facilitate the reflex. Thus, RA 642 increased sympathetic and, following clonidine treatment, decreased vagal reflex activity. RA 642 stimulated the respiration by a central action. The drug had no convulsant action.

Action Potentials↗
PubMed1976

Centrally induced reduction in sympathetic tone-a postsynaptic alpha-adrenoceptor-stimulating action of imidazolines.

Naphazoline or oxymetazoline (both 30 mug/kg) were injected into the cisterna magna of anaesthetized cats and reduced blood pressure, heart rate and the electrical discharge rate of small fibre bundles of the preganglionic sympathetic splanchnic nerve. Cats were depleted of endogenous noradrenaline by pretreatment with reserpine (5 mg/kg, 18 h) and alpha-methyl-p-tyrosine (twice 300 mg/kg, 18 and 2 h). In these animals, intracisternal injection of 30 mug/kg oxymetazoline exerted a decrease of sympathetic discharges similar to that described for non-pretreated animals. In noradrenaline-depleted cats intracisternal injection of 1 mug/kg clonidine also decreased the sympathetic discharges. It is concluded that these imidazolines exert their sympathoinhibitory and cardiovascular effects by stimulation of postsynaptic alpha-adrenoceptors in the CNS.

Adrenergic alpha-Agonists↗
PubMed1975

Investigation into some imidazoline compounds, with respect to peripheral alpha-adrenoceptor stimulation and depression of cardiovascular centers.

Peripheral alpha-adrenoceptor stimulation was tested by means of hypertensive effects of the drugs following i.v. injection in spinal rats. Naphazoline (NP), oxymetazoline (OM), St 91-2-(2,6-diethylphenylimino)-2-imidazolidine--and St 1697--2-(2-ethyl, 6-methylphenylimino)-2-imidazolidine--were 3 to 5 times more potent in tthis respect thatn clonidine (CLON) whereas St 363--2-(2,4-dichlorophenylimino)-2-imidazolidine--and xylazine (XY) exerted only approx. 1/20 the effect of that of clonidine. Sympathoinhibitory activity after i.v. injection was tested by the bradycardiac effect in vagotomized rats; St 1697, St 363 and XY were active, approx. 1/10-1/30 of CLON, whereas NP, OM and St 91 were inactive. However, following intracisternal (i.ci.) injection of cardiovascular depression, typical for clonidine: (1) in dogs with blocked beta-adrenoceptors, the drugs facilitated the vagally meditated cardiodepressor reflex in response to baroreceptor stimulation by i.v. injection of angiotensin; (2) in dogs treated with atropine and in (3) vagotomized cats (only NP, OM and St 363) a long lasting decrease in heart rate was observed. Some of the experiments were complicated by increases in blood pressure, due to the "leakage" of small amounts of the highly vasopressor active drugs, from the cisternal spaces into the peripheral circulation. The majority of results indicated, that the central cardiovascular depressor effects of the tested drugs depend on their alpha-adrenoreceptor stimulating potency and on their ability to penetrate from cerebrospinal fluid or from the blood to cardiovascular centers. Relationships between the ability for penetration and the lipoid affinity are discussed.

Adrenergic alpha-Agonists↗
PubMed1975

Localization in the CNA of adrenoceptors which facilitate a cardioinhibitory reflex.

In dogs (pentobarbitone, 25 mg/kg) the brain was removed rostrally to the pons, leaving the cerebellum intact (decerebrate animals). In other animals the cerebellum was additionally removed (bulbar animals). In all animals beta-adrenoceptors were blocked by toliprolol (5 mg/kg s.c.). Angiotensin (0.025-0.3mug/kg) was repeatedly injected i.v. and the resulting maximal reflex bradycardia was recorded. Intracisternal (i.ci.) injection of clonidine, 0.5 to 1 mug/kg, in decerebrate or i.v. injection of 10 or 30 mug/kg in bulbar animals significantly facilitated the reflex bradycardia. This effect was antagonised by a subsequent injection of piperoxan 50 mug/kg i.ci. in decerebrate or 1 mg/kg i.v. in bulbar animals. It is concluded that the facilitatory action of clonidine is mediated by alpha-adrenoceptors within the medulla oblongata.

Adrenergic beta-Antagonists↗
PubMed1975

The central modulatory effect of clonidine on the cardiodepressor reflex after suppression of synthesis and storage of noradrenaline.

Rats were decerebrated and treated with a beta-adrenoceptor blocker (toliprolol, Kö 592, 5 mg/kg). Increases of blood pressure were repeatedly elicited by i.v. injection of angiotensin (0.03-0. 125 mug/kg) ant eh accompanying reflex bradycardia was measured. The vagally mediated reflex bradycardia was significantly increased by clonidine, 3o mug/kg i.v., in non-pretreated animals as well as after pretreatment with reserpine (7.5 mg/kg s.c., 20 hr) and alpha-methyl-p-tyrosine-methylester (250 mg/kg i.p., 5 hr), separately or in combination. The facilitatory effect of clonidine was antagonized in all groups by i.v. injection of the alpha-adrenoceptor blocking drugs, phentolamine (5 mg/kg) and piperoxan (1 mg/kg). In the control periods before clonidine, reflex bradycardia was similar in pretreated animals to that in animals without pretreatment. It was concluded therefore that catecholamines have no essential transmitter functions in the cardiodepressor reflex loop. Therefore, the action of clonidine on cardiovascular centers in the medulla is independent of endogenous noradrenaline storage and synthesis. A direct effect is assumed on central alpha-adrenoceptors, which have a modulatory 'effector' function on the cardiodepressor reflex.

Adrenergic beta-Antagonists↗