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Biomedical subjects

W Kobinger

Publications and source records attributed to W Kobinger.

At least 37 records · Page 2Linked to original sources
PubMed1984

Facilitation of the Bezold-Jarisch reflex by central stimulation of alpha 2 adrenoceptors in dogs.

The Bezold-Jarisch reflex characterized by hypotension and bradycardia was elicited in anaesthetized artificially respired dogs (pretreated with a beta-adrenoceptor antagonist ) using capsaicin 10 micrograms/kg (i.v.). Intracisternal administration of the highly selective "clonidine-like" alpha 2 adrenoceptor agonists B-HT 920 (10 micrograms/kg) or B-HT 933 (30 micrograms/kg) significantly facilitated this reflex bradycardia. The involvement of central alpha 2-adrenoceptors is suggested as intracisternal administration of the alpha 2 adrenoceptor blocking drugs yohimbine (50 micrograms/kg) and piperoxan (50 micrograms/kg) antagonized this facilitation. B-HT 920 also facilitated the vagally mediated baroreceptor reflex to the hypertensive effect of intravenous noradrenaline (3 micrograms/kg). Although the Bezold-Jarisch reflex and the baroreceptor reflex have different afferent pathways, both reflexes may either converge into a common pathway or have separate neuronal chains within the medulla; however, this study indicates that both have a similar central modulatory system stimulated by alpha 2 adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1984

Decrease in bradycardic effect of AQ-A 39 and alinidine in guinea-pig sinoatrial node depolarized by high external K+-concentration.

The effects of the two "specific bradycardic agents" AQ-A 39 and alinidine on the spontaneous electrical discharge rate of intact guinea-pig sinus node preparations were investigated. At high external K+-concentrations (10.8 and 16.2 mmol/l) the bradycardic effect of the two drugs was diminished or abolished. In contrast, the negative chronotropic effect of the reference compound verapamil ("Ca2+-antagonist") was enhanced. These results show that the bradycardic effects of AQ-A 39 and alinidine are diminished in depolarized preparations, which makes it unlikely that in intact sinus node preparations the mechanism of action is the same as that of "Ca2+-antagonists".

Animals↗
PubMed1984

New concepts on alpha-adrenoceptors in pharmacology.

Alpha-adrenoceptors have been classified on a morphological basis as pre- and postsynaptic and on a pharmacological basis as alpha 1- and alpha 2-subtypes. Alpha 1 as well as alpha 2-receptors might be present at pre- as well as postsynaptic sites (fig. 1). The pressor effects after i.v. injection of alpha-adrenoceptor agonists in pithed rats are mediated by both, the alpha 1- and the alpha 2-subtype, as was shown by the different antagonistic potencies of yohimbine and prazosin respectively against the agonists methoxamine, clonidine and B-HT 920 (fig. 2). This method was extended to estimate the alpha 1/alpha 2 selectivity ratio of various agonists, by determination of the antagonistic potencies of rauwolscine ( D10R ) and prazosine ( D10P ), and calculating the ratio D10R / D10P (table I). The drugs with highest selectivity towards alpha 2 (B-HT 920) and towards alpha 1 (methoxamine) respectively were used to estimate the relative distribution of alpha 1/alpha 2 receptors ("receptor importance") in various peripheral target organs or systems by determination of the equipotent dose ratios B-HT 920/methoxamine (fig. 3, left). Later, the alpha 1-selective agonist St 587, which easily penetrates into the brain was used instead of methoxamine to estimate the ratio of alpha 1/alpha 2 "receptor importance" for several CNS activities (fig. 2, right). The presence of alpha 2-adrenoceptors in vitro was demonstrated in isolated perfused rat hindquarters after pretreatment with reserpine (fig. 4). The role of alpha-adrenoceptors in the CNS for a certain pattern of cardiovascular depression is reviewed. Stimulation of medullary alpha-adrenoceptors by e.g. clonidine mediates sympathoinhibition and facilitation of the vagally mediated baroreceptor reflex. The receptors concerned are postsynaptic as the effects were demonstrated following the depletion of brain noradrenaline by pretreatment with reserpine and alpha-methyl-p- tyrosin (table II). The receptors mediating central cardiovascular depression are of the alpha 2-type as the highly selective alpha 2-adrenoceptor agonists B-HT 920 and B-HT 933 were active whereas the alpha 1-agonist St 587 was ineffective.

Adrenergic alpha-Agonists↗
PubMed1983

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↗
PubMed1983

Comparison of the bradycardic effects of alinidine (St 567), AQ-A 39 and verapamil on guinea-pig sinoatrial node superfused with different Ca2+ and NaCl solutions.

Two new substances, alinidine (St 567) and AQ-A 39, previously described as 'specific bradycardic agents' were investigated with respect to their effects on the rate of electrical discharges from sinus nodes of isolated right guinea-pig atria. Both substances decreased the discharge rate concentration dependently within a wide range (3-100 micrograms/ml). Low external Ca2+ (0.18 mM) increased and low external NaCl (62 mM) decreased the rate lowering effect of alinidine as well as of AQ-A 39. In contrast, the reference compound verapamil (an inhibitor of slow inward current) was less effective in low Ca2+ and more effective in low NaCl. The similar reactions of alinidine and AQ-A 39 are discussed with respect to their different chemical structure and different electrophysiological action patterns as described so far.

Animals↗
PubMed1982

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↗
PubMed1982

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↗
PubMed1982

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↗
PubMed1981

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↗
PubMed1981

AQ-A 39 (5,6-dimethoxy-2-[3[[alpha-(3,4-dimethoxy)-phenylethyl]methylamino]propyl]phtalimidine), a specific bradycardic agent with direct action on the heart.

In isolated guinea-pig atria AQ-A 39 (5,6-dimethoxy-2[3[[alpha-(3,4-dimethoxy)-phenylethyl]methylamino]propyl]phtalimidine) decreased the rate of spontaneously beating preparations, the contraction amplitude and maximal driving frequency of electrically driven preparations. However, the concentrations which reduced the parameters by 30% were different: 1.4 microgram/ml, 110 microgram/ml and 19 microgram/ml respectively. The bradycardic action was not affected by atropine (0.05 microgram/ml). In the ECG of anaesthetized cats (0.1-10 mg/kg i.v.) the prominent effect of AQ-A 39 was the increase in heart period (PP') and QT in contrast to the chemically related verapamil which mainly increased PQ. Blood pressure and ejection time were slightly affected whereas the diastolic period was markedly prolonged (5 mg/kg i.v.). The 'triple product' of heart rate X ejection time X blood pressure was decreased by AQ-A 39. In cats with acute occlusion of a coronary artery branch, AQ-A 39 diminished the elevation of the ST-segment of the epicardial electrogram. AQ-A 39 decreased the heart rate in conscious dogs (5 mg/kg i.v.), provided the initial heart rate was higher than approximately 130 beats/min, but increased the heart rate when the initial rates were lower. The drug revealed an anticholinergic effect by antagonising the bradycardic action of carbachol on isolated atria from guinea pigs. The prevalent effect on heart rate differentiated AQ-A 39 from other drugs with direct action on the heart such as antiarrhythmics, the so-called 'calcium antagonists' and cholinergic drugs. The profile resembled that of alinidine (St 567) and indicated a decrease in myocardial oxygen demand.

Animals↗
PubMed1981

Modulation of motor activity by alpha 1- and alpha 2-adrenoceptor stimulation in mice.

The influence of two alpha-adrenoceptor agonists, clonidine and B-HT 920, on motor activity was tested in mice. Both, clonidine and B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine) in the dose range 30--300 micrograms/kg s.c. effectively inhibited exploratory activity. On the other hand only clonidine, which stimulates alpha 2- and alpha 1-adrenoceptors increased locomotor activity in mice treated with reserpine (5 mg/kg) and apomorphine (3 mg/kg) in the doses of 0.3 and 1 mg/kg i.p. The highly selective alpha 2-agonist B-HT 920 was ineffective under these conditions up to 30 mg/kg i.p. It is concluded, that in mice "sedative" alpha-adrenoceptors are of the alpha 2- and "excitatory" of the alpha 1-type.

Adrenergic alpha-Agonists↗
PubMed1980

Binding of an imidazolidine (clonidine), an oxazoloazepin (B-HT 933) and a thiazoloazepin (B-HT 920) to rat brain alpha-adrenoceptors and relation to cardiovascular effects.

The specific binding to alpha-adrenoceptors in crude plasma membrane preparations of the rat brain was studied by means of 3H-clonidine (specific radioactivity 26.7 Ci/mmole). Equilibrium binding of 3H-clonidine could be described adequately according to a two-site model with a minor population of high affinity sites (KD1 = 0.4 nM) and a major population of low affinity sites (KD2 = 6.1 nM). The heterogeneity of 3H-clonidine binding was also indicated by a biphasic association rate in kinetic binding studies. In competition experiments with 3H-clonidine concentrations of 0.5 or 4.0 nM respectively, concentration-dependent displacement was observed with the non-radioactive compounds: clonidine, B-HT 920 (2-amino-6-allyl-5, 6, 7, 8-tetrahydro-4H-thiazolo-[5, 4-d]-azepin-dehydrochloride) and B-HT 933 (2-amino-6-ethyl-4, 5, 7, 8-tetrahydro-6H-oxazolo-[5, 4-d]-azepin-dihydrochloride). IC50 values of 3, 21 and 160 nM or 10, 63 and 380 nM respectively were thereby evaluated. Cardiovascular effects were estimated in rats. The blood pressure increase in spinal animals was taken as parameter for alpha-adrenoceptor stimulation at peripheral vascular sites. The bradycardic effect in vagotomized animals was taken as parameter for central nervous sympathoinhibition. The ranking order of the potency of the three drugs was the same in both in vivo tests and parallels the in vitro binding affinities at both binding sites: clonidine greater than B-HT 920 greater than B-HT 933. These results indicate the similarity of the alpha-adrenoceptor structures in brain membrane preparations, at peripheral vascular sites and at central sympathoinhibitory sites.

Animals↗
PubMed1980

Relation between central sympathoinhibitory and peripheral pre- and postsynaptic alpha-adrenoceptors as evaluated by different clonidine-like substances in rats.

A series of 8 clonidine-like substances were tested in rats on central sympathoinhibition (heart rate decrease in vagotomized rats, D50 = dose which decreased heart rate by 50 beats/min), peripheral postsynaptic activity (blood pressure increase in spinal rats, PD30 = dose which increased blood pressure 30 mm Hg) and peripheral presynaptic activity (inhibition of tachycardia as elicited by electrical stimulation in the spinal canal of pithed rats, ID50 = dose which inhibited for 50%). The D50, PD30 and ID50 were converted in moles/kg and the negative logarithms thereof were correlated. There was a good correlation between the central effect (D50) and both peripheral effects (PD30 and ID50, respectively; r = 0.89 and 0.91, respectively) provided one drug with low lipoid affinity was omitted from calculation (St 600). There was also good correlation between both peripheral effects (PD30 and ID50; r = 0.94) and this could be extended to other imidazolines which are not acting centrally as antihypertensives (oxymetazoline, naphazoline, St 91, tramazoline; r = 0.90). The results were interpreted by (1) the agonistic activity of the clonidine-like drugs mainly at alpha 2-adrenoceptors and (2) the presence of alpha 2-adrenoceptors at peripheral presynaptic, peripheral postsynaptic as well as central cardiovascular sites.

Adrenergic alpha-Agonists↗