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Biomedical subjects

W Hoefke

Publications and source records attributed to W Hoefke.

At least 19 recordsLinked to original sources
PubMed1986

Interactions of MEN 935 (adimolol), a long acting beta- and alpha-adrenolytic antihypertensive agent, with postsynaptic alpha-adrenoceptors in different isolated blood vessels--influence of angiotensin II.

MEN 935 [1-(3-[3-(1-naphthoxy)-2-hydroxypropyl) amino)-3,3-dimethylpropyl)-2-benzimidazolinone-hydrochloride monohydrate, adimolol] is a long acting antihypertensive agent with beta- and alpha-adrenolytic properties. Preliminary experiments in pithed rats had led to the suggestion that the alpha-adrenolytic activity was of the alpha 2-subtype. The alpha-adrenolytic properties of MEN 935 were now tested in isolated vascular preparations of rat aorta, rabbit vena ischiadica and rabbit vena cava inferior against the selective alpha 1-adrenergic agonist phenylephrine (PE) and the selective alpha 2-adrenergic agonist B-HT 920 [2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d)azepine]. The experiments were performed in absence and in presence of 5 X 10(-9) mol/l angiotensin II (A II). MEN 935 antagonized contractions to phenylephrine as well as those to B-HT 920 in each vessel. A twofold shift to the right of the concentration-response curves to both agonists was obtained with concentrations between 1.9 X 10(-8) and 1.4 X 10(-5) mol/l, depending on the vessel under investigation. A II modulated the adrenolytic properties of MEN 935 in each vessel. However, irrespective of the presence or absence of A II, no pharmacologically relevant difference between antagonism against PE or B-HT 920 could be seen. In isolated vessels, MEN 935 exerts a nonselective alpha-adrenergic antagonism. In receptor binding studies in rat cerebellar cortex, MEN 935 showed a Ki of 5.2 X 10(-7) mol/l at alpha 1-adrenoceptors and a Ki of 1.3 X 10(-5) mol/l at alpha 2-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1986

General pharmacology of brotizolam in animals.

Brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-1,2,4-triazolo [4,3-a]-1,4-diazepine, We 941, Lendormin) is a thienotriazolo-diazepine with profound sedative and hypnogenic properties. The side effects of the drug on general behavior, motocoordination, feeding pattern, body temperature, uropoietic and gastrointestinal functions, cardiovascular system, and respiration, as well as interactions with some biogenic amines are reported and discussed. The findings correlate with those known for other diazepines. Accordingly, effects on motocoordination were prominent, but were limited to an ataxia, whereas even extremely high doses scarcely eliminated the postural reflexes. Sleeping animals could invariably be woken and were capable of locomotion; thus, no comatose condition developed. The cardiovascular functions were not appreciably altered by brotizolam in anesthetized cats, while in conscious dogs minor fluctuations of blood pressure and heart rate occurred. Respiration was clearly inhibited when brotizolam was given intravenously. The cardiovascular effects of acetylcholine, norepinephrine, epinephrine, isoprenaline, and histamine were only slightly modulated. The orexigenic and hypothermic effects equalled those of other diazepines. The functions of kidney, stomach, and intestines were not affected. The entirety of the observations procured in ten different species suggest that brotizolam is well tolerated when given orally.

Animals↗
PubMed1985

Atrial natriuretic factor.

Mammalian atria contain different peptides with potent diuretic, natriuretic, smooth muscle relaxing and blood pressure lowering properties. A preprohormone of these peptides is synthetized and stored in specific granules in atrial myocytes. Different peptides have been isolated, analyzed and in vitro synthetized. Their biological activity indicates a potential role in the regulation of volume and sodium homeostasis as well as in blood pressure regulation.

Amino Acid Sequence↗
PubMed1985

Postjunctional alpha-adrenoceptors and influence of angiotensin II in different isolated blood vessels.

The effects of the selective alpha 1-and alpha 2-adrenergic agonists phenylephrine and B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine) and the respective antagonists prazosin and yohimbine on smooth muscle activity of isolated rat aorta, rabbit vena cava inferior and rabbit vena ischiadica have been investigated. In addition, the influence of angiotensin II on the effects of these agonists and antagonists was evaluated. Among the two agonists phenylephrine was the most potent in the rat aorta and B-HT 920 in the two venous vessels. Prazosin and yohimbine revealed a competitive antagonism against both agonists in all three vessels. No differentiation between alpha 1- and alpha 2-adrenoceptor mediated responses was seen in rat aorta and rabbit vena ischiadica. In the rabbit vena cava, prazosin was more potent against phenylephrine than against B-HT 920 whilst yohimbine was more potent against B-HT 920 than against phenylephrine, thus pointing to the existence of functional alpha 1- and alpha 2-adrenoceptors. Angiotensin II (5 X 10(-9) mol/l) induced sustained contractions in rat aorta and transient contractions of different relative magnitude in the veins. Angiotensin II pretreatment increased the potency of phenylephrine in all vessels with no influence on maximum contraction. B-HT 920 potency was increased in the vein preparations; maximum contractions were increased in rat aorta, decreased in rabbit vena cava and not influenced in rabbit vena ischiadica.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1985

The influence of metabolic degradation on the blood pressure lowering effect of clonidine in rabbits after different routes of administration.

In rabbits, clonidine (200 micrograms/kg) exerted no blood pressure lowering effect after oral administration contrary to the strong decrease in blood pressure after i.v. injection. This surprising effect induced experiments on metabolic degradation of clonidine in the rabbit. After oral administration 14C-clonidine was rapidly almost totally metabolised and only minimal concentrations could be detected in the brain. In the urine (24-h collection) no clonidine was detected after oral dosing. In contrast, 15 min after i.v. injection 30% of radioactivity was unchanged clonidine in the plasma. In the brain 70% of the radioactivity during the first 2 h was clonidine. In accord with this, in the urine 22% of the dose administered was excreted as clonidine. From these experiments it is concluded that predominantly unchanged clonidine penetrates the blood-brain barrier. So the lack of effect after oral clonidine depends on the too low concentration of clonidine in the brain. To assess the pharmacological activity of clonidine metabolites identified in rabbit and other species including man, seven different compounds were injected to rabbits either systemically (i.v.) or intracisternally (i.c.i). Only p-hydroxy-clonidine-hydrobromide (St 666) induced weak blood pressure decreases after i.v. and strong ones after i.ci. injection, but to a lesser extent than clonidine itself.

Administration, Oral↗
PubMed1985

Structure-activity relationship in clonidine-like 2,3-disubstituted 2-aryl-imino-imidazolidines.

In anaesthetized rabbits the hypotensive activity of a group of 2,3-disubstituted 2-aryl-imino-imidazolidines was estimated. Compounds with 3-bromo substituents at the phenyl moiety of the molecule are more than or as active as clonidine. Correlations between blood pressure lowering effect and lipophilicity, maximum alpha-adrenergic effects (alpha E') and -log ED50 (pD2') of blood pressure increase in spinalized rats and pKA were calculated. The results show a positive linear correlation between as well partition coefficient as alpha E' and hypotension. The relationship between pD2' and hypotensive. effect is less prominent. pKA seems to have no influence on the blood pressure effects of these compounds.

Animals↗
PubMed1977

[Problems in preclinical pharmacology when deciding on suitable animal species and animal tests models].

The significance of procedures used in animal experiments for the development of new pharmaceutical agents is demonstrated on selected examples. Particular attention is given to the different degrees of sensitivity in the various species to new compounds, which are dependent on several factors such as absorption, metabolism, distribution and excretion. Comparing findings obtained in animal experiments with unknown compounds to those of standard substances facilitates extrapolation to man.

Animals↗
PubMed1977

Influence of central pretreatment with 6-hydroxydopamine on the hypotensive effect of clonidine.

Intracisternal (i.ci.) pretreatment of rabbits with 6-hydroxydopamine (6-OH-DA) (3 times 0.5 mg/kg) reduced the norepinephrine content of the brainstem significantly by 52% but did not diminish the hypotensive and bradycardiac action of 2-(2,6-dichloroanilino)-2-imidazoline (clonidine; Catapresan; Catapres) (doses 10, 30 and 100 microgram/kg i.v. and 1 microgram/kg i.ci.) in anaesthetized animals. Pretreatment with 6-OH-DA did not abolish the enhancement by clonidine (100 microgram/kg i.v.) of reflex bradycardia elicited by angiotensin 0.2 microgram/kg i.v. The conclusion is drawn that clonidine acts directly on central alpha-adrenergic receptors independent of storage and synthesis of endogenous catacholamines in the central adrenergic neurons.

Animals↗
PubMed1975

Relationship between activity and structure in derivatives of clonidine.

2-(2,6-Dichlorphenylamino)-(clonidine, Catapresan, Catapres), 2-(2,6-diethylphenylamino- (St 91), 2-(2-chloro-6-methylphenylamino)-, 2-(2-chloro-4-methylphenylamino)-, 2-(2-methyl-5-fluorophenylamino) -and 2-(2-chloro-3-methyl-phenylamino)-2-imidazoline were investigated in various pharmacological tests. 1. All substances increased blood pressure in spinal rats and initially in intact cats and dogs and increased the total peripheral resistance in the latter. As these compounds also showed mydriasis in conscious rats it has been concluded that these effects are due to stimulation of peripheral alpha-adrenoceptors. 2. With the exception of St 91 the substances lowered blood pressure following i.v. injection, they decreased heart rate in cats and dogs and the cardiac output in the latter. These four compounds also decreased heart rate in vagotomised and atropinised rats. It was concluded that these effects were due to a decrease in sympathetic activity of the CNS. 3. In anaesthetised rats with beta-adrenoceptor blockade by toliprolol, a blood pressure increase was elicited by i.v. injection of angiotensin and the resulting bradycardia was recorded as a measure of vagal reflex activity. Clonidine and three derivatives which have shown hypotensive activity facilitated the vagal cardiodepressor reflex; St 91 was inactive in this respect. It has been concluded that decrease in central sympathetic tone and increase in central vagal activity are linked together in these compounds. 4. St 91 did not lower blood pressure and did not facilitate vagal reflex bradycardia after i.v. injection in dogs, but was active after intracisternal injection. It has been concluded, therefore, that this compound is able to act on structures in the CNS like clonidine but these effects usually do not occur after systemic administration because of its poor ability to penetrate the blood-brain barrier. 5. All derivatives decreased gastric acid secretion. 6. All substances increased blood glucose levels and were sedative; St 91 was the least effective compound in both respects pointing to a central mediation of these effects. 7. The results show that clonidine and the derivatives tested have the same reaction pattern. 8. The relationship between the CNS mediated cardiovascular depression and the peripheral alpha-adrenergic stimulating potency in conjunction with the lipoid solubility have been discussed.

Animals↗