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Biomedical subjects

J M Van Nueten

Publications and source records attributed to J M Van Nueten.

At least 19 recordsLinked to original sources
PubMed1990

Effect of ridogrel on vascular contractions caused by vasoactive substances released during platelet activation.

Ridogrel (6.3 x 10(-6) to 10(-4) M) inhibited contractions of isolated rat caudal arteries and rabbit femoral arteries caused by U-46619. The slope of an Arunlakshana-Schild plot (pA2-value: 3.4 x 10(-6) M) on the caudal artery was slightly higher than one (1.14). This effect was maximal within 20 min of incubation of the blood vessel with the compound and easily reversible. Ridogrel antagonised contractions of isolated rabbit femoral arteries caused by prostaglandin F2 alpha in the same concentration range. Ridogrel also inhibited contractions induced by aggregating rat platelets on isolated rat caudal arteries (in the presence of ketanserin 4 x 10(-7) M) and on isolated rabbit pulmonary and femoral arteries (in the absence of ketanserin). Ridogrel had no effect on Ca2(+)-induced contractions in depolarised isolated rabbit femoral arteries, and at 10(-4) M antagonised serotonin-induced contractions in this blood vessel. Its effect on serotonin-induced contractions was statistically significant but very small on isolated rat caudal arteries. These observations indicate that ridogrel is an antagonist of prostaglandin endoperoxide/thromboxane A2 and prostaglandin F2 alpha receptors on vascular smooth muscle.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

R 50 595, a selective non-competitive antagonist of cisapride, BRL 24924 and 5-hydroxytryptamine on the guinea-pig ileum.

5-Hydroxytryptamine and substituted benzamides such as cisapride and BRL 24924 enhance the twitch responses of the electrically stimulated longitudinal muscle-myenteric plexus preparation of the guinea-pig. The effects of these benzamides and 5-HT could possibly be mediated via similar receptor-effector systems. The aim of our study was therefore to determine whether R 50 595, an analogue of cisapride devoid of intrinsic activity, could specifically interfere with the effects of cisapride and BRL 24924 and if so, whether it would also affect the responses to serotonin. R 50 595 had no effect on the twitch responses of the electrically stimulated preparation up to a concentration of 3 X 10(-7) M. Cisapride and BRL 24924 both enhanced the contractile response to electrical stimulation by a maximum of 37 +/- 7% at 3 X 10(-7) M for cisapride and 36 +/- 6% for BRL 24924, also at 3 X 10(-7) M. R 50 595 (10(-7)(-3) X 10(-7) M) antagonized the effects of cisapride and BRL 24924 in a non-competitive way. 5-HT enhanced the contractile responses by a maximum of 24 +/- 3.2% at 3 X 10(-8) M. The effects of 5-HT were completely abolished at a concentration of 3 X 10(-7) M R 50 595. R 50 595 also antagonized the effects of 5-HT in a non-competitive way.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Nebivolol is devoid of intrinsic sympathomimetic activity.

Nebivolol is a chemically novel, potent and selective beta 1-adrenoceptor-blocking agent that acutely lowers arterial blood pressure in hypertensive patients and rats without depressing, or even enhancing, left ventricular function. These properties could be compatible with a partial agonistic effect of beta-adrenoceptor-blocking agents. It was the aim of the present study to investigate whether nebivolol has intrinsic sympathomimetic properties. The study was performed on reserpinized dogs and spontaneously hypertensive rats, and on various isolated tissues from various species. Unlike pindolol and practolol, nebivolol did not exert a stimulating effect on the heart rate and left ventricular function in reserpinized animals and/or in isolated atria of reserpinized rats at doses that are clinically active. Nebivolol did not induce relaxation of isolated coronary arteries and saphenous veins at concentrations that block beta-adrenoceptors. These findings indicate that nebivolol is devoid of intrinsic sympathomimetic activity at clinically relevant doses.

Adrenergic beta-Antagonists↗
PubMed1989

Computer-assisted method for the analysis of postprandial gastrointestinal motility in conscious dogs.

A fully automated system to quantify different parameters of gastrointestinal motility and gastroduodenal co-ordination in conscious dogs was designed and built around a personal technical computer (HP 9816). Online it performs sampling of contractions on four different sites of the digestive tract for two dogs simultaneously, data reduction, drift correction and storage of data on hard disk. Offline it performs baseline determination, peak detection, calculation of motility parameters such as amplitude and interval, plus co-ordination between gastric and duodenal motility and presentation of the results in both tabular and graphic form. To illustrate the possibilities and advantages of the computer analysis the early postprandial motor patterns for antrum, duodenum and jejunum were quantified during the first hour after administration of a small test meal.

Animals↗
PubMed1988

Prejunctional muscarinic (M1)-receptor interactions on guinea-pig ileum: lack of effect of cisapride.

UNLABELLED: 1. Cisapride stimulates gastrointestinal motility, probably by enhancing the release of acetylcholine from myenteric nerve endings. Such an effect could be mediated via presynaptic muscarinic (M1)-receptors. Our aim was to determine whether cisapride could antagonize the inhibitory effects of a M1-agonist, McN-A-343 or mimic the effects of a M1-antagonist, pirenzepine. 2. Longitudinal segments were suspended in Krebs solution (95% O2, 5% CO2, 37.5 degrees C) for isometric tension recording (preload 1 g) during electrical transmural stimulation (0.1 Hz, 1 ms, sub- or supramaximal current). 3. McN-A-343 (2.0 x 10(-6) M) reduced the contractile response to supramaximal stimulation (EC50 = 1.6 x 10(-6) M), but had no effect on the contractions induced by exogenous acetylcholine. 4. The inhibitory effect of McN-A-343 on the contractile response to electrical stimulation could be reversed by pirenzepine (EC50 = 1.6 x 10(-8) M) but not by atropine. At these concentrations pirenzepine itself did not modify the contractile response to electrical stimulation. However, at 50 times higher concentrations pirenzepine inhibited the response to electrical stimulation as well as the response to exogenous acetylcholine (EC50 = 8.5 x 10(-7) M). 5. Cisapride enhanced the contractile response to submaximal electrical stimulation by 49 +/- 10%. This stimulating effect of cisapride was not affected by the presence of pirenzepine but was reduced in the presence of McN-A-343 (22 +/- 7%). 6. IN CONCLUSION: the effects of McN-A-343 and pirenzepine on the electrically stimulated guinea-pig ileum are compatible with an interaction on presynaptic muscarinic-(M1)-receptors. Cisapride enhances the twitch amplitude via mechanisms independent of such M1-receptor interactions.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1988

Cerebral antivasoconstrictive effects of flunarizine.

Flunarizine is a selective Ca++-antagonist with weaker H1-histaminergic antagonistic properties. Flunarizine reduces vasospasm caused by an exaggerated Ca++-influx in depolarized arteries and by vasoactive substances released from aggregating platelets. This Ca++-antagonist also antagonizes the mutual amplification of the vasoconstrictor action of the platelet products. Flunarizine is particularly effective in the cerebral blood vessels, also when they are hyperreactive because of hypoxia. The compound does not interfere with normal arteriolar autoregulation or heart function. Thus flunarizine may be particularly effective in preventing vasospasm without lowering blood pressure or inducing a steal phenomenon.

Animals↗
PubMed1988

Interaction between S2-serotonergic and alpha 1-adrenergic receptor activities at vascular sites.

Serotonin enhances (amplifies) the vasoconstrictor effect of norepinephrine not only on isolated large blood vessels and isolated perfused vascular beds but also in vivo. This amplification can be observed with endogenous serotonin released from aggregating platelets and with endogenous norepinephrine released from the adrenergic nerves in the blood vessel wall. It is due to an interaction between S2-serotonergic and alpha 1-adrenergic mechanisms. Combined S2-serotonergic and alpha 1-adrenergic antagonism is more effective than either one alone against contractions evoked with the combination of serotonin and an alpha 1-adrenergic agonist. In spontaneously hypertensive rats, S2-serotonergic antagonism alone does not reduce blood pressure but combined S2-serotonergic and alpha 1-adrenergic blockade lowers blood pressure more than alpha 1-adrenergic blockade alone. This suggests that the interaction between S2-serotonergic and alpha 1-adrenergic vasoconstrictor responses may play a role in the maintenance of high blood pressure.

Animals↗
PubMed1988

Pharmacokinetic evaluation of the in vitro and in vivo pharmacological profile of the major metabolites of ketanserin in the rat.

In order to explain the differences between the in vitro and in vivo pharmacological activity of two major metabolites of ketanserin [+)-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]-2,4(1H,3H)-quinazolinedione , R 41 468), viz. 6-hydroxyketanserin and ketanserin-ol, the pharmacokinetics of ketanserin and both metabolites were studied after oral and subcutaneous administration to male Wistar rats. The intrinsic potency of 6-hydroxyketanserin as a serotonin S2-antagonist is similar to that of ketanserin, as assessed by receptor-binding and pharmacological studies in vitro. In vivo, both substances are equipotent after s.c. administration, but 6-hydroxyketanserin is shorter acting and has a weak oral activity. In vitro studies indicated that ketanserin-ol is 2-3 orders of magnitude less potent than ketanserin and 6-hydroxyketanserin, but its in vivo activity is higher than could be expected from the in vitro studies. When ketanserin was administered to rats, only ketanserin and none of the metabolites was detected in plasma, indicating that the parent drug is the pharmacologically active substance. After s.c. administration of 6-hydroxyketanserin, its plasma levels decreased rapidly, explaining its short duration of action. The oral bioavailability of 6-hydroxyketanserin was very low, accounting for its low in vivo activity after oral administration. The rapid elimination and the low bioavailability of 6-hydroxyketanserin are explained by hepatic conjugation and subsequent biliary excretion. After administration of ketanserin-ol to rats, the metabolite was converted in vivo to ketanserin giving much higher plasma levels for ketanserin than for ketanserin-ol.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1987

Vasoconstrictor expression of human platelet-vessel wall interactions: inhibition by the Ca2+ entry blocker flunarizine.

Human blood platelets, stimulated with thrombin, induced contractions of isolated basilar artery segments of the dog. These platelet-mediated vascular contractions were inhibited in a concentration-dependent way by flunarizine, a Ca2+ entry blocker, selective for vascular tissues (IC50: 5.5 X 10(-7) M). This inhibition increased gradually as a function of the time contact with flunarizine, to reach its maximum after 60-90 min. Biochemical and pharmacological analyses using the S2-serotonin receptor antagonist ritanserin, the thromboxane A2/prostaglandin endoperoxide antagonist BM 13.177 and the fatty acid cyclo-oxygenase inhibitor suprofen showed that 5-hydroxytryptamine and prostanoids (thromboxane A2, prostaglandin endoperoxides) were the main mediators involved. The results further suggested amplification between the vascular effects of 5-hydroxytryptamine and prostanoids. Flunarizine did not affect the release of 5-hydroxytryptamine from platelets and did not interfere with their biosynthesis of thromboxane A2.

Animals↗
PubMed1986

The direct and amplifying effects of serotonin are increased with age in the isolated perfused kidney of Wistar and spontaneously hypertensive rats.

Isolated kidneys of Wistar rats and spontaneously hypertensive rats (SHR) were perfused with Tyrode's solution. In 2- and 6-month old SHR, the maximal increase in perfusion pressure caused by norepinephrine was higher than in 2- and 6-month old Wistar rats, but the sensitivity, as judged from the dose of the agonist required to reach 50% of the maximal response was the same. Both the maximal response and the sensitivity to serotonin were significantly augmented in 6-month old SHR and Wistar rats when compared to the young animals. This hypersensitivity was more pronounced in SHR than in Wistar rats. Infusion of serotonin potentiated the vasoconstriction induced by a bolus of norepinephrine. This amplification, due to activation of S2-serotonergic receptors, was more pronounced in the old animals. No amplification occurred when norepinephrine was infused instead of serotonin. Tachyphylaxis to the amplifying effect of serotonin was observed and was less pronounced in kidneys from old than from young animals. The amplifying effect of serotonin was inhibited by ketanserin at concentrations which did not, or only moderately, inhibit the response to norepinephrine.

Aging↗
PubMed1986

Augmentation of vasoconstrictor responses to serotonin by acute and chronic factors: inhibition by ketanserin.

Serotonin induces constrictor responses on smooth muscle tissues from several vascular regions mainly by its interaction with serotonin-S2 receptor sites. The individual sensitivity of various blood vessels to serotonin may vary considerably. Serotonin (e.g. released from aggregating platelets) also induces vascular contractions by amplifying the response to other vasoactive substances. The vascular reactivity to serotonin can be markedly augmented by acute hypoxia (95% N2, 5% CO2; canine coronary arteries) and by cooling from 37 degrees to 29 degrees C (rabbit tibial and canine saphenous arteries). Blood vessels become hyperreactive to the vasoconstrictor component of serotonin in a number of disease states. Isolated perfused kidneys from spontaneously hypertensive rats (SHR) exhibit direct and indirect (amplifying) vasoconstrictor responses to serotonin. The amplifying effect of serotonin is significantly more pronounced in 6-month-old than in 2-month-old SHRs. Both the direct and indirect vasoconstrictor responses to serotonin, whether or not augmented by acute or chronic conditions, are inhibited by the serotonin-S2 receptor antagonist, ketanserin (4 X 10(-10) to 4 X 10(-7) mol/l). Both the hypersensitivity of vascular tissue to serotonin and the amplifying effect of the amine may greatly contribute to hypertension and other cardiovascular disorders.

Animals↗
PubMed1985

Serotonin and vascular reactivity.

Serotonin causes contraction of the vascular smooth muscle cells in most blood vessels studied in vitro. This contraction is mainly due to activation of S2-serotonergic receptors. The monoamine can cause relaxation through activation of serotonergic receptors, different from the S2-serotonergic receptor and located on endothelial cells, or through an inhibitory effect on adrenergic neurotransmission. In certain blood vessels, the contractile effects can be markedly enhanced by hypoxia or moderate cooling. At low concentrations serotonin amplifies the vasoconstrictor responses to other vasoactive substances. Ultimately the effect of serotonin on vascular constriction is defined by the balance between these different actions. In the intact organism under normal conditions serotonin may play a modulatory role but exacerbation of the contractile effects because of hypersensitivity of the smooth muscle cells, local physical or humoral factors or loss of the relaxatory ability may lead to abnormal tissue responses. Thus, serotonin-induced vasoconstrictor responses may play a role in the etiology of vasospasm and peripheral vascular diseases, in particular at sites of endothelial lesions. Both the vasoconstrictor and the platelet aggregating effects of serotonin combined with its accelerated turnover may be important in the induction and maintenance of the augmented peripheral vascular resistance in arterial hypertension.

Animals↗
PubMed1985

Serotonin and the blood vessel wall.

When the local concentration of serotonin is raised during platelet aggregation, the direct effect of serotonin on vascular smooth muscle is to activate the contractile process. Serotonin also amplifies the constrictor responses to other neurohumoral mediators. Vascular smooth muscle can become hyperreactive to the vasoconstrictor effects of serotonin both acutely (e.g., local cold, hypoxia) and chronically (e.g., atherosclerosis, hypertension). Vasodilator responses to serotonin can be unmasked by blockade of its vasoconstrictor component. The inhibition by ketanserin of the various vasoconstrictor and platelet-aggregating effects of serotonin presumably contributes to the therapeutic effects of the compound.

Animals↗
PubMed1985

A comparative study on the effects of domperidone, metoclopramide, clebopride and trimebutine on the gastro-duodenal preparation of the guinea pig.

UNLABELLED: Domperidone (dopamine antagonist), metoclopramide and clebopride (both dopamine antagonists and stimulators of the intramural cholinergic system), and trimebutine (spasmolytic) are used in the treatment of digestive disorders such as dyspepsia or gastritis. Our aim was to compare the effects of these compounds on the isolated intact gastroduodenal preparation of the guinea pig. Domperidone (IC50 = 10(-6) M), clebopride (10(-5) M) and metoclopramide (2 X 10(-5) M) antagonized gastric relaxations induced by dopamine. In contrast with clebopride, domperidone and metoclopramide enhanced the amplitude of gastric contractions, moderately reduced contractile frequency, and enhanced antroduodenal coordination in a dose-dependent manner (EC50 for domperidone 3 X 10(-7) M, for metoclopramide 2 X 10(-5) M). Trimebutine reduced gastric spontaneous activity and antroduodenal coordination. Trimebutine had a direct relaxatory effect on gastric tone (EC50 = 4 X 10(-6) M). The mechanism of this inhibitory effect remains unknown but our data indicate that it is not mediated via dopamine or opiate receptor subtypes. CONCLUSION: domperidone, clebopride, metoclopramide and trimebutine exert distinct and diverse effects on the motility parameters of the gastroduodenal preparation of the guinea pig. These diverging actions may help explain the differences in patients' responsiveness to the treatment of digestive disorders such as dyspepsia or gastritis.

Animals↗
PubMed1985

Motor-stimulating properties of cisapride on isolated gastrointestinal preparations of the guinea pig.

The effects of cisapride (R 51619), a new non-dopamine-blocking gastrokinetic drug, on gastrointestinal contractility have been determined on isolated preparations of the guinea pig. On the intact gastroduodenal preparation, cisapride enhanced contractile amplitude (3.4 X 10(-7) M), improved antroduodenal coordination (EC50 = 1.9 X 10(-7) M) and antagonized gastric relaxation induced by phenylephrine, dopamine, isoproterenol, 5-hydroxytryptamine (in the presence of atropine) and periarterial nerve stimulation (IC50 range, 9.1 X 10(-7)-2.4 X 10(-6) M). Experiments with metoclopramide yielded similar results on amplitude, coordination and dopamine-induced relaxation at 5 X 10(-5), 2.2 X 10(-5) and 1.7 X 10(-5) M, respectively. On the ileum, cisapride enhanced the contractile response to electrical stimulation at low concentrations (EC50 = 9.2 X 10(-9) M) as compared with metoclopramide (EC50 = 3.3 X 10(-6) M). On this preparation, cisapride showed no direct cholinergic or nicotine-like effects and did not enhance the response to methacholine (indicative of a lack of inhibition of acetylcholinesterase-activity and of sensitization of the muscarine receptor). On the colon ascendens, cisapride induced contractions (EC50 = 3.5 X 10(-8) M) (metoclopramide, 3.5 X 10(-6) M), insensitive to atropine and only marginally inhibited by tetrodotoxin. In conclusion, cisapride effectively improves spontaneous or electrically evoked contractions of isolated preparations of the guinea pig, most likely via facilitation of the release of acetylcholine. However, the inhibition of gastric relaxation and the induction of colonic contractions in the presence of atropine indicate that, besides cholinergic neuronal pathways, other mechanisms are involved in the motor-stimulating properties of cisapride.

Acetylcholine↗
PubMed1984

Ketanserin and vascular contractions in response to cooling.

Rings of tibial arteries of the rabbit were suspended for isometric tension recording in organ chambers filled with oxygenated physiological salt solution. 5-Hydroxytryptamine caused contractions which were enhanced by cooling from 37 to 29 degrees C. Both the contractions induced by 5-hydroxytryptamine and their augmentation by cooling were inhibited by similar concentrations of the serotonergic 5-HT2 antagonist ketanserin. These experiments demonstrate that cooling augments the responsiveness of peripheral arteries to 5-hydroxytryptamine and that the augmentation is mediated by 5-HT2 serotonergic receptors.

Animals↗