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W J Janssens

Publications and source records attributed to W J Janssens.

18 recordsLinked to original sources
PubMed1992

In vitro pharmacology of R 80122, a novel phosphodiesterase inhibitor.

The cardiac in vitro effects of R 80122, a novel phosphodiesterase (PDE) inhibitor, were investigated and compared with those of the reference compound milrinone and of the calcium-sensitizer adibendan. In guinea pig left atria, both milrinone and R 80122 increased contractile force; 10 microM milrinone was equieffective to 1 microM R 80122. The rate of spontaneously beating atria was not altered by R 80122 in the concentration range of 0.01-0.3 microM. Higher concentrations (1-10 microM) led to a statistically insignificant increase of 20%. Milrinone's effect on frequency was more pronounced and amounted to 21% at 10 microM and to 40% at 100 microM. Adibendan increased heart rate (HR) by 10% at a concentration of only 0.03 microM. This effect was not enhanced any further by increasing the concentration. In papillary muscle, the positive inotropic effects of both milrinone and R 80122 were inhibited by carbachol, indicating involvement of cyclic AMP. Further indications for a cyclic AMP-dependent action were obtained by induction of slow action potentials and synergism with isoprenaline. In electrophysiologic measurements, milrinone reduced action potential duration (APD) in a high concentration whereas R 80122 had no effect. Action potential changes elicited by a toxic concentration of ouabain were reduced by R 80122. Relaxation of rat aortic rings contracted by KCl and relaxation of guinea pig aortic rings contracted by norepinephrine (NE) was comparable for both milrinone and R 80122. R 80122 also caused relaxation of canine coronary arteries constricted with prostaglandin F2 alpha (PGF2 alpha) both with and without endothelium. NE-induced contractions in canine gastrosplenic arteries were not affected by R 80122. Cardiac contractility that had been impaired to various degrees by pentobarbital or by aging was restored to control values by both milrinone and R 80122. R 80122 enhanced cardiac contractility at lower concentrations than milrinone with no concomitant increase in frequency or shortening of the action potential, which may be advantageous for treatment of heart failure.

Action Potentials↗
PubMed1991

Nebivolol induces endothelium-dependent relaxations of canine coronary arteries.

Nebivolol is a new beta 1-antagonist that acutely reduces arterial blood pressure without depressing cardiac function. The present study was designed to determine the effect of nebivolol on coronary arteries. Rings of canine left anterior descending coronary (LAD) artery with or without endothelium were suspended in organ chambers and the isometric tension was recorded. In some experiments, the transmembrane potential of the smooth muscle cells was recorded by electrophysiological methods. During contractions to prostaglandin F2 alpha, nebivolol induced concentration-dependent relaxations of the coronary arteries. The enantiomer, l-nebivolol, also induced comparable relaxations; however, d-nebivolol induced smaller relaxations. The relaxations induced by nebivolol and its enantiomer were significantly larger in tissues with than in those without endothelium. The differences between tissues with and without endothelium were abolished by nitro-L-arginine (3 x 10(-5) M) or methylene blue (10(-5) M). The nebivolol-induced relaxations were not affected by indomethacin (10(-5) M), phentolamine (5 x 10(-6) M), propranolol (5 x 10(-6) M), or methysergide (3 x 10(-6) M). Nebivolol at a subthreshold concentration for inducing relaxation (3 x 10(-7) M) did not significantly affect endothelium-dependent relaxations to acetylcholine but potentiated ADP-induced endothelium-dependent relaxations. The potentiation is stereoselective for l-nebivolol. Nebivolol induced a small hyperpolarization of the coronary smooth muscle with endothelium (1 mV).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
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↗
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↗
PubMed1988

Calcium antagonism and vascular smooth muscle.

Vasoconstriction results from an exaggerated increase of intracellular Ca2+ concentration which initiates the contractile process within the vascular smooth muscle. The dependency of these cells on extracellular Ca2+ to trigger the contractile process when exposed to naturally occurring vasoactive substances such as those released from aggregating blood platelets varies in different vascular areas. This is one of the factors that determine the different sensitivity to the inhibitory effect of various calcium antagonist. A blood vessel can be more reactive to some calcium antagonists than to others, depending on the vascular area. Experiments on isolated cerebral arteries suggest that inhibition of cerebral vasoconstriction is observed with substances such as flunarizine under conditions of vascular hyperresponsiveness generated by acute or chronic pathological conditions or triggered by interaction between vasoactive substances. In this regard marked differences exist between the individual calcium antagonists. Those that are selective for slow Ca2+ channels will inhibit myocardial contractile force and decrease vascular myogenic activity (e.g., at the arteriolar level). Such inhibitory activity is not observed with flunarizine, which affects Ca2+ entry rather selectively, when calcium overload is imposed upon the vasculature, in particular at cerebrovascular sites. This suggests a potential use of this compound in a number of neurological disorders related to cerebral ischemia.

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↗
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↗
PubMed1978

Instantaneous changes of alpha-adrenoceptor affinity caused by moderate cooling in canine cutaneous veins.

Experiments were performed to investigate why cooling augments the contractile responses of superficial veins, but depresses that of deep limb veins. Rings of dog's saphenous veins were mounted in an organ chamber for isometric tension recording. Cooling (from 37 to 24 degrees C) depressed the tissular uptake of [3H]norepinephrine and potentiated the contraction caused by norepinephrine and sympathetic nerve stimulation; this potentiation persisted after inhibition of the disposition mechanisms for the catecholamine and in the presence of ouabain or iproveratril. The affinity of the alpha adrenoceptors, to judge from the KA values for norepinephrine and from the pA2 values for the competitive antagonist phentolamine, was significantly greater at 24 degrees C than at 37 degrees C. Thus, an instantaneous change in the affinity of alpha adrenoceptors explains the augmented response of the cutaneous veins to adrenergic stimulation. By contrast, cooling depressed the response of femoral veins to norepinephrine and did not significantly affect the affinity of alpha adrenoceptors in this preparation, indicating that the temperature sensitivity of alpha adrenoceptors in cutaneous veins is related to chronic exposure to variations in local temperature.

Animals↗
PubMed1977

Alpha-adrenergic blocking properties of droperidol on isolated blood vessels of the dog.

Concentrations of droperidol which caused a shift to the right of the dose-response curve to noradrenaline in the pulmonary artery and the saphenous vein of the dog did not affect myogenic activation by K+; they did not inhibit spontaneous activity of portal-mesenteric veins. Droperidol inhibited the contractile response to nerve stimulation, but did not affect the evoked release of 3H-noradrenaline. These experiments indicate that the vasodilator properties of smaller doses of droperidol are a result of its ability to block alpha-adrenergic receptors.

Adrenergic alpha-Antagonists↗
PubMedDate not supplied

Pharmacology of nebivolol.

Nebivolol is a mixture of equal amounts of two enantiomers: SR3-nebivolol (d-nebivolol) and RS3-nebivolol (l-nebivolol). SR3-nebivolol is a potent and selective beta 1-adrenergic antagonist both in vitro and in vivo. Nebivolol acutely lowers blood pressure in spontaneously hypertensive rats and induces a slight decrease in total peripheral vascular resistance and a slight increase in cardiac output in anaesthetised dogs. These hemodynamics effects cannot be explained by beta 1-adrenergic antagonism and are largely attributable to RS3-nebivolol.

Adrenergic beta-Antagonists↗