J.M. Van Nueten

Serotonergic receptor subtypes and vascular reactivity

Two distinct binding sites for serotonin have been identified in brain tissue and labeled 5-HT1 and 5-HT2 binding sites. The receptor mediating contractions of several types of vascular smooth muscle (including the canine basilar artery), aggregation of blood platelets, and contractions of tracheal muscle can be defined as a 5-HT2 serotonergic receptor. The prejunctional inhibitory effect of serotonin on adrenergic neurotransmission is mediated by receptors which have the same affinity for agonists as the 5-HT1 binding sites. The other peripheral actions of serotonin, in particular its vasodilator effects and its excitatory effects on gastrointestinal smooth muscle, do not involve 5-HT2 serotonergic receptors.

Platelet-vessel wall interactions: Implication of 5-hydroxytryptamine. A review

The evidence for an impact of platelet-derived 5-hydroxytryptamine (5-HT) on local tissue perfusion is reviewed. By interacting with 5-HT2 serotonergic receptors, 5-HT, directly or through amplification, activates platelets, endothelial and vascular smooth muscle cells producing platelet aggregation, vascular permeability increase and large vessel constriction. Pharmacodissection in experimental animals with selective serotonergic 5-HT2 receptor antagonists, e.g. ketanserin, shows that 5-HT largely contributes to the platelet-mediated increase in vascular permeability, to platelet-vessel wall interaction during hemostasis, to cardiopulmonary dysfunction provoked by thromboembolism and to the platelet-mediated inhibition of peripheral collateral circulation. Clinical results obtained with ketanserin further substantiate an involvement of platelet-derived 5-HT in the pathogenesis of impaired tissue perfusion in some cardiovascular conditions.

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.

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.

Oxatomide, a new orally active drug which inhibits both the release and the effects of allergic mediators.

Oxatomide is a new potent inhibitor of anaphylactic and allergic reactions. After oral administration, the compound both inhibits the release of endogenous histamine and prevents the effects of exogenous histamine, at comparable doses. The combination of these effects appears to be the basis of the effectiveness of oxatomide in allergic reactions and may lead to clinical applications different from classical antihistaminics and from cromoglycate.

Comparative bioassay of vasoactive drugs using isolated perfused rabbit arteries

Abstract A simple and reliable assay technique for vasoactive drugs is described. Using KCl-depolarised central artery preparations from the rabbit ear, and saphenous artery preparations from the hind leg, the following drugs were assayed for potency, rate of onset and duration of action (in inhibiting KCl-depolarisation-induced vasoconstriction): papaverine hydrochloride, cyclandelate (Cyclospasmol®), cinnarizine (Stugeron®), xanthinol niacinate (Complamin®) and dihydroergotoxine methanesulphonate - DEM - (Hydergin®). The effects of the drugs on the two types of preparation were similar. For the central artery, potency decreased in the order: cinnarizine > papaverine > DEM > cyclandelate > xanthinol niacinate, duration of action in the order: cinnarizine > cyclandelate > xanthinol niacinate > papaverine > DEM, and speed of onset of action in the order: DEM > papaverine > xanthinol niacinate > cyclandelate > cinnarizine.

Mechanisms of Vasodilatation and Antivasoconstriction

It is debatable whether vasodilator therapy is beneficial in patients with severe obstruction of arterial inflow to peripheral tissues. However, there is little doubt that in vascular disorders in which vasospasms are the main cause of the disease (e.g. Raynaud’s disease), or even in patients with mild occlusive lesions, &dquo;vasodilator agents&dquo; have beneficial effects, although it is not exactly understood why. Vasodilatation is an increase in blood vessel diameter due to relaxation of

Evidence that pimozide is not a partial agonist of dopamine receptors

Abstract The dopamine receptor antagonist pimozide, at concentrations up to 10 nM, competitively antagonized the inhibitory action of a pomorphine on prolactin (PRL) secretion by cultured rat pituitary cells. At higher concentrations pimozide as well as the analogues clopimozide and penfluridol suppressed PRL secretion. The latter effect could not be reversed by dopamine antagonists devoid of intrinsic effects on PRL release. Suppression of PRL release was also observed with compounds which were devoid of dopamine receptor agonistic or antagonistic properties such as R 6694 and R 5052, structurally related to pimozide, and also with loperamide. The inhibitory action of pimozide on PRL release resembled that of the calcium antagonist flunarizine. Concentration effect curves showed parallel slopes and the effect of both compounds could be reversed by increasing the concentration of calcium ions (Ca 2+ ). Both flunarizine and pimozide were also capable of inhibiting releasing factor-stimulated luteinizing hormone secretion, an effect not shared by apomorphine. Pimozide and the various structurally related compounds used, also antagonized Ca 2+ -induced smooth muscle contractions of the isolated caudal artery of the rat. The present findings indicate that pimozide is a competitive antagonist without partial agonistic activity on apomorphine-sensitive dopamine receptors in the pituitary and that its inhibitory effect on PRL release as well as on vascular smooth muscle contractions is due to interference with a Ca 2+ -dependent mechanism of the stimulus-effect coupling process.

Effects of Flunarizine on the Distribution of Calcium in Vascular Smooth Muscle

Exposure of depolarized caudal artery preparations of the rat to various calcium concentrations evoked sustained contractions of the smooth muscle in a dose-dependent way. Flunarizine was shown to suppress this sustained muscle contraction. Experiments were undertaken to determine the subcellular site where flunarizine interferes with the calcium-induced contractile process. The subcellular distribution of calcium was assessed by electron microscopy, using a combined oxalate-pyroantimonate method. In depolarized strips precipitated calcium was mainly distributed over the contractile elements and the microvesicles lining the cell membrane. When flunarizine was added to the preparation, the precipitate was predominantly confined to the extracellular space, whereas only spotty precipitates were seen in mitochondria and sarcoplasmic reticulum. The myofibrils were almost free of deposits. Without previous depolarization, the smooth muscle cells demonstrated a moderate amount of precipitate over the mitochondria, nuclei, sarcoplasmic vesicles, plasmalemmal microvesicles and myofibrils. In these conditions neither the amount nor the intracellular distribution of the precipitate was influenced by the addition of flunarizine. These observations suggest that flunarizine interfers with the entry of calcium at the plasma membrane level, but only in conditions where the influx of the ion is stimulated.

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

SummaryIsolated kidneys of Wistar rats and spontaneously hypertensive rats (SHR) were perfused with Tyrodes 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.