W. J. Janssens

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.

Animal Pharmacology of Nebivolol

SummaryNebivolol is a mixture of equal amounts of 2 enantiomers: SR3-nebivolol (d-nebivolol) and RS3-nebivolol (l-nebivolol). SR3-nebivolol is a potent and selective β1-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 haemodynamic effects cannot be explained by β1-adrenergic antagonism and are largely attributable to RS3-nebivolol.

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.

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.

The discovery of a series of new non-indole 5HT1D agonists

Abstract The synthesis and SAR of a series of non-indole 5HT1D agonists is described. The most interesting molecule of this series is compound 13, alniditan. It is active as a constrictor of the saphenous vein of the dog and of the pig basilar artery with ED50 values of 9.09×10−9M and 2.29×10−8M respectively, and it has high affinities to the 5HT1D-receptor and to the 5HT1D-receptor with pKi values of 8.6 and 8.3 respectively.

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.

In vitro pharmacology of R 80122, a novel phosphodiesterase inhibitor

Summary: 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 µM milrinone was equieffective to 1µM R 80122. The rate of spontaneously beating atria was not altered by R 80122 in the concentration range of 0.01-0.3 1 µM. Higher concentrations (1-10 µM) led to a statistically insignificant increase of 20%. Milrinones effect on frequency was more pronounced and amounted to 21% at 10 µM and to 40% at 100 ¯M. Adibendan increased heart rate (HR) by 10% at a concentration of only 0.03 µM. 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 KCI and relaxation of guineapig 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 F2α (PGF2α) 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. R80122 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.

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.

Amplifying Effect of Serotonin in the Control of Vascular Tone

Threshold or subthreshold concentrations of serotonin, either exogenously applied or released from aggregating platelets, amplify the vasoconstriction caused by low concentrations of neurohumoral mediators in large or small arteries. This amplifying effect of serotonin is larger than would be expected from a merely additive effect. In most blood vessels it can be inhibited by 5HT2-serotonergic antagonists such as ketanserin, indicating that 5HT2- serotonergic receptors are involved. The amplifying effect may be enhanced at older age or in hypertension. The amplification is relatively more important at lower concentrations of the agonists. When the uptake or storage of serotonin in blood platelets is impaired, or when platelets aggregate, the low amounts of serotonin then present in the plasma may cause vasospasms because of the amplifying effect of the monoamine. The findings that the 5HT2-serotonergic antagonist ketanserin improves blood flow in atherosclerotic animals or in thrombotic obstruction and that it lowers high blood pressure suggests that the amplifying effect of serotonin may play a role in cardiovascular pathology.