Alfred Pletscher

Modulation of gene expression by high and low density lipoproteins in human vascular smooth muscle cells

Low density lipoprotein and its oxidized form has been implicated in the process of arteriosclerosis which involves growth-related events in the smooth muscle cells of the arterial wall. The induction of so-called early-growth response genes e.g. c-myc and c-fos can serve as an indicator for these growth-related events. In cultured human vascular smooth muscle cells, both LDL and HDL3 were individually capable of stimulating c-myc and c-fos expression in a concentration dependent manner. However, when they were used in combination, depending on the proportion of HDL3 to LDL, c-fos but not c-myc expression was less pronounced than with the single components. In contrast to HDL3 and LDL alone, a combination of the two lipoproteins also blunted both the expression of autoinduced transforming growth factor beta transcripts and the transforming growth factor beta-induced increase of c-fos mRNA. It is concluded that a) the inhibition of transforming growth factor beta autostimulation by HDL3 plus LDL may involve reduced AP-1 activity via a reduction of c-fos expression by the lipoprotein combination and b) the ratio HDL3:LDL might influence the pathogenesis of arteriosclerosis via growth-related events in the arterial wall.

5-Hydroxytryptamine kinetics and activation of blood platelets in patients with essential hypertension.

To investigate possible alterations in 5-hydroxytryptamine (5HT) kinetics and sensitivity of blood platelets in patients with essential hypertension, 45 essential hypertensive patients and 45 normotensive healthy subjects matched in pairs for age, sex, and smoking status were compared. There were 18 women and 27 men in each group, ranging from 30 to 73 years of age. Results of essential hypertensive patients differed in several ways from those of normotensive subjects. In essential hypertensive patients, maximal 5HT uptake velocity (Vmax) decreased with increasing blood pressure and age and was reduced the most in older men. Vmax was positively related to the EC50 of 5HT for inducing a shape change reaction. In essential hypertensive patients, both Vmax of 5HT uptake and the EC50 of 5HT for shape change showed positive correlations with the 5HT content in platelets; the former relation was different between the essential hypertensive and normotensive groups (F = 5.53; p = 0.02). These results indicate reduced uptake of 5HT by blood platelets and suggest enhanced 5HT plasma concentrations in local areas, especially vascular lesions in essential hypertensive patients. Increased periplatelet concentrations of 5HT may lead to preactivation of platelets and possibly stimulation of vascular smooth muscle via their 5HT2-receptors. These changes are likely to be involved in the pathogenesis of increased thromboembolic complications in essential hypertensive patients, particularly in older men.

Impaired uptake of 5 hydroxytryptamine platelet in essential hypertension: clinical relevance.

SummarySerotonin (5-hydroxytryptamine; 5HT) kinetics and platelet activation by 5HT were studied in patients with essential hypertension (n=45), and in matched normotensive subjects (n=45). Platelet response to 5HT and plasma beta-thromboglobulin increased with age in men, both normotensives and hypertensives. Beta-thromboglobulin and 5-hydroxyindoleacetic acid (5HIAA) excretion were higher in hyypertensive men than in wpmen. In women, no changes in platelet activity or 5HIAA excretion were found. 5HT plasma concentrations increased with blood pressure. Platelet 5HT uptake (Vmax and KM) were the lowest in hypertensive men ≥ 60 years of age. This may indicate that 5HT uptake in vivo in normotensives is far below maximum (VNT≪Vmax), whereas in hypertensive men it may be close to maximum (VHT ∼ Vmax). This could reflect significantly higher 5HT plasma concentrations in vivo hypertensives than in normotensives. The reduced uptake (which was found only in hypertensive men) may indicate an insufficient compensation of the enhanced 5HT release from aggregating platelets in older men, in whom platelet activity is enhanced in vivo. It is concluded that the defect in platelet 5HT uptake in hypertensives—along with the enhanced platelet aggregation—may contribute to a critical increase in 5HT plasma concentrations locally. An increase in 5HT concentrations leads to biochemical changes (higher 5HIAA excretion) as well as to an enhanced stimulation by 5HT. This may be of clinical relevance especially in older men, in whom 5HT2-receptor mediated responses are enhanced.

Platelet deactivation by 5HT2-receptor blockade parallels the antihypertensive response to ketanserin

Serotonin (5HT) has been implicated in thromboembolic complications and blood pressure elevation and both may be reduced with the 5HT2-receptor blocker ketanserin. In 17 patients with essential hypertension (WHO I and II, diastolic pressure V greater than or equal to 100 mmHg) blood pressure, platelet 5HT uptake, content and release as well as 5HT-induced shape change and aggregation were measured before and immediately after 8 weeks oral ketanserin at 20-40 mg twice daily. During ketanserin therapy, platelet 5HT release, shape change reaction and aggregation to 5HT were significantly reduced by more than 50%. These platelet effects were more pronounced in patients responsive to ketanserin (greater than or equal to 10% decrease of diastolic pretreatment pressure) and the fall in diastolic pressure correlated with the inhibition of 5HT-induced aggregation as well as the change in 5-hydroxy-indoleacetic acid (5HIAA) in platelet-rich plasma (PRP; P less than 0.05). Serotonin-receptor-independent platelet events were not affected by ketanserin. Ketanserin corrects 5HT2-receptor-mediated platelet function along with the reduction of blood pressure.

Low-density lipoprotein enhances platelet activation in parallel with the height of blood pressure.

The platelet-activating effect of low-density lipoprotein, ADP and collagen was investigated in 45 essential hypertensive patients (27 men, 18 women) and 45 healthy normotensive subjects strictly matched for age and sex. No differences in mean values were found between essential hypertensive and normotensive subjects. However, in essential hypertensive patients platelet sensitivity to low-density lipoprotein correlated positively whereas ADP and collagen correlated negatively with blood pressure (P < 0.05). Diminished platelet sensitivity to ADP and collagen may reflect receptor desensitization. The pressure-dependent increase in platelet response to low-density lipoprotein possibly contributes to enhanced thrombo-embolic complications and platelet-mediated vasoconstriction as well as to low-density lipoprotein-related vascular damage in essential hypertension.

Serotonin Metabolism and Age-Related Effects of Antihypertensive Therapy with Ketanserin

SummaryConcentrations of serotonin and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in platelet rich plasma, the urinary 5-HIAA excretion rate, and serotonin-induced platelet aggregation were measured in 17 patients with essential hypertension before, and at the end of 8 weeks of oral ketanserin therapy at 20 to 40mg twice daily. Ketanserin lowered systolic and diastolic blood pressure (p < 0.01) and led to a reduction of serotonin concentration in platelet rich plasma in all patients (p = 0.05), as well as a decrease in 5-HIAA excretion rates in patients older than 55 years (p < 0.05). Changes in 5-HIAA concentration in platelet rich plasma correlated with the fall in diastolic blood pressure (r = 0.67, p < 0.05). Serotonin-induced platelet aggregation was inhibited by ketanserin (p < 0.05), and this was more pronounced in older patients. Thus, antihypertensive therapy with ketanserin reduced platelet aggregation and serotonin metabolism in relation to the age of patients, and this may contribute to the reduction of their elevated rates of thromboembolic complications.RésuméLes concentrations de sérotonine et de son métabolite, l’acide 5-hydroxyindole acétique (5-HIAA), dans du plasma riche en plaquettes, le taux d’excrétion urinaire du 5-HIAA et l’agrégation plaquettaire induite par la sérotonine ont été mesurés avant et à la fin d’un traitement oral de 8 semaines par la kétansérine chez 17 patients souffrant d’hypertension artérielle essentielle et recevant 20 à 40 mg du produit deux fois par jour. La kétansérine a abaissé la pression artérielle, tant systolique que diastolique (p < 0,01) et a entraîné une diminution de la concentration de sérotonine dans le plasma riche en plaquettes de tous les patients (p = 0,05). Elle a également réduit le taux d’excrétion urinaire du 5-HIAA chez les patients âgés de plus de 55 ans (p < 0,05). Les modifications de la concentration de 5-HIAA dans le plasma riche en plaquettes ont été corrélées à la chute de la pression artérielle diastolique (r = 0,67, p < 0,05). La kétansérine a inhibé l’agrégation plaquettaire induite par la sérotonine (p < 0,05), cette action étant plus prononcée chez les patients âgés. Le traitement anti-hypertenseur par la kétansérine a donc diminué l’agrégation plaquettaire et le métabolisme de la sérotonine de façon proportionnelle à l’ âge des patients; ce phénomène a peut-être contribué à la réduction du nombre élevé de complications thrombo-emboliques observée dans ce groupe de malades.ZusammenfassungBei 17 Patienten mit essentieller Hypertonie wurden vor und nach 8wöchiger oraler Ketanserintherapie mit zweimal täglich 20 bis 40 mg die Konzentrationen von Serotonin und seinem Metaboliten 5-Hydroxyindolessigsäure (5-HIES) in plättchenreichem Plasma, die 5-HIES-Ausscheidungsrate im Urin und die serotonininduzierte Thrombozytenaggregation bestimmt. Ketanserin senkte den systolischen und diastolischen Blutdruck (P < 0,01) und führte bei allen Patienten zu einer Reduktion der Serotoninkonzentration im plättchenreichen Plasma (P = 0,05) und bei über 55jährigen Patienten darüber hinaus zu einer Minderung der 5-HIES-Ausscheidungsrate (P < 0,05). Die Veränderungen der 5-HIES-Konzentrationen im plättchenreichen Plasma korrelierten mit der Abnahme des diastolischen Blutdrucks (r = 0,67, P < 0,05). Die serotonininduzierte Thrombozytenaggregation wurde durch Ketanserin gehemmt (P < 0,05), und diese Hemmung war bei älteren Patienten deutlicher ausgeprägt. Die antihypertonische Therapie mit Ketanserin reduzierte also die Thrombozytenaggregation und den Serotoninmetabolismus in Relation zum Alter der Patienten, was möglicherweise zur Reduktion der erhöhten Rate thromboembolischer Komplikationen beiträgt.ResumenEn 17 pacientes afectos de hipertensión arterial esencial se determinaron las concentraciones de serotonina, y su metabolito, el á cido 5-hidroxiindolacético (5-HIAA), en plasma enriquecido en plaquetas, la tasa de excreción urinaria de 5-HIAA, y la agregación plaquetaria inducida por serotonina, en situación basai y después del tratamiento con ketanserina por via oral a dosis de 20–40 mg dos veces al dia durante 8 semanas. La ketanserina redujo la tensión arterial, tanto diastólica como sistólica (p < 0,01), y en todos los casos indujo una disminución de la concentración de serotonina en plasma enriquecido en plaquetas (p = 0,05). Asimismo, se observó una reducción de las tasas de excreción urinaria de 5-HIAA en pacientes mayores de 55 años (p < 0,05). Los cambios en los niveles de 5-HIAA en plasma enriquecido en plaquetas se correlacionaron con la disminución de la tension arterial diastólica (r = 0,67, p < 0,05). La agregación plaquetaria inducida por serotonina se inhibió con ketanserina (p < 0,05), siendo dicha inhibición más pronunciada en los pacientes de mayor edad. Por tanto, el tratamiento antihipertensivo realizado con ketanserina reduce la agregación plaquetaria y el metabolismo de la serotonina, y dicho efecto está en relación con la edad del paciente. Ello puede contribuir a una disminución de la elevada incidencia de complicaciones tromboembólicas en estos pacientes.