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.

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.

Antihypertensive efficacy and well-being during monotherapy and combination therapy with ketanserin.

The effects of ketanserin on blood pressure and well-being were investigated in 188 patients, aged 41-82 years, with mild to moderate essential hypertension. At entry, 107 were untreated, 42 were taking the diuretic combination hydrochlorothiazide (50 mg/day) plus amiloride (5 mg/day) and another 39 were taking the beta-blocker atenolol (100 mg/day). A single-blind, 4-week placebo run-in period was followed by 12 weeks' oral ketanserin treatment at 20 or 40 mg twice a day. This regimen significantly reduced systolic and diastolic blood pressures in each group. Response rates were greater in patients aged over 60 years. Compared with placebo, sleep disturbances, daytime fatigue and overall weakness decreased during ketanserin treatment (P less than 0.05 for all), but the incidence of dry mouth and stuffy nose increased. In patients older than 60 years there was a greater reduction of complaints than in younger patients. Ketanserin proved effective and well tolerated, improving peripheral circulatory symptomatology, particularly in older patients and those with a good blood pressure response.

5HT-kinetics and sensitivity of human blood platelets: variations with age, gender and platelet number.

Platelet shape change and aggregation as well as serotonin (5-hydroxytryptamine; 5HT) content in platelets, spontaneous release of 5HT, 5HT plasma levels, urinary excretion of 5-hydroxyindoleacetic acid (5HIAA) and plasma beta-thromboglobulin (beta-TG) were investigated in 45 healthy subjects (27 men, 18 women). Platelets from women were more susceptible to aggregation (both by 5HT and ADP) than platelets from men. However, in men, 5HT-induced shape change and aggregation as well as plasma beta-TG concentration increased with age. In men, 5HT-induced platelet aggregation correlated positively with 5HT plasma levels. An inverse relationship was found in men between platelet number on the one hand and platelet 5HT content, 5HT release, 5HT plasma levels and urinary 5HIAA excretion rates on the other hand. In all subjects 5HT-induced platelet aggregation correlated negatively with platelet number. These results indicate that age and gender must be considered in designing clinical studies on 5HT and in evaluating human platelet 5HT kinetics. The platelet number seems to be related to 5HT kinetics of platelets and their reaction to 5HT in men. An age-dependent change in the reactivity of platelets to 5HT (rather than their absolute 5HT sensitivity) may contribute to the enhanced platelet turnover and higher incidence of cardiac events in older men.

Serotonin metabolism and age-related effects of antihypertensive therapy with ketanserin.

Concentrations 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 40 mg twice daily. Ketanserin lowered systolic and diastolic blood pressure (p less than 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 less than 0.05). Changes in 5-HIAA concentration in platelet rich plasma correlated with the fall in diastolic blood pressure (r = 0.67, p less than 0.05). Serotonin-induced platelet aggregation was inhibited by ketanserin (p less than 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.

Age, platelet serotonin kinetics and 5HT2-receptor blockade in essential hypertension.

Serotonin (5HT) released from activated platelets causes platelet aggregation and vasoconstriction which are both exaggerated in older age and contribute to the development of thromboembolic complications. Platelet 5HT kinetics and reactivity were investigated in 45 patients with essential hypertension and 45 healthy control subjects matched for age, sex and smoking status. An age-dependent attenuation of total 5HT turnover and platelet 5HT release was revealed in control subjects but not in patients with essential hypertension. In the latter, especially in men, platelet 5HT uptake decreased with age and high blood pressure, leading to elevated 5HT plasma concentration. In parallel, platelet reactivity was increased with advancing age as shown by a greater 5HT induced aggregation and higher beta-thromboglobulin plasma concentration. Antihypertensive treatment with ketanserin resulted in inhibition of 5HT-induced shape change reaction and aggregation as well as a decrease in platelet 5HT release. Age contributes to altered platelet 5HT kinetics and 5HT2-receptor reactivity thereby elevating thromboembolic risk. 5HT2-receptor blockade with ketanserin interferes with these events by inhibition of platelet 5HT release and by a greater antiaggregatory and antihypertensive action in older age.

Age and 5HT 2-receptor blockade with ketanserin in essential hypertension.

Platelet derived serotonin (5HT) contributes to blood pressure elevation and the development of thromboembolic complications. Among the pathophysiological mechanisms involved in these vascular events, derangements in 5HT kinetics and exaggerated platelet response to 5HT may be part of the major triggering factors. An age-dependent attenuation platelet 5HT kinetics was revealed in normotensive control subjects but not in patients with essential hypertension. In older hypertensive patients, particularly in men, platelet 5HT uptake was decreased. In parallel, platelet reactivity was increased with advancing age as shown by a greater 5HT induced platelet aggregation and higher plasma concentration of beta-thromboglobulin. Antihypertensive treatment with the 5HT2-receptor antagonist ketanserin attenuated platelet 5HT turnover and inhibited 5HT induced platelet aggregation; the latter was more pronounced in older patients. The clinical efficacy and tolerability of ketanserin 20-40 mg twice daily given as mono- or combination therapy was evaluated in 188 patients with mild to moderate essential hypertension for a period of 12 weeks. A greater fraction of patients greater than or equal to 60 years achieved diastolic target pressure of less than or equal to 95 mgHg. Complaints related to the central nervous system or the peripheral circulation were greatly reduced in patients older than 60 years. In older patients, over and above the antihypertensive effect, 5HT2-receptor blockade may play an important role in the prevention of thromboembolic complications by inhibition of 5HT induced platelet activation.

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 less than 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.

Platelet serotonin-LDL interaction in essential hypertension.

Serotonin (5-HT) released from activated blood platelets plays a pivotal role in the development of thromboembolic complications. Essential hypertension, elevated plasma cholesterol, older age, and smoking are predisposing factors for these vascular events, and they all lead to platelet activation. In hypertensive patients, platelet 5-HT uptake is reduced with increasing age and blood pressure. This uptake inhibition is paralleled by an exaggerated platelet shape change and aggregation response. As a consequence, periplatelet 5-HT plasma concentrations are increased and promote further platelet aggregation and vasoconstriction. Low-density lipoproteins (LDL) induce a platelet shape change reaction and amplify the aggregatory response to serotonin. This effect is enhanced in smokers and even greater in hypertensive patients. LDL also inhibit endothelium-dependent relaxations to serotonin thereby unmasking the vasoconstrictor effect. 5-HT2-Receptor blockade with ketanserin interferes with this chain of events at several sites. Ketanserin inhibits platelet 5-HT release and 5-HT-induced platelet aggregation. It exerts a beneficial influence on the lipid profile. Blockade of 5-HT2 receptors leads to direct vascular smooth muscle dilatation as well as unopposed activation of endothelial 5-HT1-like receptors with the subsequent release of endothelium-derived relaxing factor. Taken together, the antihypertensive agent ketanserin may provide a new approach for multiple risk factor intervention therapy, eventually to prevent thromboembolic complications.

Serotonin and preactivated platelets in essential hypertension.

In patients with essential hypertension, an activated platelet serotonin-induced vasoconstrictor axis can be postulated. Platelets from hypertensive patients have a shortened half-life, and turnover of serotonin is increased. Vasoconstriction may be produced through activation of 5-HT2 receptors secondary to high wall concentrations of serotonin released from "activated" platelets. The pharmacotherapeutic relevance of this pathophysiological chain of events can be tested with the 5-HT2-receptor blocker ketanserin, but the drug's alpha 1-blocking activity has to be taken into account. Ketanserin lowers blood pressure effectively and to a greater extent in older patients. This points to an age-linked mode of action, possibly related to greater endothelial and blood vessel damage with older age.

Age and the platelet serotonin vasoconstrictor axis in essential hypertension.

This review addresses the question of whether platelet-derived serotonin locally released at the resistance vessel wall may contribute via selective 5-hydroxytryptamine (5-HT) receptors to vasoconstriction and whether this chain of events is enhanced with age and high blood pressure. In platelets from animals and humans, both age and hypertension are associated with greater shape change and aggregation responses, reduced serotonin uptake and content, and increased release. Removal of the endothelium, age, and high blood pressure enhance vasoconstrictor responses to serotonin. In the presence of endothelial damage and arteriosclerotic vascular disease, particularly with reduced blood flow in areas of stenosis, platelets may aggregate, resulting in high local 5-HT concentrations and 5-HT-induced vasoconstriction. Since alpha 1-adrenoceptor-mediated vasoconstriction is independent of age, the age-related antihypertensive efficacy of the 5-HT2-receptor antagonist ketanserin (with alpha 1-blocking property) helps to define pharmacologically 5-HT2-receptor-mediated platelet aggregatory and vasoconstrictor mechanisms. 5-HT2-receptor antagonists represent a new antihypertensive tool with the potential of reducing thromboembolic complications and vascular damage, particularly in older patients.

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

Serotonin (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 hypertensive men than in women. 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 greater than or equal to 60 years of age. This may indicate that 5HT uptake in vivo in normotensives is far below maximum (VNT much less than Vmax), whereas in hypertensive men it may be close to maximum (VHT approximately 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.

Antihypertensive efficacy of ketanserin alone or in combination with a beta-blocker or a diuretic: the Swiss Ketanserin Study.

In the Swiss Ketanserin Study the antihypertensive efficacy and tolerability of ketanserin (given in 20 or 40 mg doses twice daily) was investigated, after a placebo run-in phase, as monotherapy (n = 68) as well as in combination with either atenolol (100 mg/day) (n = 30) or the potassium-sparing diuretic hydrochlorothiazide (50 mg/day) and amiloride (5 mg/day) (n = 26) in 124 patients with essential hypertension, aged 41 to 82 years. With the addition of ketanserin, diastolic blood pressure fell by 8 +/- 8, 8 +/- 8, and 7 +/- 9 (+/- SD) mm Hg, respectively (p less than 0.05 for all) in the three treatment groups; heart rate remained unchanged or fell slightly. Ketanserin had no effect on body weight, or biochemical variables, including total serum cholesterol and triglycerides, with the exception of a minor increase in apolipoprotein B. Using a patient self-assessment questionnaire (30 items), the addition of ketanserin was associated with a reduction of most of the symptoms encountered in the placebo phase, including sleep disturbances, general feeling of weakness, headaches, nervousness, and fatigue, but there was a tendency toward increases in stuffy nose and dry mouth. In patients older than 60 years, the antihypertensive efficacy of ketanserin was greater, with 59% achieving a diastolic pressure less than or equal to 95 mm Hg versus 45% in the younger patients. This age trend also emerged when ketanserin was combined with either atenolol or the diuretic.

[Blood pressure lowering action and tolerance of ketanserin in mono- or combination therapy]. / Blutdrucksenkende Wirksamkeit und Verträglichkeit von Ketanserin in Mono- oder Kombinationstherapie.

The antihypertensive efficacy and tolerability of the 5HT2-receptor antagonist ketanserin was investigated in 188 patients aged 41 to 82 years with mild to moderate essential hypertension. Ketanserin was given as monotherapy (n = 107) as well as in combination with either the diuretic hydrochlorothiazide/amiloride (n = 42) or the betablocker atenolol (n = 39) for 12 weeks. Compared to placebo, ketanserin lowered systolic blood pressure by 11 +/- 16 (SD), 9 +/- 13 and 9 +/- 11 mm Hg (p less than 0.01 for all) and diastolic blood pressure by 9 +/- 10, 10 +/- 9 and 7 +/- 9 mm Hg (p less than 0.001 for all), in the three treatment groups; body weight, serum sodium, potassium, uric acid, cholesterol and triglycerides remained unchanged. The incidence of withdrawals due to unwanted effects was 4% on ketanserin monotherapy, and 12% and 10% on the diuretic/ketanserin and the betablocker/ketanserin combination respectively. Well-being during ketanserin therapy was improved in the older patients in particular; sleep disturbances, daytime fatigue and overall weakness decreased. Ketanserin was well tolerated in combination with the diuretic, whereas in combination with the betablocker the occurrence of dry mouth and stuffy nose was slightly higher. - Ketanserin proved to be an effective antihypertensive drug comparable to other blood pressure lowering agents. It can be combined advantageously with a potassium sparing diuretic or a betablocker. The greater efficacy and tolerability in patients greater than or equal to 60 years qualify ketanserin primarily as an antihypertensive agent for older patients.