Effects of dihydropyridines and their combination with aspirin on blood pressure and circadian platelet activity in patients with essential hypertension.

The objective of this double-blind study was: 1) to evaluate and compare the effects of treatment with two dihydropyridines--isradipine and nitrendipine--on basal and circadian blood pressure and on 24-h platelet activity; and 2) to investigate the influence of low-dose aspirin on the antihypertensive, antiplatelet (antiaggregatory) efficacy of dihydropyridines. After a 4-week placebo period, 39 patients with mild-to-moderate essential hypertension were treated for 8 weeks, according to a double-blind design, with either isradipine at 2.5 mg/day (n = 20) or nitrendipine at 10 mg/day (n = 19). After this treatment period, aspirin at 100 mg/day was added to both treatments for a further 8 weeks. At week 0 (after placebo), week 8 (after dihydropyridines), and week 16 (after dihydropyridines + aspirin), blood pressure, plasma levels of beta-thromboglobulin (beta-TG) and platelet aggregation induced by serotonin (5-HT) were measured six times a day (at 5:30 AM, 9:00 AM, noon, 3:30 PM, 7:00 PM, and 11:30 PM). Both isradipine and nitrendipine significantly lowered basal and circadian blood pressure with no differences in antihypertensive efficacy between them. Low doses of aspirin did not interfere with the antihypertensive efficacy of either agent. All patients exhibited increased platelet activity after the placebo period in the form of increased beta-TG levels with circadian changes. The steepest increase in beta-TG was observed during the morning hours until midday. Treatment with the dihydropyridines inhibited platelet aggregability, shifting the beta-TG curve toward lower values. Addition of aspirin to nitrendipine produced a significant decrease and flattening of the beta-TG curve, whereas the combination of aspirin and isradipine was accompanied by a partial increase in plasma beta-TG levels. In conclusion, treatment with dihydropyridines alone or in combination with low-dose aspirin can prevent circadian increases in platelet activity in patients with essential hypertension.

Factors influencing isradipine and amlodipine binding to human plasma lipoproteins.

The objectives of this study were to determine the distribution of isradipine among individual plasma lipoproteins ex vivo in healthy volunteers (n = 8) and in hypercholesterolaemic patients (n = 12), and to investigate the mechanisms involved in the interaction of isradipine and amlodipine with isolated lipoprotein fractions in vitro. The distribution study ex vivo demonstrated the different relative affinity of isradipine for the plasma lipoproteins: high-density lipoprotein (HDL) > low-density lipoprotein (LDL) > very low-density lipoprotein (VLDL). Isradipine binding correlated linearly with the cholesterol levels in LDL and VLDL; however, binding to HDL did not correlate with the cholesterol level in this fraction. The total binding affinity of isradipine to isolated LDL was markedly higher compared with amlodipine; total binding affinity (nKa) of isradipine vs amlodipine was (1.60 +/- 0.08) x 10(7) l/mol vs (4.14 +/- 0.33) x 10(6) l/mol, respectively. Binding to HDL was also higher with isradipine --nKa = (1.04 +/- 0.04) x 10(5) l/mol--compared with that of amlodipine: nKa = (3.82 +/- 0.18) x 10(4) l/mol. There was no significant competitive binding effect of cyclosporin A (CyA) on isradipine binding to individual lipoprotein fractions. It is likely that, in addition to the structure of surface apoproteins, the factors determining the interaction of calcium antagonists with plasma lipoproteins also include the plasma level of each lipoprotein fraction as well as the lipophilicity of the drug.

Treatment of hypertension with dihydropyridine calcium antagonists and aspirin.

The effects of dihydropyridine calcium antagonists on blood pressure and platelets, and the effects of aspirin on the circadian antihypertensive efficacy of dihydropyridines and on the 24-h platelet-activity profile, were the focus of a double-blind study. Patients with essential hypertension were treated for 8 weeks with either isradipine focus of double-blind study. Patients with essential hypertension were treated for 8 weeks with either isradipine (2.5 mg/day) or nitrendipine (10 mg/day). Aspirin (100 mg/day) was added to both treatment groups for a further 8 weeks. Measurements were taken after 4 weeks of placebo, after 8 weeks of dihydropyridine treatment, and after 8 weeks of treatment combined with aspirin. Plasma levels of beta-thromboglobulin (beta-TG) and platelet aggregation induced by serotonin were measured six times during 24 h. Both dihydropyridines significantly lowered systolic and diastolic blood pressure. The addition of aspirin to dihydropyridine treatment had no significant effects on systolic or diastolic blood pressure. Dihydropyridine treatment lowered the increased 24-h plasma beta-TG profile and inhibited platelet aggregability. Aspirin added to nitrendipine led to a further significant decrease in beta-TG levels whereas its addition to isradipine was accompanied by a partial increase in plasma beta-TG. It is concluded that increases in platelet activity in hypertensive patients can be prevented with either isradipine alone or nitrendipine plus aspirin. Aspirin in a daily dose of 100 mg does not affect the antihypertensive efficacy of calcium antagonists.

Treatment of hypertension with calcium antagonists and aspirin. Effects on 24-h platelet activity.

The effects of calcium antagonists on platelets, and the effects of aspirin on the antihypertensive efficacy of calcium antagonists and on the 24-h platelet-activity profile were investigated in a double-blind study. Patients with essential hypertension were treated for 8 weeks with either nitrendipine (10 mg once daily) or isradipine (2.5 mg once daily). Aspirin (100 mg once daily) was added to both treatments for a further 8 weeks. Measurements were taken after placebo, after 8 weeks of active treatment, and after 8 weeks of treatment plus aspirin. Plasma levels of beta-thromboglobulin (beta-TG) and platelet aggregation (PA) were measured six times over 24 h. Isradipine and nitrendipine significantly lowered systolic and diastolic blood pressure. The addition of aspirin had no effect on blood pressure. Platelet activity before treatment exhibited circadian variations with the lowest values of beta-TG and PA at 0530 h and the steepest increases between 0530 and 0900 h. Although both calcium antagonists decreased beta-TG levels (P < .05), the effect with isradipine was more pronounced than that with nitrendipine (P < .05). Aspirin added to nitrendipine produced a significant decrease in beta-TG levels whereas isradipine plus aspirin was accompanied by a partial increase in beta-TG. It is concluded that hypertensive patients exhibit circadian increases in platelet activity that can be prevented by either isradipine alone or by treatment with nitrendipine plus aspirin. Chronic aspirin intake at a daily dose of 100 mg does not affect calcium antagonist antihypertensive efficacy.

MIS (Multicentric Isradipine Study of antihypertensive therapy).

One-year open Multicentric Isradipine Study (MIS) performed in 7 centres in Czechoslovakia included 144 patients with mild and moderate hypertension. Isradipine was given at a dose of 2.5 mg daily. If normalization of diastolic blood pressure (BP) had not been reached, the dosage was increased to 5 mg. Monotherapy with isradipine normalized diastolic BP in 44% of patients. Isradipine (5 mg daily) was combined with bopindolol in patients in whom isradipine alone failed to normalize diastolic BP. These had higher mean systolic and diastolic BP, body weight, erythrocyte and platelet counts at the beginning of the study. The combination of isradipine with bopindolol normalized diastolic BP in 87% of the group at the end of 48 weeks' treatment. Tolerance was excellent in 82% of patients. Treatment was discontinued in 8% patients, undesirable effects being the reason in 2%, ineffective therapy in 2% and poor adherence to therapy in 4%. Isradipine in monotherapy or in combination with bopindolol did not exert an adverse effect on the metabolic risk factors of ischaemic heart disease (cholesterol, glycaemia).

Platelet activation by low-density lipoprotein and serotonin: effects of calcium antagonists.

Epidemiological studies indicate that there are biological interrelationships between blood pressure and blood lipids that may influence the mechanisms whereby hypertension is associated with an increased risk of coronary artery disease. Serotonin (5-HT) and thromboxane A2, which are released from aggregating platelets, mediate platelet-induced vasoconstriction, which itself significantly contributes to coronary artery constriction in vivo. Platelet aggregatory response to serotonin is modulated by disparate effects of lipoprotein fractions. This corresponds to the recognized differences in degree of atherogenicity of low- (LDL) and high-density lipoprotein (HDL). Amplification of serotonin-induced platelet aggregation by LDL and its inhibition by HDL support the hypothesis that 5-HT-mediated effects represent a mechanism clinically relevant to both chronic progression of atherosclerosis (particularly at sites of vascular injury and atherosclerotic plaques) and acute thrombotic events. Calcium antagonists differ in their platelet-inhibition potency, including their effects on platelet response to 5-HT and LDL. Verapamil and isradipine inhibit platelet aggregation induced by 5-HT at therapeutic concentrations. Isradipine also inhibits the amplifying effect of LDL on 5-HT-induced aggregation. These platelet effects of calcium antagonists appear to be neither group- nor class-specific but, rather, drug-specific.

Platelet-activating effect of low-density lipoprotein and its reversal by isradipine.

The effect of the calcium antagonist isradipine on platelet aggregation (induced ex vivo by serotonin and low-density lipoprotein [LDL]) was studied in 17 nonsmoking patients with essential hypertension. Platelet aggregation was measured after a four-week placebo period, and after four and 12 weeks of treatment with isradipine. Both the serotonin-induced and the LDL plus serotonin-induced platelet aggregation were significantly decreased after four weeks of isradipine treatment compared with placebo. The amplifying effect of LDL on the serotonin-induced aggregation was significant both after placebo and after active treatment with isradipine. A further decrease in platelet aggregation induced by LDL plus serotonin was observed after 12 weeks of isradipine treatment so that no amplification of serotonin-induced aggregation by LDL could be detected. In conclusion, it appears that treatment with isradipine restores the impaired platelet response to serotonin and LDL in hypertensive patients. The inhibition of this response may represent a cellular mechanism of thrombovascular protection.

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 platelet activation during treatment with isradipine.

The effect of the calcium antagonist isradipine on serotonin metabolism and platelet aggregation was studied in 17 patients with essential hypertension. Platelet serotonin content, plasma serotonin, 5-hydroxyindoleacetic acid levels, and platelet aggregation [induced ex vivo by serotonin and low-density lipoprotein (LDL)] were measured after a 4-week placebo period and after 12 weeks of oral treatment with isradipine. Isradipine treatment significantly inhibited platelet aggregation induced by LDL and serotonin; the amplifying effect of LDL on serotonin-induced aggregation seen with placebo was not observed after 12 weeks of treatment with isradipine. Platelet serotonin content increased significantly during isradipine treatment; this increase was inversely related to the pretreatment content of serotonin in platelets. The results indicate that treatment with isradipine restores the impaired handling of platelet serotonin as well as the platelet response to serotonin and LDL in hypertensive patients. This effect of isradipine may be regarded as one of the cellular mechanisms of thrombovascular protection and may be of clinical significance in terms of platelet and vessel wall interaction.

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.

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.

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.

Isradipine in monotherapy and in combination with bopindolol: results of a 3-month multicentre study in hypertensives.

The antihypertensive effect and safety of treatment of hypertension with isradipine, a Ca antagonist of dihydropyridine group in monotherapy and in combination with the betablocker bopindolol was assessed in a multicentre study joined by six Czechoslovak centres. When administered alone to 102 patients with essential hypertension stages I and II, isradipine was effective in 59%. Forty-one per cent of patients required combined therapy. The treatment led to a marked decrease in diastolic BP in smokers and non-smokers alike. A significant rise in ALP was observed during therapy in both therapeutic regimens. A significant decrease in cholesterolaemia was found in patients treated with the isradipine-bopindolol combination. No serious adverse effects were seen during three-month follow-up.

Low-density lipoprotein amplifies the platelet response to serotonin in human plasma.

The effect of low-density lipoprotein, serotonin and low-density lipoprotein plus serotonin on platelet aggregation (measured ex vivo in plasma) was studied in 28 normotensive subjects (15 non-smokers, 13 smokers) and 15 previously untreated non-smoking patients with essential hypertension. Low-density lipoprotein alone had no platelet-activating effect. Serotonin-induced platelet aggregation was enhanced by low-density lipoprotein in both the normotensive and the hypertensive subjects. The platelet response to low-density lipoprotein plus serotonin was higher in the smokers than in the non-smokers; it was also higher in the hypertensive patients than in the normotensive controls. We conclude that low-density lipoprotein activates platelets in plasma via an interaction with a serotonergic mechanism. Low-density lipoprotein amplifies the serotonin-induced platelet aggregation (normally reversible), making it irreversible. A higher platelet response to low-density lipoprotein plus serotonin in patients with essential hypertension may be of pathophysiological relevance in respect to the thrombovascular lesions accompanying hypertension and/or atherosclerosis.

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 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.

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 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.