Effect of spirapril and hydrochlorothiazide on platelet function and euglobulin clot lysis time in patients with mild hypertension.

Thirteen patients with mild hypertension (untreated diastolic blood pressure of 95 to 114 mmHg) received, in random order, three successive treatments of four weeks with placebo, spirapril (6 mg daily), or hydrochlorothiazide (HCT2) (24 mg daily). At the end of each treatment, blood samples for assessment of platelet aggregation and platelet release of platelet factor 4 (PF4) and for assessment of fibrinolysis, estimated by tissue plasminogen activator (t-PA), plasminogen activator inhibitor-type 1 (PAI-1), and euglobulin clot lysis time (ECLT), were taken, first at rest, then immediately after five to ten minutes of vigorous exercise, and finally after the subsequent hour of recovery rest. Platelet aggregation induced in vitro by adrenaline significantly decreased during treatment with HCT2, the threshold rising to 10 microM as compared with 1.0 with placebo (P < 0.05) at rest, and the threshold for adenosine diphosphate (ADP) aggregation also rose, from 2 microM to 4 (NS). The resting plasma PF4 value fell, although not significantly, during HCT2 treatment from the placebo value of 3.28 to 2.56 ng/mL. During spirapril treatment there was no change in the threshold of either adrenaline or ADP for aggregation of platelets sampled at rest, and the PF4 plasma levels showed no significant reductions at rest. However, during exercise PF4 showed an approximate doubling of the resting value irrespective of therapy. This exercise-induced increase in PF4 was significantly reduced by spirapril as compared with placebo (P < 0.05). ECLT and t-PA did not shift significantly from the placebo level during either therapy. PAI-1 did not change during spirapril therapy, but during HCT2 treatment it fell, although not significantly, to 9.36 IU/mL from 15.91 with placebo (NS). Spirapril and HCT2 did not produce any unwanted side effect on platelet function or fibrinolysis. HCT2 seems to decrease platelet activity at rest, whereas spirapril seems to some extent to decrease platelet activity at exercise.

ACE inhibition with spirapril improves diastolic function at rest independent of vasodilation during treatment with spirapril in mild to moderate hypertension.

The effects of the ACE inhibitor spirapril and of hydrochlorothiazide on left ventricular diastolic function were studied. Thirteen patients with mild to moderate essential hypertension completed this randomized, double-blinded, placebo-controlled, crossover study. After a three-week run-in period the patients entered three periods lasting four weeks each, wherein they were treated with placebo, spirapril, or hydrochlorothiazide. Blood pressure, hemodynamic variables (stroke volume, heart rate, cardiac output, index of contractility, and systemic vascular resistance), echocardiography (left ventricular mass), and Doppler-derived atrial to early (A/E)-ratio velocity time integrals (VTI) were measured at the end of each of the four periods. Spirapril lowered the A/E-ratio VTIs (0.57, 0.12-1.00) (P < 0.02) as compared with both placebo (0.80, 0.50-2.67) and hydrochlorothiazide (0.83, 0.44-1.25), and the drug normalized the A/E-ratio VTI in those patients with elevated values. The hemodynamic variables, left ventricular mass, and end-systolic wall stress were unchanged during all three treatments. There were no significant changes in mean blood pressure during the treatment periods. These results indicate that spirapril lowers A/E ratio within four weeks in patients with mild to moderate essential hypertension. It thereby seems able to improve left ventricular diastolic function. The effect is not dependent upon changes in hemodynamic variables, blood pressure, left ventricular mass, or end-systolic wall stress.

Smoking further increases platelet activity in patients with mild hypertension.

In this study the authors examine whether smoking further heightens platelet activity and reduces fibrinolysis above that already present in mild hypertension. Ten smokers and 11 non-smokers, all with mild hypertension (defined as a diastolic pressure between 90 and 110 mm Hg) were compared for their platelet activity in vitro and in vivo and for their fibrinolytic activity. Successive measurements were made with the patients lying at rest after they had assumed the erect posture for 10 min and at the end of a 5-min moderately strenuous exercise test. The threshold for platelet aggregation by ADP in vitro was significantly lower in samples taken from the smokers at rest (1.4 +/- 0.9 mumol L(-1)) than in the non-smokers (3.5 +/- 2.5 mumol L(-1)), and the difference persisted both in the upright posture and after exercise. The level of platelet release of beta-thromboglobulin was, likewise, higher in the smokers in the upright posture. Neither standing up nor physical exercise had any significant influence on either of these two indices of platelet activity. The euglobulin clot lysis time was slightly longer in the smokers than in the non-smokers in all three experimental situations, but the differences were not significant. Inhibitor of tissue plasminogen activator was not materially different in the two groups (Table 2). The results indicate that smoking adds a further element of heightened platelet activity to that inherently present in hypertension.

The effect of ageing on platelet function and fibrinolytic activity.

Twelve healthy male volunteers, mean age twenty-five, range twenty-one to thirty years, and 12 healthy middle-aged male volunteers mean age fifty-eight, range forty-four to seventy-two years, were tested regarding platelet aggregation induced by adenosine diphosphate and fibrinolytic activity, estimated as euglobulin clot lysis time (ECLT), tissue plasminogen activator (t-PA), and the fast-acting inhibitor against t-PA normally referred to as (PAI-1). Platelet aggregation increased significantly in the middle-aged group as compared with the young, as shown by a decrease in ADP thresholds for irreversible aggregation (P < 0.01). In healthy young volunteers, vigorous cycling exercise by itself caused platelet aggregability to decrease (P < 0.05). Such changes were not observed in the elderly. Fibrinolytic activity decreased significantly in the middle-aged group as shown by a prolongation of the ECLT (P < 0.01) and PAI-1, although not significantly, increased by approximately 100%, whereas t-PA significantly increased in the middle-aged group (P < 0.01). The present results suggest that increasing age is associated with not only increased platelet aggregability but also decreased fibrinolytic activity.

Platelet function and fibrinolytic activity during rest and exercise in borderline hypertensive patients.

In this study we examined whether the reduced fibrinolysis and increased platelet activity that are known to occur in hypertension are already present in borderline hypertension. Twelve patients with 'borderline' hypertension (diastolic blood pressure 90-95 mmHg) were found to have substantially reduced fibrinolytic activity, both at rest and during exercise, compared with 12 normotensive controls. Euglobulin clot lysis time (ECLT) was significantly higher in hypertensive subjects (218 min vs. 145 min; P < 0.05), and this difference persisted during exercise. Resting tissue plasminogen activator activity (t-PA) did not differ in the two groups, but the brisk increase in t-PA in controls during exercise (0.64 rising to 1.44 IU mL-1; P < 0.01) did not occur to the same extent in the borderline hypertensive subjects. Levels of the fast-acting t-PA inhibitor, normally referred to as PAI-1, were considerably higher in hypertensives (9.22 vs. 4.41 IU mL-1; P < 0.02), and this difference persisted in the upright posture, indicating a decrease in fibrinolytic activity. Platelet aggregability induced by ADP in vitro was not significantly higher in the hypertensive subjects, but indices of platelet activity in vivo (B-TG and PF-4 levels) revealed enhanced platelet function in the hypertensives. These results indicate that the indicators of altered haemostatic function known to occur in hypertension, namely diminished fibrinolytic activity and increased platelet function, are already detectable during the very earliest stage of the disease.

Platelet function and fibrinolytic activity in hypertensive and normotensive sleep apnea patients.

Platelet function and fibrinolytic activity was studied during rest and after ergometric exercise in 13 hypertensive or normotensive patients with obstructive sleep apnea (OSA) and in 10 sex- and weight-matched controls. All patients had undergone a complete polysomnography for the diagnosis of OSA. The controls did not undergo any sleep investigation but had no history of snoring or witnessed apneas during sleep. On antihypertensive drug wash-out, two of the patients were normotensive, whereas 11 had mild to moderate hypertension. Platelet aggregation measured by adenosine 5'-diphosphate- or adrenaline-induced aggregation, platelet factor-4 or beta-thromboglobulin did not differ between patients and controls. During exercise beta-thromboglobulin decreased significantly in both OSA patients and controls. Plasma tissue plasminogen activator activity was similar in OSA patients and controls and increased significantly in both groups after exercise. Plasminogen activator inhibitor type 1 (PAI-1) was 18.4 +/- 3.6 IU/ml in OSA patients compared with 8.2 +/- 1.7 IU/ml in controls (p < 0.029) during rest, indicating decreased fibrinolytic activity. The difference between groups remained after exercise (p < 0.017). Blood pressure elevation was more common and body mass index (BMI) was higher in patients with OSA, but there was no direct relation between blood pressure level or BMI and PAI-1. Nevertheless, differences between groups were smaller when blood pressure and obesity were accounted for. It is concluded that patients with OSA may exhibit decreased fibrinolytic activity. Low fibrinolytic activity may represent a confounding pathophysiological mechanism behind the high incidence of myocardial infarction and stroke in patients with OSA.

Does calcium channel blockade and beta-adrenergic blockade affect platelet function and fibrinolysis to a varying degree?

The effects of isradipine and atenolol on platelet function and fibrinolytic activity were studied in 10 male patients with mild untreated hypertension. After a 2-week placebo run-in period, the volunteers were randomized to either isradipine 2.5 mg twice daily or atenolol 100 mg daily for a 6-month period. Those initially receiving isradipine then received atenolol and vice versa. After each therapy regimen, blood was drawn at rest and 1 h after exercise during a maximum exercise test. Platelet activity in vivo was estimated as release of B-TG and PF-4. Fibrinolytic activity was estimated as the fast-acting inhibitor against tissue plasminogen activator usually termed PAI-1. During atenolol and isradipine therapy, blood pressure (BP) was equally reduced (p < 0.05). Heart rate (HR) decreased during atenolol treatment but was not changed by isradipine. Platelet activity in vivo estimated as B-TG and PF-4 decreased irrespective of therapy (p < 0.02). During atenolol, as during placebo therapy, exercise resulted in a significant increase in platelet activity, as shown by an increase in B-TG (p < 0.02) and in PF-4 (p < 0.01). Such increase was not observed during isradipine treatment. Both treatments tended to improve fibrinolysis, as shown by a decrease in PAI, 1 h after exercise. Reducing BP with isradipine or atenolol results in a similar decrease in platelet activity and PAI-level, tested at rest and 1 h after rest, respectively. During exercise, platelet activity increased during atenolol treatment; such change did not occur during isradipine treatment.

Effect of supine exercise on platelet aggregation and fibrinolytic activity.

In 12 healthy young men, strenuous cycling exercise in the supine position, caused platelet aggregability to decrease and the ADP threshold to rise from 7.0 microM resting, to 9.5 exercising (P < 0.01). At the same time, fibrinolytic activity increased markedly: euglobulin clot lysis time shortened from 178 to 68 min, PAI-1 fell from 8.91 to 5.16 IU ml-1, and t-PA rose from 0.56 to 3.95 IU ml-1, all three values were significant to P < 0.01. When the erect posture was assumed after lying at ease for 1 h after exercise, it did not increase platelet activity as expected, but caused a modest increase of fibrinolytic activity. These results suggest that supine exercise will not affect the haemostatic system adversely.

The impact of static work on fibrinolysis and platelet function.

Brief stress such as dynamic work protects against thrombosis by enhancing blood fluidity. The effect of isometric work on blood fluidity, however, is not known. The aim of the present study therefore was to test the effect of isometric work on heart rate (HR), blood pressure (BP), platelet function and fibrinolytic activity. Twelve healthy male volunteers were tested before and after isometric work. Isometric work resulted in an increase in HR from 62.4 to 110.0 beats/min and in systolic BP from 118.3 to 134.5 mmHg (p < 0.01). No significant change occurred in platelet release estimated as plasma levels of B-TG and PF-4, or platelet aggregation induced by ADP. Fibrinolytic activity increased, as evidenced by a decrease in ECLT from 136.7 + 10.5 to 72.3 + 9.8 min) (p < 0.01) and an increase in t-PA of 400%. No significant change was observed in PAI. The present data suggest that isometric work increases fibrinolytic activity significantly, but leaves platelet function unchanged.

Beneficial effect of isradipine on the development of left ventricular hypertrophy in mild hypertension.

The objective of this study was to analyze the long-term hemodynamic effects of the calcium antagonist isradipine in mild hypertension compared with those of the beta 1-selective adrenoceptor antagonist atenolol, focusing in particular on the development of cardiac hypertrophy. Ten male patients with mild essential hypertension were entered into a double-blind crossover study. Examinations were carried out after 2 weeks of placebo run-in, and after 6 and 12 months of active treatment. Mean resting blood pressure was reduced from 115 +/- 12 mm Hg to 106 +/- 12 mm Hg with atenolol, and to 107 +/- 8 mm Hg with isradipine. The increase in the product of heart rate times blood pressure was significantly greater during isradipine treatment, as was the maximum exercise capacity. Left ventricular mass was increased from 228 +/- 36 g to 305 +/- 68 g with atenolol whereas it remained unchanged with isradipine (254 +/- 55 g). The results indicate that antihypertensive treatment with isradipine as monotherapy may prevent the development of left ventricular hypertrophy whereas treatment with atenolol as monotherapy does not appear to offer this possibility.

Serotonin-induced platelet aggregation predicts the antihypertensive response to serotonin receptor antagonists.

The 5-HT2-receptor antagonist ketanserin (20-40 mg b.i.d.) was administered to 62 patients of both sexes with uncomplicated primary hypertension. After 4 weeks of treatment about 50% of the patients had reached the target diastolic blood pressure of 90 mm Hg or below. Interindividual variability was large. In a retrospective analysis the variability could not be explained by sex or the dose of ketanserin. There was a weak association between age and systolic blood pressure response (r = 0.24; P = 0.06), which could be entirely accounted for by the higher base line blood pressure in the elderly patients. In one group of patients (n = 12), the ex vivo aggregation to serotonin (10(-6) M) was studied during treatment with placebo and ketanserin. Ketanserin completely inhibited 5-HT-induced aggregation in all patients. There was a close correlation between the area under the 5-HT-induced platelet aggregation curve during placebo and the subsequent reduction in diastolic blood pressure after 4 weeks of treatment with ketanserin. The present data suggest that the blood pressure response to ketanserin can be predicted from the ex vivo sensitivity of platelets to serotonin. By implication, they also support a role for serotonergic mechanisms in hypertension.

Enhanced risk of thromboembolic disease in hypertension from platelet hyperfunction and decreased fibrinolytic activity: has antihypertensive therapy any influence?

Enhanced platelet function and a decrease in fibrinolytic activity have been reported in patients with mild hypertension after treatment with various nonselective beta-blockers. Until now, such changes have not been reported during treatment with beta 1-selective drugs or with agents that have intrinsic sympathomimetic activity. The impact of angiotensin-converting enzyme inhibitors and diuretics on platelet function and fibrinolytic activity has not been fully elucidated. Calcium antagonists of various types, however, are known to decrease platelet release in vivo whereas their effects on platelet aggregation and fibrinolytic activity are less clear. The new dihydropyridine calcium antagonist isradipine, when tested in a group of patients with mild hypertension, resulted in a decrease in platelet aggregation, a shortened euglobulin clot-lysis time, and a dramatic increase in t-PA (tissue-plasminogen activator) activity after 14 days of treatment. These changes remained stable throughout the 1-year study period. The fact that antihypertensive therapy does not always result in the hoped-for prolongation of life, despite satisfactory blood pressure reduction, may be in part due to an unfavorable impact on various components of the blood-clotting system.

Decreased fibrinolytic activity and increased platelet function in hypertension. Possible influence of calcium antagonism.

Twelve patients with mild hypertension were compared, after 14 days of placebo, with an age- and gender-matched group of 12 healthy volunteers for platelet aggregability and fibrinolytic activity. Following this, 10 of the 12 hypertensives were treated with the calcium antagonist isradipine for 12 months. Blood was drawn for determinations of platelet aggregation and fibrinolytic activity after two weeks and 12 months of treatment. Platelet aggregation tended to increase in the hypertensives compared with controls, indicated by a lowering of the adenosine diphosphate (ADP) threshold value for irreversible aggregation. Tissue-plasminogen activator (t-PA) activity was significantly decreased in hypertensives compared to controls (P less than .05). During therapy, platelet aggregation decreased and t-PA activity increased (P less than .05). The present data suggest that fibrinolytic activity is decreased and platelet aggregation increased in mild hypertension. Besides the blood pressure-lowering effect, isradipine may protect against thromboembolic diseases by modifying platelet function and fibrinolytic activity.

Does antihypertensive therapy affect the natural protection against thrombosis?

Fibrinolytic activity was measured in a 14-day placebo-controlled study of propranolol and the calcium antagonist isradipine in 20 mildly hypertensive patients (diastolic blood pressure 95-115 mm Hg) compared with 24 healthy volunteers. The parameters under study included euglobulin clot-lysis time, and tissue-plasminogen activator activity and its inhibitor (PAI). The two drugs exerted equal antihypertensive effects in the patients who had raised blood pressure, but had markedly different actions on the fibrinolytic system. Propranolol substantially reduced the fibrinolytic activity in both the hypertensive and healthy control groups. Isradipine, on the other hand, had no effect on fibrinolytic activity in the controls, but augmented the activity in the hypertensive subjects. The possible mechanisms for the different actions of the two agents may be related to the vascular endothelium.

Platelet function and fibrinolytic activity in hypertension: differential effects of calcium antagonists and beta-adrenergic receptor blockers.

Platelet function was investigated in healthy volunteers and patients with essential hypertension by measurement of thresholds for ADP and adrenaline-induced aggregation and plasma concentrations of platelet factor 4 (PF-4) and beta-thromboglobulin (beta-TG) after administration of antihypertensive drugs. Fibrinolytic activity was investigated by the euglobulin clot lysis time (ECLT) and tissue plasminogen activator (t-PA) activity. Compared to normotensive controls, patients with essential hypertension showed increased aggregation as evidenced by a decrease in ADP thresholds for ex vivo platelet aggregation. ECLT was significantly prolonged and t-PA significantly lowered, indicating impaired fibrinolytic activity in mild hypertension. In different studies, we have shown that various antihypertensive drug regimens differ in their effects on platelet function and fibrinolytic activity when given to healthy volunteers or patients with mild-to-moderate essential hypertension. In normal volunteers, treatment with the calcium antagonists verapamil, nifedipine, and felodipine lowered plasma concentrations of PF-4 and beta-TG, indicating a reduced platelet activity in vivo. Fibrinolytic activity was not influenced by calcium antagonist treatment in the normal volunteers. Interestingly, however, t-PA increased significantly in the hypertensive group. When compared to placebo or beta 1-selective blockers, propranolol, a non-selective beta-adrenergic blocker without partial agonist activity, reduced ADP and adrenaline threshold values for ex vivo platelet aggregation in hypertensive subjects and impaired fibrinolytic activity in the normal volunteers as well as in the hypertensive groups by increasing ECLT and reducing t-PA. Hypothetically, the effects of antihypertensive drugs on platelet function and fibrinolytic activity could be of importance for their proposed actions on cardiovascular morbidity and mortality.

Effect of disulfiram on the platelet function and fibrinolysis in healthy volunteers.

Disulfiram was studied for platelet and fibrinolytic activity in 12 healthy volunteers of both sexes (age 23-75 years). Placebo was given for 7 days, followed by disulfiram, 800 mg for 2 days and 400 mg for an additional 12 days. Finally, there was another placebo period of 14 days. With the exception of an initial platelet activation on day 2, no significant effects were found on the platelet variables studied: platelet aggregation with collagen, ADP and adrenaline, beta-thromboglobulin and platelet factor 4. Treatment for 14 days with disulfiram resulted in a decreased euglobulin clot lysis time: from 421 +/- 82 to 246 +/- 41 min (p less than 0.01). After an initial increase, plasminogen activator inhibitor activity was slightly decreased on disulfiram, from 8.4 +/- 1.6 on placebo to 6.0 +/- 1.2 U/ml (p less than 0.05) after 14 days of treatment. Plasminogen, fibrinogen and alpha 2-antiplasmin were unchanged. It is concluded that disulfiram can increase fibrinolytic activity in healthy subjects.

Differential effects of non-specific beta-blockade and calcium antagonism on blood-clotting mechanisms.

The effects of non-selective beta-blockade (timolol, 5 mg twice daily) and calcium antagonism (isradipine, 2.5 mg twice daily) on heart rate, blood pressure, platelet aggregation, fibrinolytic activity, and platelet cyclic adenosine monophosphate content were investigated in 10 patients with mild hypertension in a randomized, placebo-controlled, double-blind study. Each patient served as his or her own control, taking each drug in turn for two weeks. Both drugs lowered blood pressure to the same degree. During timolol treatment, however, platelet aggregation increased whereas isradipine resulted in a shortening of the euglobulin clot lysis time (p less than 0.05), indicating increased fibrinolytic activity. Platelet aggregation and fibrinolytic activity are modified by cyclic adenosine monophosphate. Since beta-adrenoceptors are present on platelets and endothelial cells, the differences in platelet behavior and fibrinolytic activity may reflect a decreased cyclic adenosine monophosphate production caused by non-selective beta-adrenoceptor blockade.