BACKGROUND: In 1989, the European Working Party on High Blood Pressure in the Elderly started the double-blind, placebo-controlled, Systolic Hypertension in Europe Trial to test the hypothesis that antihypertensive drug treatment would reduce the incidence of fatal and nonfatal stroke in older patients with isolated systolic hypertension. This report addresses whether the benefit of antihypertensive treatment varied according to sex, previous cardiovascular complications, age, initial blood pressure (BP), and smoking or drinking habits in an intention-to-treat analysis and explores whether the morbidity and mortality results were consistent in a per-protocol analysis. METHODS: After stratification for center, sex, and cardiovascular complications, 4695 patients 60 years of age or older with a systolic BP of 160 to 219 mm Hg and diastolic BP less than 95 mm Hg were randomized. Active treatment consisted of nitrendipine (10-40 mg/d), with the possible addition of enalapril maleate (5-20 mg/d) and/or hydrochlorothiazide (12.5-25 mg/d), titrated or combined to reduce the sitting systolic BP by at least 20 mm Hg, to below 150 mm Hg. In the control group, matching placebo tablets were employed similarly. RESULTS: In the intention-to-treat analysis, male sex, previous cardiovascular complications, older age, higher systolic BP, and smoking at randomization were positively and independently correlated with cardiovascular risk. Furthermore, for total (P = .009) and cardiovascular (P = .09) mortality, the benefit of antihypertensive drug treatment weakened with advancing age; for total mortality (P = .05), the benefit increased with higher systolic BP at entry, while for fatal and nonfatal stroke (P = .01), it was most evident in nonsmokers (92.5% of all patients). In the perprotocol analysis, active treatment reduced total mortality by 24% (P = .05), reduced all fatal and nonfatal cardiovascular end points by 32% (P<.001), reduced all strokes by 44% (P = .004), reduced nonfatal strokes by 48% (P = .005), and reduced all cardiac end points, including sudden death, by 26% (P = .05). CONCLUSIONS: In elderly patients with isolated systolic hypertension, stepwise antihypertensive drug treatment, starting with the dihydropyridine calcium channel blocker nitrendipine, improves prognosis. The per-protocol analysis suggested that treating 1000 patients for 5 years would prevent 24 deaths, 54 major cardiovascular end points, 29 strokes, or 25 cardiac end points. The effects of antihypertensive drug treatment on total and cardiovascular mortality may be attenuated in very old patients.

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Brain stem mechanisms of sleep.

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Evaluation of a slow-release clonidine preparation by direct continuous blood pressure recording in essential hypertensive patients.

The antihypertensive effect of a slow-release (SR) clonidine preparation was evaluated in hypertensive patients not confined to bed using a 24-h intraarterial blood pressure monitoring (Oxford) method. The monitoring was carried out during placebo administration and after 7-10 days of daily administration of SR clonidine in a single oral dose (250 or 500 microgram). An analysis of all the blood pressure values obtained was performed by computer. The results were as follows: (a) SR clonidine significantly reduced the 24-h systolic and diastolic arterial pressure by 16 and 10 mm Hg, respectively (mean +/- SE). (b) The reduction was well evident throughout the 24-h period, the average decrease in mean arterial pressure observed during the first, second, and third 8-h period after the administration of the drug being 11, 14, and 14 mm Hg, respectively. (c) The blood pressure reduction was similar during the daytime and the nighttime, despite the lower base-line value that occurred in the latter condition. (d) There was no consistent change in blood pressure variability, as measured in each patient by the standard deviation of the blood pressure values, with SR clonidine. SR clonidine caused a reduction in heart rate that, as that in blood pressure, was well evident throughout the 24 h. It is concluded that SR clonidine is an effective antihypertensive agent and that a single administration of this drug can produce a clear-cut reduction in the blood pressure values of hypertensive patients for a 24-h period.

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Effects of single and repeated doses of the calcium antagonist felodipine on blood pressure, renal function, electrolytes and water balance, and renin-angiotensin-aldosterone system in hypertensive patients.

Doses of 10 mg b.i.d. of the new dihydropyridine calcium antagonist, felodipine, were tested for seven consecutive days in 11 hospitalized hypertensive patients. A significant reduction of both systolic and diastolic blood pressures, with patients in both the supine and upright positions, occurred immediately after the first dose and was maintained (daily average 15%) throughout the following days. An increase in heart rate was observed after the first dose (15 and 23 beats/min, in supine and upright postures), and subsequently declined to average values of 8 and 14 beats/min on the seventh day. There was a marked natriuretic response during the first and second day, during which an average negative sodium balance of 95 mmol developed; on the following days sodium output was not significantly different from control, but a negative balance averaging 135 mmol was still present on the seventh day of felodipine administration. A moderate negative potassium balance also progressively developed and reached -48 mmol on the seventh day. Glomerular filtration rate was unchanged, but renal plasma flow increased significantly during administration of felodipine. Plasma renin activity and plasma aldosterone were also increased very moderately by felodipine. Compared with previous observations by our group with higher doses of felodipine (12.5, 25, and 50 mg t.i.d.), 10 mg b.i.d. of this new calcium antagonist appear to exert a marked and prolonged blood pressure reduction, accompanied by a definite natriuretic instead of an antinatriuretic effect.

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Haemodynamic effects of isometric handgrip exercise in patients convalescent from myocardial infarction.

1. Cardiac performance in response to 30% maximal isometric handgrip exercise was studied in fourteen patients convalescing uneventfully from a first myocardial infarction. In each patient, heart rate, mean arterial blood pressure and cardiac index were measured, and total peripheral resistance was calculated. The covariance of changes in the mean arterial blood pressure and cardiac index in these patients was matched against tolerance limits calculated from published data for normal subjects. 2. All patients had normal haemodynamic values at rest, and showed the usual rise of heart rate and mean arterial pressure during handgrip exercise. However, in six patients (group 1) the rise in mean arterial pressure was, as in normal subjects, accounted for mainly by a rise in cardiac index, with no consistent change in peripheral resistance. In eight patients (group 2), the mean arterial pressure rose to the same level as in group 1, but with a consistent increase in peripheral resistance and a smaller rise in the cardiac index. 3. It is suggested that in a substantial proportion of patients who are making a seemingly uncomplicated recovery from myocardial infarction, it may be possible to unmask an impairment of left ventricular function by means of isometric handgrip exercise.

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Does the baroreceptor-heart rate reflex indicate the capacity of the arterial baroreceptors to control blood pressure?

1. We have examined the question asked in the title by studying: the carotid baroreceptor reflex in man with a variable-pressure neck chamber; the carotid baroreceptor reflex in conscious rabbits with a variable-pressure capsule around the carotid bifurcation; and the barorecptor-heart rate reflex. 2. At rest, the association between the sensitivities of the carotid baroreceptor-blood pressure and -heart rate reflexes, and of these with the baroreceptor-heart rate reflex, is weak. Exercise causes dissociation between control of blood pressure and heart rate. In hypertension, depression of the baroreceptor-heart rate reflex does not reflect the altered characterisitics of the carotid sinus-blood pressure reflex.

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Cryoactivation fails to augment plasma renin activity in the cat.

1. Active and cryoactivated renin (plasma renin) activity after incubation at -5 degrees C for 4 days, were measured in cat plasma sampled before and during the following procedures: suprarenal aortic stenosis, electrical stimulation of the pons and mild hypotensive haemorrhage. 2. Under all experimental conditions the values of plasma renin activity for both the activated and non-activated samples were similar. 3. The absence of a cryoactivatable aliquot of renin suggests that in cat plasma the inactive form of the enzyme either is actually absent or has a liability to the action of cold different than in other animal species.

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Clonidine and carotid baroreflex in essential hypertension.

Clonidine is believed to reduce blood pressure by a neural action and animal experiments suggest that this consists in potentiation of baroreflexes. In 16 patients with essential hypertension we studied the effects of alterations in carotid sinus baroreceptor activity (neck chamber technique) on arterial blood pressure (catheter measurements) and heart rate, before and after intravenous administration of 150 microgram and 300 microgram of clonidine. The magnitude of the reflex responses was assessed by the slope of the linear regressions relating applied increase and decrease in tissue pressure at the carotid sinus (and therefore applied decrease and increase in carotid sinus transmural pressure) and resulting changes in mean arterial pressure and R-R interval. Clonidine caused a marked reduction in mean arterial pressure (-26 +/- 3 mm Hg) and a slight but significant reduction in heart rate (-5 +/- 1 b/min). There was no evidence for a potentiation of the baroreceptor influence on blood pressure, although a slight potentiation of the baroreceptor influence on heart rate was observed in few instances. We conclude that in man clonidine can exert a pronounced hypotensive effect without potentiating baroreceptor influence on blood pressure. Therefore this mechanism does not play a prominent role in the clinical antihypertensive action of the drug.

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