Clinical trials on the treatment of hypertension. A critical appraisal.
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Australia↗
Biomedical subjects
A Zanchetti
Publications and source records attributed to A Zanchetti.
[Use of lasers in arterial revascularization].
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Aortic Diseases↗
Carotid sinus reflexes during postural changes, naturally elicited fighting behaviour, and phases of sleep in the cat.
Reflex responses of mean blood pressure and of heart rate to either bilateral common carotid occlusion (CO) or unilateral carotid sinus dilatation (CSD) during rest and different behaviours have been compared in conscious cats. Unloading and loading the carotid sinus receptors elicited equal reflex responses both of mean blood pressure and of heart rate during control immobile behaviour (CO: +34 +/- 6 mmHg and +35 +/- 6 beats . min-1; CSD: -37 +/- 4 mmHg and -52 +/- 11 beats . min-1), standing on the hindlimbs (CO: +36 +/- 5 mmHg and +29 +/- 5 5 beats . min-1; CSD: -40 +/- 6 mmHg and -61 +/- 10 beats . min-1), fighting against an attacking animal (CO: +34 +/- 5 mmHg and +31 +/- 5 beats . min-1; CSD: -37 +/- 5 mmHg and -56 +/- 10 beats . min-1), quiet wakefulness (CO: +37 +/- 5 mmHg and +38 +/- 4 beats . min-1; CSD: -34 +/- 4 mmHg and -53 +/- 8 beats . min-1) and synchronised sleep (CO: +36 +/- 5 mmHg and +37 +/- 4 beats . min-1; CSD: -36 +/- 4 mmHg and -52 +/- 6 beats . min-1). Desynchronised sleep was associated with an identical response to CSD (-30 +/- 4 mmHg and -51 +/- 7 beats . min-1) but with a reduced (p less than 0.01) reflex response to CO (+18 +/- 3 mmHg These data indicate that carotid sinus baroreflexes largely maintain their ability to modulate pressure upwards and downwards when blood pressure has been reset at somewhat higher levels by standing and fighting and at somewhat lower levels by synchronised sleep. The selective depression of carotid occlusion responses during desynchronised sleep suggests a central or peripheral shift of the baroreflex stimulus-response curve or a selective central inhibition of the reflex response to baroreceptor unloading.
Animals↗
Participation of the renin-angiotensin system in the maintenance of blood pressure during changes in posture in patients with essential hypertension.
To assess whether and how the activation of the renin-angiotensin system that occurs in response to changes in posture contributes to the maintenance of blood pressure, we measured blood pressure, heart rate, plasma noradrenaline and plasma active and inactive renin in patients with essential hypertension in the supine, sitting and standing positions, (each sustained for 30 min), before and after administration of captopril. These studies were performed before and after a brief period of diuretic therapy. Both in the normal and in the sodium depleted state captopril reduced the normal adaptive response of blood pressure to changes in body position, whereas the responses of heart rate and plasma noradrenaline to these stimuli were unaffected by captopril. In contrast, the postural increases in active renin were magnified after captopril while inactive renin was unchanged throughout these acute studies. Our results indicate that during mild but rather prolonged postural stresses the generation of angiotensin by active renin supports blood pressure either through its direct vasoconstrictive effect and/or by potentiating the activity of the sympathetic nervous system. It is unlikely that the changes in active renin depend upon conversion from the inactive form.
Adult↗
Reflex cardiovascular regulation in humans.
Although studies of the cardiovascular control exerted by arterial baroreceptors in man are limited by technical and ethical problems, the variable-pressure neck-chamber technique has provided a considerable amount of information about this topic. This paper focuses on the carotid baroreceptor reflex as evaluated by studies using the neck-chamber technique and examines this control in a number of physiological and pathophysiological states. The results of these studies suggest that in normotensive subjects the set-point of the reflex is located eccentrically toward its saturation, which makes this homeostatic mechanism more effective in counteracting a blood-pressure fall than a blood-pressure rise. They also suggest that the concept of an impairment of the arterial baroreflex in aging, exercise, and hypertension, though valid for the baroreceptor control of heart rate, is no longer tenable for the baroreceptor control of arterial pressure. The paper also reviews in humans the effects of arterial baroreceptors on regional circulations and on the excretion of humoral substances such as renin, and compares them with those of the cardiopulmonary receptors. It is suggested that the latter predominate over the former in the reflex modulation of plasma-renin activity, and that this is part of a homeostatic mechanism for blood-volume control.
Blood Pressure↗
Adrenergic sodium handling and the natriuretic action of calcium antagonists.
Stimulation and denervation experiments have provided evidence that adrenergic mechanisms can enhance sodium and water reabsorption from the renal tubule, and that this influence is probably exerted on the entire tubular extent. Reflexes originating from cardiopulmonary and renal receptors can control adrenergic renal sodium handling, and evidence has recently been presented that a reno-renal reflex tonically inhibits the contralateral sympathetic control of tubular reabsorption of sodium and water. Other investigations indicate that adrenergic renal sodium handling is mediated through alpha-rather than beta-receptors, and that the alpha-receptors are of the alpha 1-subtype. The question of whether the natriuretic action of calcium antagonists is, at least in part, mediated by interference with adrenergic control of tubular reabsorption cannot yet be definitely answered. Although available data are only preliminary, they do not support an important action of calcium antagonists on adrenergic renal sodium handling, but a separate contribution of impaired adrenergic control and of a direct tubular effect of calcium antagonists cannot be excluded.
Adrenergic Fibers↗
Natriuretic effect of calcium antagonists.
Calcium antagonists differ from traditional vasodilators by increasing renal water and sodium excretion, although the various calcium antagonist compounds influence renal excretory functions to a different extent. Two important aspects of the renal response to calcium antagonists are discussed, as they still need clarification: (a) the mechanisms of the diuretic and natriuretic effect; (b) the duration of this effect. Various mechanisms and sites of action can be envisaged to account for the diuretic and natriuretic action of these compounds. The action may be due to (a) a change in glomerular filtration rate and/or renal blood flow; (b) interference with renin release; (c) interference with aldosterone secretion and/or aldosterone action on distal tubule; (d) interference with adrenergic sodium handling; (e) a direct tubular action. Although the mechanisms may be multiple, the last type of action is likely to be the most important one. Recent balance studies of our group show that, although the diuretic and natriuretic actions of calcium antagonists are displayed acutely on the first or second day of administration, a negative sodium balance is maintained for at least 1 week, and the diuretic and natriuretic effects of these compounds are not overcome by water- and sodium-retaining mechanisms, unless the doses given are too large.
Aldosterone↗
International views of the use of calcium antagonists in the treatment of hypertension.
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Aging↗
Hemodynamic factors changing blood flow velocity waveform and profile in normal human brachial artery.
We have investigated the influence of changes of perfusion pressure and local peripheral resistance on blood flow velocity waveform and profile in normal human peripheral arteries. Blood flow velocity and profile were recorded from the distal end of the left brachial artery in ten normal subjects by means of an ultrasonic device. The records were obtained in basal conditions and after blood pressure in the brachial artery and local peripheral vascular resistance were changed, separately or together, by progressive inflation of two arm cuffs, one encircling the proximal half of the left arm and the other the middle part of the left forearm. Both blood flow velocity waveform and profile were shown to be markedly modified by changes in perfusion pressure and local peripheral vascular resistance. Reduction of perfusion pressure decreased both forward and reverse peak velocities, but had the largest effect upon reverse velocity. The upslope and the downslope of the forward velocity wave were left unchanged. Increase in local peripheral vascular resistance markedly augmented reverse peak velocity, whether perfusion pressure was normal or reduced. Increased resistance only slightly influenced peak forward velocity.
Arm↗
A non-invasive index of leg arterial perfusion pressure during walking, derived from cutaneous toe temperature.
This article describes and evaluates a non-invasive technique for continuous monitoring of hemodynamic changes in the legs during walking. The method involves monitoring of cutaneous toe temperature. In six normal subjects we have shown that, during exercise under carefully controlled conditions, a unique steady-state toe temperature exists for any given leg arterial perfusion pressure, when perfusion pressure is varied by means of an external occluding ankle cuff. Further, we have demonstrated a strong correlation between this external ankle cuff pressure and the time rate of changes of toe temperature during the test-period following occlusion. Correlation coefficients, r1, were between -1 and -0.88 (mean -0.95; standard deviation +/- 0.03) for big toe and between -1 and -0.87 (mean -0.94; standard deviation +/- 0.03) for third toe. We conclude that during walking the time profile of toe temperature changes is a useful index of changes in leg perfusion pressure. Therefore, toe temperature may be used to study the dynamics of leg arterial circulation in atherosclerotic occlusive diseases.
Adult↗
Antihypertensive and water and sodium balance effects of felodipine, a new vasodilating calcium antagonist, in hypertensive patients.
Felodipine, a new dihydropyridine derivative with a selective action on vascular smooth muscle, was investigated in 2 short term studies in hypertensive patients. In the first study, oral administration of felodipine 12.5 mg three times daily in a preliminary tablet formulation for 3 days significantly reduced supine and upright blood pressure with only a slight increase in heart rate and no clinically relevant signs of sodium and water retention. By increasing each dose to 25 and 50 mg three times daily, there was a further, but quite moderate, decrease in blood pressure; however, this was accompanied by an increase in heart rate and a tendency towards a reduction of creatinine clearance and urinary sodium output. In the second study, a new oral formulation containing 10 mg felodipine, administered twice daily for 7 days, was effective in lowering blood pressure without a clinically relevant tachycardia. Following the first dose of felodipine, urinary sodium excretion was slightly increased while potassium excretion showed only minor changes. The new calcium antagonist, felodipine, lowers blood pressure without the clinically relevant adverse reactions commonly related to other direct vasodilator antihypertensive drugs.
Adult↗
Mechanisms of blood pressure variability in man.
This paper will touch on three points derived from the studies our group has performed by means of continuous 24 hour blood pressure recording in humans. The first point will concern a description of the factors involved in the production of spontaneous blood pressure variability and in particular of our evidence that the magnitude of this phenomenon depends on arterial baroreflexes but also, and perhaps to a larger extent, on central modulation of the cardiovascular system. The second point will deal with the differences in blood pressure variability we have observed in subjects with normal and high blood pressure. Finally, the third point will briefly address the changes in blood pressure variability that take place with ageing.
Aging↗
Which drug to which patient?
When a decision to treat a given patient is taken, the embarrassing position arises of deciding which drug should first be prescribed. How can the safest choice be made? Should the physician follow a pathophysiological or an empirical approach? There is no doubt that the most rational approach would consist of matching the pharmacological properties of the drug with the pathophysiological disturbances of the patient. However, these are complex and variable, and their precise assessment in every hypertensive patient is hardly practicable. On the other hand, the pharmacological properties of drugs are often multiple, and sometimes imperfectly understood. The practical impossibility of obtaining a satisfactory pathophysiological profile of each hypertensive patient in order to choose the most suitable drug has strengthened the trend toward formulating and using stepped-care programmes. The philosophy behind these is that of lowering blood pressure with agents most likely to be effective with a minimum of untoward effects, of progressing from a simple start, generally prescribing a single drug at a low dose, to more complex therapeutic regimens. There is some evident soundness in this approach, but stepped-care programmes are sometimes criticized as dogmatic, and are contrasted with the individualized approach, the custom-tailoring provided by pathophysiological profiling. Undoubtedly, the first stepped-care programmes, as formulated in the USA in the 1970s, giving no other first choice than a thiazide diuretic, were rigid and had limitations. On the other hand, the 1978 WHO guidelines were more flexible, suggesting a first choice between either a diuretic or a beta-blocker.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Antagonists↗
Angiotensin converting enzyme inhibition in clinical practice. A re-examination of stepped-care: a retrospective and a prospective.
Diuretics have so far enjoyed a prominent position in all stepped-care programs, as the preferred first choice drug in most American schemes or as an alternative first choice drug with respect to beta-blockers in the WHO scheme. Among various reasons for this prominence has been that antihypertensive drugs available until recently all gradually led to sodium and water retention, and therefore required to be combined with a diuretic. This is no longer true: several antihypertensive agents are available now that do not require combination with diuretics, these new agents including not only beta-blockers but also angiotensin-converting enzyme (ACE) inhibitors and calcium entry blockers. Furthermore, some concern about the metabolic effects of diuretics has recently been raised, especially because of the failure to prevent coronary heart disease by the current diuretic-based antihypertensive regimens. Without denying the importance that diuretics have had in the past in making antihypertensive therapy successful and their continuing essential role in treating severe hypertension, it is likely, in my opinion, that in future years diuretics are going to be more often used as agents of second choice, mostly in combination with beta-blockers, ACE inhibitors, and, perhaps, some of the calcium blockers. In conclusion, although opinions of various experts about the sequence of choices between antihypertensive drugs may obviously differ, there is no doubt that the addition of new classes of effective agents, such as the ACE inhibitors and the calcium entry blockers, is making antihypertensive therapy more flexible and more easily suitable to the needs of individual patients.
Adrenergic beta-Antagonists↗
Renal and antihypertensive effects of felodipine in hypertensive patients.
The effects of small doses of felodipine (10 mg twice daily) on blood pressure, renal function and sodium and water balance were studied in 11 patients with arterial hypertension. Felodipine significantly reduced systolic and diastolic blood pressure: most of the antihypertensive effect was already evident on day 1 of administration (-18/-11 mmHg) and only slightly increased during the subsequent week. Heart rate rose moderately only during day 1 of felodipine administration (+7 beats/min). Sodium excretion was increased during days 1 and 2, and no signs of water and electrolyte retention was observed in the week during which the balance study could be performed (Na, -135 +/- 65 mmol/7 days). At relatively low doses felodipine appears to be an effective antihypertensive agent, initially exerting some diuretic and natriuretic action and subsequently being devoid of a water- and sodium-retaining action.
Adult↗
Acute and chronic converting enzyme inhibition reduces the vasomotor response to reflex sympathetic activation in man.
Several lines of evidence indicate that angiotensin II (ANG II) may potentiate the vascular response to sympathetic stimulation. However, there are no clear signs that this action of ANG II is physiologically relevant in man. To investigate this problem, we used the lower body negative pressure technique (LBNP, -15 mmHg) to deactivate cardiopulmonary receptors and reflexly stimulate the sympathetic nervous system. The haemodynamic (changes in blood pressure, heart rate, central venous pressure, forearm blood flow) and humoral effects [changes in plasma noradrenaline (PNA) and plasma renin activity (PRA)] of this manoeuvre were examined before and after blockade of angiotensin formation achieved by the administration of the converting enzyme inhibitor, captopril. Studies were performed in patients with essential hypertension in control conditions and after acute and chronic captopril treatment. We found that the reduction in forearm blood flow induced by LBNP was significantly diminished after acute and chronic captopril in spite of the fact that the fall in central venous pressure and the increases in PNA were similar to those observed in control conditions. In contrast, the response of renin to LBNP was enhanced, at least after acute captopril administration. These findings suggest that efficiency of the reflexes originating from the cardiopulmonary receptors is impaired after captopril. Angiotensin II contributes to the vasoconstrictive ability of the sympathetic nervous system, either through a direct vascular action or by enhancing the vascular responsiveness to noradrenaline stimulation. However, this sympathetic facilitatory action of ANG II does not appear to be extended on the adrenergic mechanisms which regulate renin release.
Adult↗
Doctor-elicited blood pressure rises at the time of sphygmomanometric blood pressure assessment persist over repeated visits.
Blood pressure assessment by a doctor triggers an alerting reaction which may raise patients' blood pressure to a marked degree. Because this may lead to an overestimation of the prevalence of hypertension, it is important to determine whether attenuation of this blood pressure rise occurs with repetition of the doctor's visit. In 16 ambulant inpatients with mild essential hypertension, blood pressure was recorded intra-arterially for 2 days, using the Oxford method. During the recording the patients had four 10-min visits during which blood pressure was repeatedly measured by a sphygmomanometer. The visits to each patient were made by a doctor who had never seen him or her before and were regularly distributed over the total daytime available. In nearly all patients intra-arterial blood pressure and heart rate were elevated throughout the 10 min of each visit, with a peak during the first 4 min and a subsequent decline. The peak mean blood pressure rises were 22.6 +/- 1.8, 20.3 +/- 2.4, 19.3 +/- 2.4 and 21.4 +/- 3.1 mmHg (means +/- s.e.m.) in the four visits. Respective peak heart rate rises were 17.7 +/- 1.7, 20.7 +/- 2.4, 19.8 +/- 2.2 and 17.0 +/- 1.9 beats/min. The reduced pressor and tachycardic responses observed at the 10th min of the visit were also similar in the four visits (blood pressure: 19, 15, 28 and 24% of the peak response; heart rate 21, 13, 24 and 9% of the peak response, respectively). These findings show that the blood pressure rise often accompanying sphygmomanometric blood pressure assessment by the doctor persists after several visits spaced at close time intervals.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Renal effects of calcium antagonists in hypertensive patients.
This summary report of various clinical studies by our group describes the effects on renal excretion of water and sodium of several different calcium antagonists (verapamil, gallopamil, nifedipine and felodipine) which were administered for variable periods of time (from a single administration to repeated doses over up to 10 days) to hypertensive patients. All calcium antagonists tested displayed some diuretic and natriuretic action, despite profound differences in chemical nature and in pharmacodynamic properties. On single-dose administration the renal action of calcium antagonists was prompt, appearing during the first few hours, and decaying and ending after 6 h. When repeated doses were administered over several days the effect was at a maximum during the first 2 days and then disappeared in the following days, but the negative sodium balance which developed during the first 2 days was maintained for at least 7-10 days. The natriuretic effect was not accompanied by any change in the glomerular filtration rate, but with felodipine, a natriuretic effect observed at small doses reverted to an antinatriuretic effect at higher doses, at which the glomerular filtration rate was slightly decreased.
Calcium Channel Blockers↗