Combination treatment in antihypertensive drug trials.
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Antihypertensive Agents↗
Biomedical subjects
G Mancia
Publications and source records attributed to G Mancia.
Comparison between reproducibility and sensitivity of muscle sympathetic nerve traffic and plasma noradrenaline in man.
1. Although plasma noradrenaline and muscle sympathetic nerve traffic have been shown to be suitable markers of sympathetic activity in man, no study has systematically compared the reproducibility and sensitivity of these two indices of adrenergic tone. 2. Reproducibility data were collected in 10 subjects, in whom plasma noradrenaline was assessed by HPLC on blood samples withdrawn from an antecubital vein and efferent postganglionic muscle sympathetic nerve activity was measured by microneurography from a peroneal nerve, together with arterial blood pressure (Finapres technique). Measurements were obtained in a first session (session 1), 60 min later (session 2) and after 14 days (session 3). While muscle sympathetic nerve activity values recorded in the three different experimental sessions were closely and significantly correlated with each other (r always > 0.90, P < 0.001), noradrenaline showed a less significant correlation between sessions 1 and 2 (r = 0.71, P < 0.05) or no correlation between sessions 1 and 3 (r = 0.45, P not significant). 3. Sensitivity data were collected by evaluating muscle sympathetic nerve activity and noradrenaline values in three different age groups (young, middle-age and old subjects, n = 18), in three groups with different blood pressures (normotensive, mild and severe hypertensive subjects, n = 30) and in a group of eight subjects before and after a physical training programme, i.e. conditions known to increase or reduce sympathetic cardiovascular drive. Muscle sympathetic nerve activity was significantly increased by aging and hypertension, and reduced by physical training. The noradrenaline changes were much less marked and consistent. 4. These data suggest that muscle sympathetic nerve activity has a greater short- and medium-term reproducibility than noradrenaline. In several conditions known to modify sympathetic cardiovascular drive muscle sympathetic nerve activity also appears to change more clearly than noradrenaline.
Adolescent↗
Blood pressure, ageing and mortality.
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Age Distribution↗
Structural arteriolar changes in diabetes mellitus.
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Arterioles↗
Large and medium sized artery abnormalities in untreated and treated hypothyroidism.
BACKGROUND: Hypothyroidism is frequently accompanied by cardiac dysfunction, increased vascular resistance and a greater prevalence of hypertension. Whether this condition is also accompanied by alterations of large artery function and structure is not known, however. PATIENTS AND METHODS: We investigated radial artery compliance and wall thickness as well as carotid artery compliance in 11 normotensive recently diagnosed and never treated hypothyroid patients. Fifteen euthyroid healthy age- and sex-matched subjects served as controls. No subject had evidence of large artery atherosclerotic lesions. Carotid artery diameter was evaluated continuously by a B-M mode device and carotid compliance obtained by the Reneman formula. Radial artery diameter and wall thickness were continuously acquired over the systodiastolic blood pressure range (beat-to-beat finger measurement) by an echo-tracking device, and compliance (Langewouters formula) was expressed as the integral of the area under the compliance/blood pressure curve normalized for pulse pressure. RESULTS: Patients with hypothyroidism showed greater radial wall thickness (+109%, P < 0.01) and compliance (+58%, P < 0.03) than controls. Carotid artery compliance was not different in the two groups. In 10 hypothyroid patients L- tiroxine therapy for 9.0 +/- 2.3 months did not change carotid artery function but markedly reduced radial artery wall thickness (-36%, P < 0.05) and compliance (-20%, P < 0.05). CONCLUSIONS: Hypothyroidism is associated with early arterial structural and functional alterations, which involve more muscular than elastic arteries. These alterations, however, are reversible by hormonal replacement therapy.
Blood Pressure↗
Assessment of antihypertensive treatment by ambulatory blood pressure.
ADVANTAGES OF AMBULATORY BLOOD PRESSURE MONITORING: Ambulatory blood pressure monitoring is now used widely to assess the efficacy of antihypertensive drugs in daily life conditions. These 24-h measurements have a number of advantages compared to conventional sphygmomanometric readings. Although a small placebo effect is observed in the first few hours after placebo administration, 24-h average blood pressure is substantially devoid of any placebo effect. Moreover, ambulatory blood pressure is not affected by the alerting reaction usually observed during the doctor's visit. When the 24-h average value is considered, ambulatory blood pressure is more reproducible than clinic blood pressure. Finally, ambulatory blood pressure is prognostically more important than clinic blood pressure, since the end-organ damage associated with hypertension is more closely related to 24-h than to clinic blood pressure. Ambulatory blood pressure monitoring is therefore particularly useful when testing the efficacy of new antihypertensive agents on 24-h blood pressure. TESTING THE COMBINATION OF VERAPAMIL AND TRANDOLAPRIL: In a recent study we evaluated the efficacy of a fixed combination of verapamil and trandolapril using both clinic and ambulatory blood pressure measurements. Ambulatory blood pressure monitoring showed that the effect of the combination of verapamil and trandolapril was greater than the effect of either of the two drugs administered alone. However, the clinic blood pressure measurements failed to show any systemically greater effect with the combination versus monotherapy. This further indicates that ambulatory blood pressure is superior to conventional blood pressure in the assessment of antihypertensive drugs.
Antihypertensive Agents↗
Björn Folkow Award Lecture. The sympathetic nervous system in hypertension.
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Animals↗
Autonomic cardiac regulation in obstructive sleep apnea syndrome: evidence from spontaneous baroreflex analysis during sleep.
OBJECTIVE: To assess spontaneous baroreceptor-heart rate reflex sensitivity during sleep in patients with obstructive sleep apnea syndrome, a condition associated with increased cardiovascular morbidity and mortality and characterized by marked sympathetic activation, which is believed to originate from hypoxic chemoreceptor stimulation, although little is known of other possible mechanisms such as baroreflex impairment. DESIGN AND METHODS: In 11 patients with severe obstructive sleep apnea syndrome (mean+/-SD age 46.8+/-8.1 years, apnea/hypopnea index 67.9+/-19.1 h), who were normotensive or borderline hypertensive during wakefulness by clinic blood pressure measurements, finger blood pressure was monitored beat-by-beat non-invasively (Finapres) at night during polysomnography. Periods of wakefulness and sleep were identified based on electroencephalographic recordings. Baroreflex sensitivity was assessed by the sequence technique, as the slope of the regression line between spontaneous increases or reductions in systolic blood pressure (SBP) and the related lengthening or shortening in the RR interval, occurring over spontaneous sequences of four or more consecutive beats. The number of these sequences was also computed, as an additional index of baroreflex engagement by the spontaneous blood pressure fluctuations. The controls were age-related normotensive or borderline hypertensive subjects without sleep apnea who had been investigated in previous studies; in these subjects blood pressure was recorded intra-arterially over 24 h in ambulatory conditions and spontaneous baroreflex sensitivity was assessed by the sequence technique. RESULTS: In our patients the lowest nocturnal arterial oxygen saturation was 78.6+/-12.1% (mean+/-SD). During sleep, the number of pooled +RR/+SBP and -RR/-SBP sequences per hour was 20.3+/-2.7 per h in patients with sleep apnea and 27.1+/-2.1 /h in controls (means+/-SEM). The average baroreflex sensitivity during sleep periods was 7.04+/-0.8 ms/mmHg in sleep apnea patients and 10.05+/-2.1 ms/mmHg in controls. Both the pooled number of sequences and baroreflex sensitivity values of the sleep apnea patients were significantly (P < 0.01) less than the corresponding night values of control subjects. In the sleep apnea patients, at variance from controls, baroreflex sensitivity did not show any increase during sleep compared with its values during wakefulness (6.9+/-1.0 ms/mmHg). CONCLUSIONS: Our data provide evidence that spontaneous baroceptor reflex sensitivity is depressed in severe obstructive sleep apnea syndrome. This suggests that in such patients baroreflex dysfunction and not only chemoreceptor stimulation by hypoxia may be involved in the sympathetic activation which occurs during sleep. Such dysfunction may contribute to the higher rate of cardiovascular morbidity and mortality reported in these patients.
Adult↗
Effects of cigarette smoking on carotid and radial artery distensibility.
OBJECTIVE: Cigarette smoking acutely induces a marked increase of blood pressure and heart rate. This is accompanied by a marked reduction of radial artery distensibility. Whether this reflects an alteration of arterial mechanics of large elastic arteries as well is not established, however. DESIGN AND METHODS: In this study we addressed the acute effects of smoking on the stiffness of a peripheral medium-sized muscular artery and a large elastic vessel. We studied seven healthy normotensive smokers (age 28+/-7 years, mean+/-SEM), in the absence of smoking for at least 24 h. Radial artery (NIUS 02) and carotid artery diameter (WTS) were concomitantly acquired beat-to-beat in the 5 min before, during and after smoking of a cigarette containing 1.2 mg of nicotine. Blood pressure and heart rate were concomitantly recorded by a Finapres device. Radial and carotid artery distensibility were calculated according to the Langewouters and Reneman formulae, respectively. Data were collected for consecutive 30 s periods. Statistical comparisons were performed between the three different phases and, within each phase, between 30 s periods. In five subjects the protocol was repeated after 1 week using a stran rather than a cigarette to obtain data under sham smoking. RESULTS: Smoking increased systolic blood pressure by 14%, diastolic blood pressure by 10% and heart rate by 27%. Radial artery diameter was reduced during smoking (-3.7%) and more so after smoking (-14.8%), while carotid artery diameter did not change significantly either during or after smoking. Radial artery distensibility was also significantly reduced only after smoking (-41.3%, P < 0.01), while carotid artery distensibility was significantly reduced both during (-33.3%) and after smoking (-27.2%) (P < 0.01 versus before). No changes in blood pressure, heart rate and arterial wall mechanics were induced by sham smoking. CONCLUSIONS: Acute cigarette smoking reduces distensibility not only in medium-sized but also in large elastic arteries, therefore causing a systemic artery stiffening. The mechanisms of these effects remain to be determined. However, it is likely that adrenergic mechanisms are responsible for the arterial distensibility alterations.
Adult↗
Differential alterations of common carotid and femoral artery distensibility in 12-week-old spontaneously hypertensive rats.
OBJECTIVE: In essential hypertension, the mechanical properties of the radial artery have been shown to be largely unaltered, whereas more controversial and less reliable data have been obtained for the common carotid artery. We therefore examined the distensibility/pressure relationships of the predominantly elastic common carotid artery and of the predominantly muscle-type femoral artery in 12-week-old normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). METHODS: Eleven 12-week-old SHR and 10 age-matched WKY rats were anesthetized with sodium pentobarbitone. Blood pressure and pulse rate were measured by catheters inserted in the common carotid and in the femoral arteries, while contralateral arterial diameter was continuously recorded via an echo-tracking device. Arterial compliance was derived according to the Langewouters formula, and its values were normalized for the diameter, to obtain distensibility/pressure curves and to calculate the distensibility index. The Peterson elastic modulus was also calculated in order to obtain a pressure-independent estimate of arterial mechanical properties. RESULTS: Femoral artery distensibility/pressure curves and distensibility index were similar in the two groups of rats, the latter being 1.13+/-0.13 mm/mmHg10(-3) in SHR and 1.28+/-0.15 mm/mmHg10(-3) in WKY rats (means+/-SEM; NS). In contrast, in SHR, common carotid artery mechanical properties were clearly impaired, as shown by a marked reduction in distensibility index (2.55+/-0.16 mm/mmHg10(-3) in SHR versus 3.4+/-0.3 mm/mmHg10(-3) in WKY rats; P< 0.05), and by a significant increase in the Peterson elastic modulus. CONCLUSIONS: In the SHR model, high blood pressure alters the mechanics of large arteries even in the relatively early stage of the disease; however, the alterations are not homogeneous inasmuch elastic-type vessels are affected to a much greater extent than muscle-type vessels.
Animals↗
Antihypertensive effects of combined lisinopril and hydrochlorothiazide in elderly patients with systodiastolic or systolic hypertension: results of a multicenter trial.
This study was aimed at evaluating the antihypertensive effect of lisinopril and hydrochlorothiazide administered in the fixed combination of 20 and 12.5 mg, respectively, on clinic and 24-h blood pressure in elderly patients (age, 68.8 +/- 5.8 years, mean +/- SD) with mild-to-moderate essential systodiastolic or isolated systolic hypertension. After a washout period of 4 weeks, patients received once daily lisinopril combined with hydrochlorothiazide for a 6-week period. At the end of the washout and treatment periods, clinic blood pressure was assessed 24 h after dosing, and 24-h ambulatory blood pressure was monitored, taking blood pressure readings every 15 min. Pretreatment clinic blood pressure was 171.3 +/- 14.0/103.7 +/- 5.1 mm Hg (systolic/diastolic) in the group with systodiastolic hypertension (n = 405) and 179.6 +/- 9.4/83.6 +/- 5.4 mm Hg in the group with isolated systolic hypertension (n = 165). The corresponding 24-h average blood pressures were 144.1 +/- 13.9/88.7 +/- 8.4 mm Hg (n = 114) and 150.7 +/- 15.5/80.8 +/- 9.4 mm Hg (n = 40). Clinic blood pressure was significantly reduced by treatment in both groups. This was the case also for ambulatory blood pressure, which was reduced by 9.6 +/- 0.9%/9.9 +/- 0.9% in systodiastolic and by 11.8 +/- 1.3%/8.5 +/- 1.5% in isolated patients with systolic hypertension (p < 0.05 at least for all differences). The antihypertensive effect was similar in patients older and younger than 70 years. In all groups, it was manifest both during the day and the nighttime and was still significant after 24 h. Thus single daily administration of combined lisinopril-hydrochlorothiazide effectively reduces blood pressure in elderly patients with hypertension.
Aged↗
Smoking impairs baroreflex sensitivity in humans.
In 10 healthy smokers, finger blood pressure was recorded continuously for 1 h in a supine control condition and for 1 h while smoking four cigarettes, one every 15 min. Smoking increased average systolic blood pressure (+19%, P < 0.01) and its variability and reduced pulse interval (reciprocal of heart rate, -22%, P < 0.01) and its variability. Baroreflex sensitivity, as assessed by the slope of spontaneous hypertension/bradycardia or hypotension/tachycardia sequences and by the alpha-coefficient (squared ratio between pulse interval and systolic blood pressure spectral powers at 0.1 Hz) was significantly decreased (P < 0.01) during smoking, whereas there were no effects of smoking on the reflex changes in pulse interval induced by carotid baroreceptor stimulation through a neck suction device. Sham smoking by a drinking straw had no effects on any of the above parameters. Thus, when assessed in the absence of laboratory maneuvers in daily life conditions, baroreflex sensitivity is markedly impaired by smoking. This impairment may contribute to the smoking-induced increase in blood pressure and heart rate as well as to the concomitant alterations in their variability.
Adult↗
Performance of the AM-5600 blood pressure monitor: comparison with ambulatory intra-arterial pressure.
The AM-5600 is a new device that simultaneously monitors electrocardiogram (ECG) and noninvasive blood pressure (BP) over a 24-h period. BP readings (Korotkoff sounds and cuff air pressure) are stored into the recorder, allowing the removal of BP artifacts after a visual check. In 12 subjects with essential hypertension, we compared BP values simultaneously provided by the AM-5600 and intra-arterial recordings. At rest, noninvasive systolic BP (SBP) values were lower (5.4 +/- 4.9 mmHg) and diastolic BP (DBP) values were higher (7.3 +/- 7.3 mmHg) than were intra-arterial values. In ambulatory conditions (9 subjects), between-method discrepancies were +0.8 +/- 6.1 and +12.2 +/- 7.4 mmHg for 24-h SBP and DBP, respectively. AM-5600 underestimated 24-h intra-arterial SBP and DBP SD, but it accurately tracked intra-arterial SBP and DBP changes. Editing removed 22.1% of total readings, slightly reducing between-method discrepancies. Thus the AM-5600 provides an accurate average estimate of resting and ambulatory SBP and, for DBP, a less accurate estimate that is slightly improved by editing. The AM-5600 allows accurate description of SBP and DBP profiles and thus may be suitable to describe the abrupt BP changes accompanying a number of clinical events.
Adult↗
Primary prevention of cardiovascular disease.
Antihypertensive drug treatment has been shown to significantly decrease cardiovascular morbidity and mortality rates in hypertensive subjects and to reduce the occurrence of major hypertension-related complications, such as stroke, coronary artery disease, congestive heart failure and renal insufficiency. Despite these favorable effects, several issues related to antihypertensive treatment remain to be clarified. This paper will discuss some of these issues, with particular reference to the effects of blood pressure lowering on renal diseases and coronary heart disease. It will also discuss the ongoing clinical trials aimed at clarifying some unsolved issues of antihypertensive treatment. The objective of the International Nifedipine GITS Study Intervention as a Goal in Hypertensive Treatment was to provide information on the effects of calcium antagonist treatment on high blood pressure values and on hypertension-related cardiovascular complications in a high-risk hypertensive population.
Antihypertensive Agents↗
Combined effects of hypertension and hypercholesterolemia on radial artery function.
Compliance and distensibility of middle-sized conduit arteries are increased in hypertension and reduced in hypercholesterolemia. Despite their frequent association in the same individual, the combined effect of these two conditions on arterial mechanical properties is unknown. We studied four groups of age- and sex-matched subjects: 10 normotensive normocholesterolemic subjects, 10 mild hypertensive normocholesterolemic subjects, 10 mild hypercholesterolemic normotensive subjects, and 10 mild hypertensive and mild hypercholesterolemic subjects. We measured radial artery diameter by an echotracking device and beat-to-beat blood pressure from an ipsilateral finger. Compliance-pressure and distensibility-pressure curves were derived by Langewouters' formula. Between-group comparisons were made by calculating for both compliance and distensibility the integral of the area under the portion of the curve common to the four groups ("isobaric" compliance and distensibility). Blood pressure was similarly elevated in the two hypertensive groups, and serum cholesterol was similarly elevated in the two hypercholesterolemic groups. Compared with values in normotensive normocholesterolemic subjects, isobaric compliance and distensibility were greater in hypertensive normocholesteroclemic (+38% and 47%, respectively) and smaller in normotensive hypercholesterolemic (-6% and -23%) subjects. However, when both hypertension and hypercholesterolemia were present, isobaric compliance and isobaric distensibility were significantly reduced (-26% and -18%, P < .05). Therefore, hypercholesterolemia reverses the effect of hypertension on arterial compliance and causes arterial stiffening, as when present alone.
Adult↗
Baroreflex impairment by low sodium diet in mild or moderate essential hypertension.
Low sodium intake is the most widely used nonpharmacological approach to the treatment of hypertension. Although nonpharmacological treatment is by definition regarded as safe, the suggestion has been made that low sodium intake is not totally devoid of inconveniences, and animal data have shown it to be accompanied by an impairment of reflex blood pressure control and homeostasis. However, no data exist on this issue in humans. In mild essential hypertensive patients (age, 34.1+/-3.3 years [mean+/-SEM]), we measured beat-to-beat arterial blood pressure (finger photoplethysmographic device), heart rate (electrocardiogram), and efferent postganglionic muscle sympathetic nerve activity (microneurography) at rest and during baroreceptor stimulation and deactivation, induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Measurements were performed at the end of three dietary periods, ie, after 8 days of regular sodium intake (210 mmol NaCl/d), low sodium intake (20 mmol NaCl/d) with unchanged potassium intake, and again regular sodium intake. Compared with the initial regular sodium diet, low sodium intake reduced urinary sodium excretion, whereas urinary potassium excretion was unchanged. Systolic blood pressure was significantly (P<.05), although slightly, reduced, whereas diastolic blood pressure was unaffected. Muscle sympathetic nerve activity was increased by 23.1+/-5.2% (P<.05). The increase was accompanied by a clear-cut impairment of the baroreceptor ability to modulate muscle sympathetic nerve activity, ie, by a 43.9+/-5.7% (P<.01) reduction in the sensitivity of the baroreceptor-muscle sympathetic nerve activity reflex compared with the control condition. Baroreceptor modulation of heart rate was also impaired, although to a smaller and less consistent extent. When regular sodium intake was restored, all the above-mentioned parameters and baroreflex responses returned to the values observed at the initial regular sodium diet. These data raise evidence that in humans sodium restriction may impair the arterial baroreflex. This may be responsible for the sympathetic activation occurring in this condition and for the impairment of blood pressure homeostasis.
Adult↗
Ambulatory and home blood pressure normality in the elderly: data from the PAMELA population.
To determine ambulatory blood pressure (BP) means and distributions in an elderly population, we studied a random sample of 800 subjects stratified by sex and representative of residents aged 65 to 74 years of the city of Monza. Participation was 50%. Measurements consisted of clinic BP (average of three measurements with mercury sphygmomanometry), home BP (average of morning and evening measurements with a semiautomatic device), and ambulatory BP (SpaceLabs 90207). Clinic BP was obtained before and after home and ambulatory BP measurements. In normotensive and untreated hypertensive subjects (n=248), clinic, home, and ambulatory BPs were significantly related (P<.001). The means of the clinic BPs obtained on consecutive days were very similar and markedly higher than 24-hour average BP (+25 mm Hg systolic and + 10 mm Hg diastolic, P<.001). Nighttime BP was markedly less than daytime BP (-14 and -13 mm Hg, P<.001), whereas home BP values occurred approximately midway between clinic and 24-hour average BP values. Only minor differences existed between data in men and women, and the differences in clinic, home, and ambulatory BP values occurred in both normotensive and untreated hypertensive subjects. All BPs were similar in the untreated and treated hypertensive groups. Thus, as previously reported in subjects younger than 65 years, in the elderly fraction of the population, 24-hour average BP is much lower than clinic BP. The upper limit of normality for 24-hour average BP (calculated as the value corresponding to 140/90 mm Hg clinic BP) is about 120 mm Hg systolic and 76 mm Hg diastolic. At variance with data from younger subjects, home BP in the elderly is higher than 24-hour average BP. However, similar to data from younger subjects, clinic, home, and ambulatory BPs are higher in treated hypertensive than normotensive elderly subjects, indicating that in hypertensive elderly subjects, antihypertensive treatment does not commonly achieve full BP control both inside and outside the clinic environment.
Age Factors↗
Broadband spectral analysis of blood pressure and heart rate variability in very elderly subjects.
Systolic blood pressure (SBP) variability is increased and R-R interval variability is reduced in the elderly. Little is known, however, about how SBP and R-R interval variabilities change in the very elderly. More important, however, it is not known which frequency components of SBP and R-R interval variability are affected significantly. We addressed this issue in subjects older than 70 years by broadband spectral analysis, which allows all variability components from the lowest to the highest frequency to be considered. In 20 very elderly normotensive subjects (mean +/- SD age, 78.1 +/- 6.8 years) and 28 normotensive adult subjects (36.1 +/- 7.1 years), noninvasive finger blood pressure and R-R intervals were recorded continuously for 30 minutes in the supine position and 15 minutes in the upright position. SBP and R-R interval power spectral densities were computed over the entire frequency region between 0.005 Hz (0.007 Hz in the upright position) and 0.5 Hz. Overall SBP variability (SD) was greater and overall R-R interval variability was less in very old subjects than in adult subjects. All spectral R-R interval powers were reduced significantly in very elderly individuals. The spectral SBP powers were greater in the very elderly group than in the adult group only in the very-low-frequency range (<0.04 Hz). This was true in the supine and the standing positions. With subjects in the standing position, the shape of the broadband spectra differed in the very old and adult subjects because in the former group the increase in SBP and R-R interval power around 0.1 Hz that was seen in the latter was blunted. Therefore, in very elderly subjects a reduction in overall R-R interval variability is accounted for by a reduction in all of its frequency components. The accompanying increase in overall BP variability, however, results from a nonhomogeneous behavior of its frequency components, which consists of an increase in the very low frequency and a concomitant reduction in the higher frequency powers. The mechanisms responsible for these changes may be complex, but at least they may in part reflect the baroreflex impairment and autonomic dysfunction that characterize aging.
Adult↗