Supine Blood Pressure Research Articles

Variation in the Human Matrix Metalloproteinase-9 Gene Is Associated With Arterial Stiffness in Healthy Individuals

Arterial stiffness is an important determinant of cardiovascular risk. Elastin is the main elastic component of the arterial wall and can be degraded by a number of enzymes including serine proteases and matrix metalloproteinases (MMPs). Serum MMP-9 levels correlate with arterial stiffness and predict cardiovascular risk. Polymorphisms in the MMP-9 gene are also associated with large artery function in subjects with coronary artery disease. Therefore, we investigated the influence of known MMP-9 (-1562C>T, R279Q) polymorphisms on arterial stiffness in a large cohort of healthy individuals (n=865). Aortic pulse wave velocity (PWV) and augmentation index were assessed. Supine blood pressure, biochemical markers, MMP-9 levels, and serum elastase activity (SEA) were also determined. Genomic DNA was extracted and genotyping performed. Aortic PWV, serum MMP-9, and SEA were higher in carriers of the rare alleles for the -1562C>T and R279Q polymorphisms. These polymorphisms were also associated with aortic PWV after correction for other confounding factors. Stepwise regression models with known or likely determinants of arterial stiffness revealed that approximately 60% of the variability in aortic PWV was attributable to age, mean arterial pressure, and genetic variants (P<0.001). We have demonstrated for the first time that aortic stiffness and elastase activity are influenced by MMP-9 gene polymorphisms. This suggests that the genetic variation in this protein may be involved in the process of large artery stiffening.

Physiological and catecholamine response to sympathetic stimulation in turner syndrome

Women with Turner syndrome have increased heart rate and high blood pressure (BP), and have been described as having high tolerance for emotional stress. We hypothesized that women with Turner syndrome have reduced catecholaminergic and physiological response to sympathetic stimulation, and that changes in BP and heart rate are related to their catecholamine response to sympathetic stimulation. Ten young women with Turner syndrome, age 17-34 years were the subjects of this study. Their response to sympathetic stimulation was compared to a group of 10 age-matched healthy women. After a period of 30 min resting, subjects and controls were subjected to an escalating series of sympathetic stimulation: orthostatic, cold pressor and exercise, and their plasma catecholamines and haemodynamic response were monitored and compared to resting levels. Resting heart rate was higher in Turner syndrome patients at 83 +/- 9 beats per min (bpm, mean +/- SD), as compared to controls (74 +/- 10 bpm, P < 0.05). Their supine BP was also higher at 122 +/- 9/84 +/- 6 vs. 106 +/- 11/70 +/- 9 mmHg (P < 0.02/< 0.02). The corresponding resting norepinephrine, but not epinephrine, was higher in Turner syndrome patients (2.54 +/- 1.09 nmol/l) as compared to controls (1.69 +/- 0.55 nmol/l, P < 0.02). In response to orthostatic stimulation and cold pressor test the systolic, but not the diastolic BP or heart rate, increased in Turner syndrome patients but not in the control group (P < 0.01). The change in blood catecholamine levels was comparable in both groups. Their physiological response to exercise was normal. Yet, the exercise-induced surge of norepinephrine and epinephrine in Turner syndrome patients was lower (P < 0.02). Turner syndrome is associated with dysregulation of the sympathetic nervous system (SNS), leading to tachycardia and high BP, increased resting norepinephrine levels, and a greater tolerance of the cathecholamine response to exercise.

Pyridostigmine Treatment Trial in Neurogenic Orthostatic Hypotension

Midodrine hydrochloride is the only drug demonstrated in a placebo-controlled treatment trial to improve orthostatic hypotension (OH) but it significantly worsens supine hypertension. By enhancing ganglionic transmission, pyridostigmine bromide can potentially ameliorate OH without worsening supine hypertension. To evaluate the efficacy of a single 60-mg dose of pyridostigmine bromide, alone or in combination with a subthreshold (2.5 mg) or suprathreshold (5 mg) dose of midodrine hydrochloride, compared with placebo. We report a double-blind, randomized, 4-way cross-over study of pyridostigmine in the treatment of neurogenic OH. A total of 58 patients with neurogenic OH were enrolled. After 1 day of baseline measurements, patients were given 4 treatments (3 active treatments [60 mg of pyridostigmine bromide; 60 mg of pyridostigmine bromide and 2.5 mg of midodrine hydrochloride; 60 mg of pyridostigmine bromide and 5 mg of midodrine hydrochloride] and a placebo) in random order on successive days. Blood pressure (BP) and heart rate were measured, both supine and standing, immediately before treatment and hourly for 6 hours after the treatment was given. No significant differences were seen in the supine BP, either systolic (P = .36) or diastolic (P = .85). In contrast, the primary end point of the fall in standing diastolic BP was significantly reduced (P = .02) with treatment. Pairwise comparison showed significant reduction by pyridostigmine alone (BP fall of 27.6 mm Hg vs 34.0 mm Hg with placebo; P = .04) and pyridostigmine and 5 mg of midodrine hydrochloride (BP fall of 27.2 mm Hg vs 34.0 mm Hg with placebo; P = .002). Standing BP improvement significantly regressed with improvement in OH symptoms. Pyridostigmine significantly improves standing BP in patients with OH without worsening supine hypertension. The greatest effect is on diastolic BP, suggesting that the improvement is due to increased total peripheral resistance.

β2-Adrenoceptor Genotype and Function Affect Hemodynamic Profile Heterogeneity in Postural Tachycardia Syndrome

Previous studies suggest that the beta2-adrenoceptor functions abnormally in patients with postural tachycardia syndrome (POTS) and may contribute to their altered hemodynamic profile. To test the hypothesis that the beta2-adrenoceptor response is decreased in POTS, we studied: (1) the arterial vasodilation response to the beta agonist, isoproterenol, and (2) the distribution of common polymorphisms (codons 16 and 27) of the gene coding the receptor (beta2-AR) in a large population with POTS. We measured plasma catecholamines and monitored hemodynamics and changes in forearm and leg blood flow to incremental doses of intraarterial isoproterenol in 9 patients with POTS compared with 8 healthy subjects. For polymorphism assessment we collected DNA from 57 patients with POTS and compared with 67 age-sex matched healthy subjects. Circulating catecholamines were significantly higher in POTS subjects compared with controls. Intrabrachial and intrafemoral isoproterenol infusion elicited a dose-dependent increase in blood flow. In healthy subjects, blood flow increased (mean+/-SEM) 400+/-70% in the forearm and 170+/-40% in the leg, but only 280+/-60% in forearms and 120+/-20% in legs of patients with POTS (ANOVA for both P<0.001). The genotype and allele distributions for codons 16 and 27 beta2-AR variants were not different in the 2 groups. However, the blood pressure and plasma norepinephrine levels diverged in patients according to their genotype. Patients with Gly16Gly and patients with Glu27Glu had lower plasma catecholamines and higher supine and upright blood pressure, compared with other genotypes. Therefore, both decreased beta2-adrenoceptor-related vasodilation and beta2-AR polymorphisms may contribute to the hemodynamic diversity of patients with POTS.

Blood pressure rise with swimming versus walking in older women: the Sedentary Women Exercise Adherence Trial 2 (SWEAT 2)

Swimming is often recommended in the prevention and treatment of hypertension. Few studies have investigated the effect of swimming training on blood pressure (BP). Our objective was to evaluate 6 months of supervised moderate swimming or walking on BP in previously sedentary, normotensive, older women. Women aged 50-70 years (n = 116) were randomly assigned to a supervised 6-month swimming or walking programme. They were further randomized to receive usual care or a behavioural intervention package. Exercise comprised 3 sessions/week with a warm-up, cool down, and 30-min of moderate intensity walking or swimming. BP was recorded for 20 min supine, and 5 min standing. Assessments were made at 0 and 6 months. At baseline, mean supine BP (+/- SD) was 115.7 +/- 1.3/66.8 +/- 0.7 mmHg. Swimming improved swim distance by 78.1 m (29.3%) [95% confidence interval (CI); 66.7, 89.4] and walk time by 0.58 min (3.8%) (0.41, 0.74). Walking decreased walk time by 1.0 min (6.5%) (0.81, 1.19). After adjustment for initial BP, age, hypertension treatment status and change in weight, swimming increased supine and standing systolic BP relative to walking by 4.4 mmHg (1.2, 7.5) (P = 0.008) and 6.0 mmHg (2.6, 9.5) (P = 0.001), respectively. Supine and standing diastolic BP increased by 1.4 mmHg (-0.14, 3.0) (P = 0.07) and 1.8 mmHg (-0.02, 3.5) (P = 0.05), respectively. Relative to moderately paced walking, regular swimming significantly elevates BP in previously sedentary, normotensive, older women. This finding may have important implications for exercise prescription in older subjects.

Clonidine for the Treatment of Supine Hypertension and Pressure Natriuresis in Autonomic Failure

Patients with autonomic failure are disabled by orthostatic hypotension, which can be worsened by the nighttime pressure natriuresis induced by associated supine hypertension. Several pharmacological agents are available that effectively reduce nighttime hypertension, but none of them prevent pressure natriuresis. Because hypertension of autonomic failure can be driven by residual sympathetic tone, we hypothesized that clonidine would be effective in reducing blood pressure (BP) and nocturnal natriuresis. Therefore, we determined the effect of placebo, 0.1 mg clonidine, and 0.1-mg/h nitroglycerin transdermal patch on supine BP, orthostatic hypotension, and pressure natriuresis in 23 patients with primary autonomic failure and supine hypertension. Medications were given at 8:00 PM, and BP was recorded every 2 hours for 12 hours. The maximal decrease in BP was seen 6 to 8 hours after drug administration and was similar to clonidine and nitroglycerin (-29+/-9 and -30+/-10 mm Hg, respectively), as was the average fall in BP throughout the night. However, only clonidine effectively reduced nocturnal natriuresis (-0.09 mmol/mg Cr; 95% CI, -0.13 to -0.04; P=0.004), but this was not associated with improvement in morning orthostatic hypotension because of a residual hypotensive effect. The decrease in BP induced by clonidine was modestly but significantly correlated with the magnitude of residual sympathetic tone determined in 10 subjects by the fall in BP induced by ganglionic blockade (r=0.66; P=0.043). These results are consistent with residual sympathetic tone contributing to supine hypertension in autonomic failure, which can be targeted with clonidine to decrease BP and nocturnal natriuresis.

Effect of time standing up on orthostatic blood pressure change in the elderly: The J‐SHIPP Study

Background: Orthostatic dysregulation of blood pressure (BP) has been shown to be associated with an increased incidence of future cardiovascular disease, stroke and even mortality. To make a meaningful assessment of this association, we evaluated the effect of time elapsed after standing on any change in orthostatic BP.Methods: This study concerns 237 community‐dwelling elderly people free from any history or symptoms of cardiovascular disease and not on medication. Basal BP was determined by averaging two determinations of supine BP measured with an automatic oscillometric BP recorder after resting for more than 10 min. Orthostatic change in BP was determined at 1 min and 3 min intervals after standing up.Results: The orthostatic change in systolic BP (ΔSBP) had a Gaussian distribution with a pivot at 1.2 ± 14 mmHg. The prevalence of subjects showing more than a 10% decrease in SBP at the 1‐min interval was 14.3% (34 subjects). At the 3‐min interval, 11 of them showed ΔSBP within ± 10%. However, another 17 subjects (7.2%) were newly diagnosed as having orthostatic hypotensive disorder. Similarly, 17.3% (41 cases) of subjects showed more than a 10% increase in ΔSBP at the 1‐min interval. Among them, 22 (9.3%) subjects showed ΔSBP within ± 10% at the 3‐min interval. However, another 20 (8.4%) subjects were newly diagnosed as having orthostatic hypertensive disorder.Conclusion: These results suggests that orthostatic dysregulation of BP could be evaluated by measuring at 1‐min interval. However, if abnormal variation of BP was not observed, repeated measurement at 3 min would be necessary.

C-344T polymorphism of the aldosterone synthase gene and blood pressure in the elderly: a population-based study

Whether the C-344T polymorphism of the aldosterone synthase gene is important for blood pressure control remains controversial. It has been proposed that an association between this polymorphism and blood pressure might be evident in elderly subjects. The aim of the present study was to test this hypothesis in an epidemiological context. A cross-sectional epidemiological evaluation of a highly homogeneous unselected general population of elderly Caucasians. Lifestyle, medical history, anthropometrics, skinfold thickness, supine blood pressure, heart rate and biochemical measures were recorded in 437 subjects aged > or = 65 years living in a secluded valley. All were genotyped for C-344T allele status and underwent measurements of plasma aldosterone and renin. The C-344T genotypic frequency did not deviate from Hardy-Weinberg equilibrium. The aldosterone to renin ratio was 19% lower in the CC than in the TT genotype. Systolic blood pressure was significantly lower in subjects with the CC genotype, higher in the TT (+9.6 mmHg versus CC) and intermediate in the CT (+7.9 mmHg versus CC). Adjustment for age, gender, smoking and antihypertensive treatment did not affect this association. Diastolic blood pressure did not differ across genotypes. A significant increase of systolic blood pressure with increasing age and with increasing skinfold thickness was observed in the TT homozygotes but not in the C-carriers. These data support the concept that the C-344T polymorphism plays a role in controlling systolic blood pressure and the age-related increase in systolic blood pressure in response to age and to body fat, possibly through differences in modulation of aldosterone synthesis.

Effects of oral fixed-dose combinations of telmisartan plus ramipril and losartan plus ramipril in hypertension: A multicenter, prospective, randomized, double-blind, phase iii trial in adult indian patients

Background: A new oral fixed-dose combination (FDC) of telmisartan plus ramipril is being introduced in India for the treatment of patients with stage 2 hypertension. Objective: The aim of this study was to compare the effectiveness and tolerability of an oral FDC of telmisartan plus ramipril with those of an oral FDC of losartan plus ramipril in adult Indian patients with stage 2 hypertension. Methods: This multicenter, prospective, randomized, double-blind, Phase III study was conducted at 5 centers in India. Indian patients aged 18 to 65 years with uncomplicated stage 2 essential hypertension (systolic/diastolic blood pressure [SBP/DBP], >160/>100 mm Hg) were enrolled. After a 2-week placebo run-in period, patients were randomly assigned to receive telmisartan 40 mg plus ramipril 5 mg (T + R) or losartan 50 mg plus ramipril 5 mg (L + R), PO (tablet) QD (before the morning meal) for 8 weeks. Supine blood pressure (BP) was measured at 0 (baseline) and 8 weeks of treatment. The primary end point was the mean reduction from baseline in BP. Responders were classified as patients who had a DBP <90 mm Hg at the end of 8 weeks of therapy. Tolerability was assessed using spontaneous reports of adverse events (AEs) during the follow-up visits and laboratory analyses performed at week 8. Results: A total of 289 patients were enrolled (155 men, 134 women; mean age, 50.74 years). Of these, 8 patients in the T + R group and 7 in the L + R group were lost to follow-up and considered withdrawals. At the end of week 8, the mean percentage reduction in SBP was significantly greater in the T + R group compared with that in the L + R group (24.1% vs 19.4%; P < 0.05). The mean percentage reduction in DBP was also significantly greater in the T + R group compared with that in the L + R group (17.3% vs 12.5%; P < 0.05). The response rates in the T + R and L + R groups were statistically similar (79.1% vs 68.7%). The most common AEs in the T + R and L + R groups were cough (9 [6.1%] and 11 [7.8%] patients, respectively) and headache (7 [4.7%] and 8 [5.7%] patients, respectively). Conclusions: The results in this study in Indian patients with stage 2 essential hypertension suggest that the FDC of T + R controlled BP more effectively compared with the FDC of L + R over 8 weeks. The response rates were similar between the 2 groups. Both treatments were well tolerated.

Determination of changes in blood pressure during administration of sildenafil (Viagra®) in patients with spinal cord injury and erectile dysfunction

Prospective, open-label, comparative study, to assess the effects of sildenafil on blood pressure in a population of patients with spinal cord injury (SCI). To determine the effect of sildenafil on blood pressure in patients with erectile dysfunction secondary to SCI by comparing changes in blood pressure in SCI patients with a neurologic level below T5 versus higher levels. To establish a relationship between the potential hypotensive effect and protective muscle spasm against blood pressure reduction. To assess the effects of age, complexity and duration of SCI on changes in blood pressure. To record any adverse effects occurring during the study. Spinal Cord Injury Unit, Insular University Hospital of Gran Canaria, Canary Islands, Spain. In total, 22 male SCI patients aged 18 years or older with a history of SCI greater than 3 months in duration. Patients with erectile dysfunction secondary to SCI were included in the study, without excluding patients with a neurologic level above 75 or asymptomatic low blood pressure. Patients with specific contraindications for use of the drug were excluded. A personal history was obtained, and the level of injury (ASIA/IMSOP scales of international standards), impairment grade (ASIA impairment scale), spasticity grade (modified Ashworth scale) and baseline sitting and supine blood pressure values were determined. A single dose of 50 mg of sildenafil was administered, and patients remained sitting at 45 degrees . Blood pressure was monitored every 10 min for 4 h and whenever the patient reported symptoms. Any relevant signs and symptoms manifested during the study period were also recorded. Analysis of the changes in blood pressure values was performed using a paired t-test in each group of patients according to neurologic level and spasticity grade. A decrease in blood pressure was observed in all patients, although patients with a level of injury at T5 or above and those with a complete SCI showed a less intense decrease (P<0.05). The spasticity grade of the patients was protective against the fall in blood pressure, as it was less significant in patients with grade 3 (P>0.1) than in those with grade 0. Adverse effects were few and transient. None were related to hypotension. Sildenafil caused a decrease in blood pressure in SCI patients with a neurologic level of injury above T5 and complete injuries (grade A), but did not have clinical implications in the patients studied. A higher spasticity grade tends to protect the patient from the fall in blood pressure. Age and duration of injury do not appear to influence this decrease.

Influence of an Insertion Variant in the 5ʹUTR of the Endothelin-1 Gene on Orthostatic Intolerance

Orthostatic intolerance is a multifactorial disease in which the genetic contribution is probably the result of a number of genes acting in combination. Recent work has shown that orthostatic intolerance is influenced by endothelial nitric oxide synthase gene polymorphisms. Since endothelin-1 (ET-1) is one of the most important vasoconstrictor peptides, a frequent adenine insertion polymorphism within the 5'-untranslated region (5'UTR), which is of functional importance for ET-1 expression, could influence orthostatic intolerance. The aim of this study was therefore to ascertain whether this frequent variant of the endothelin-1 gene influences the risk for orthostatic intolerance. We studied 257 white patients (120 cases with orthostatic intolerance and 137 controls) for genotyping of the 5'UTR I variant. From this cohort, 111 patients and 99 control subjects underwent a tilt-table test or an upright posture study, including monitoring of blood pressure, heart rate, and plasma catecholamines, in the supine position and during 30 minutes of standing. Genotyping was performed in all participants. Chi tests of independence were used to test for associations between orthostatic intolerance and genotype. In addition, an association of the insertion polymorphism with hemodynamic variables (heart rate, supine and upright blood pressure) was ascertained using one-way analysis of variance. The 5'UTR I variant was significantly less common in patients with orthostatic intolerance (allele frequency 0.36 and 0.28, in controls and cases, respectively). Additionally, we found a significant decrease in the risk of orthostatic intolerance among people who were homozygous for the 5'UTR variant (I/I) compared with the wild-type variant (D/D) (odds ratio, 0.41; 95% confidence interval, 0.17 to 0.97; P = 0.04). No association between the 5'UTR variant and heart rate or blood pressure regardless of diagnosis was found. Our current results suggest that the hereditary adenine insertion variant in the 5'-UTR of the endothelin-1 gene is protective for orthostatic intolerance. The increased ET-1 protein expression that has been linked with the I variant might be associated with a more efficient hemodynamic response to standing. This is likely one of several common genetic loci that may represent modifiers of orthostatic intolerance phenotypes.

A Summary of the Effects of Antihypertensive Medications on Measured Blood Pressure

Epidemiologic analysis of family data on blood pressure (BP) is often compromised by the effects of antihypertensive medications. A review of numerous clinical trials that investigated the effects of BP-lowering medications is summarized here. Published clinical trials, including 137 clinical trials with monodrug therapies and 28 clinical trials of combination drug therapies with a total of 11,739 participants, were reviewed from PubMed. Six major classes/groups of antihypertensive medications were categorized by ethnicity, including angiotensin-converting enzyme (ACE) inhibitors, alpha1-blockers, cardioselective beta-blockers (beta1-blockers), calcium channel blockers, thiazide and thiazide-like diuretics, and loop diuretics. Using sitting or supine BP, for ethnic groups combined, monodrug therapy with ACE inhibitors showed a weighted average effect of lowering the systolic and diastolic BP by 12.5/9.5 mm Hg; alpha1-blockers by 15.5/11.7 mm Hg; beta1-blockers by 14.8/12.2 mm Hg; calcium channel blockers by 15.3/10.5 mm Hg; thiazide diuretics by 15.3/9.8 mm Hg; and loop diuretics by 15.8/8.2 mm Hg. However, ACE inhibitors, alpha1-blockers, and beta1-blockers were less effective in African Americans than in non-African Americans, whereas calcium channel blockers, thiazide diuretics, and loop diuretics were more effective in African Americans than in non-African Americans. For two-drug combination therapy with ethnic groups combined, the BP-lowering effect of the second medication, when compared to its effect as monodrug therapy, was 84% and 65% for systolic and diastolic BP, respectively. The BP-lowering effects reported here may be used to impute the pretreatment BP levels, which can improve the information content and hence the power of epidemiologic analysis in studies where use of antihypertensive medications is a confounding factor in the BP measurements.

Epidemiology of falls in elderly semi‐independent residents in residential care

Objectives: To determine the incidence and consequences of falls in elderly people living in hostels, and the role of comorbidity, orthostatic hypotension and medications as risk factors for falls. Methods: Cross‐sectional prevalence and event association was studied in eight aged‐care hostels (Canberra, ACT, 1999) of 179 residents aged 65 years and older (83 ± 7 years (mean ± standard deviation), 80% women) independent in activities of daily living. History of falls and injuries on falling, comorbidity, medications and mobility data were obtained. Measurements of blood pressure and heart rate were made supine after waking from overnight sleep and after standing for 1 and 3 min. Results: Forty‐three per cent of subjects had fallen in the last year (1.3 ± 2.6 falls per person per year) and 29% of these had sustained a fracture, 53% of fallers had recurrent falls. In multivariate analysis, four factors were associated independently with falling within a year: using a walking device, history of cancer, taking selective serotonin reuptake inhibitors (SSRI) and cigarette smoking. For recurrent falls, cerebrovascular disease and using nitrates were also independent risk factors. In univariate analysis, reversible inhibitors of monoamine oxidase and potassium‐sparing diuretics were negatively associated with falls. There were no differences between fallers and non‐fallers in blood pressure in supine and standing positions, although one‐third of residents had orthostatic hypotension. Conclusions: Falls in elderly hostel residents are common and often have serious consequences. Living in an institution is associated with an increased risk of fractures. The study identified several novel potential risk factors for falls in this population: using a walking device, history of falls, presence of cancer, presence of cerebrovascular disease, taking SSRIs, taking nitrates and cigarette smoking. These can be used to identify hostel residents at high risk of falling who can then be targeted for monitoring, specific treatment and prevention strategies.

Paradoxical effect of sibutramine on autonomic cardiovascular regulation in obese hypertensive patients

Sibutramine, a serotonin and norepinephrine transporter blocker, is a common adjunctive obesity treatment. Acute studies in healthy subjects suggested that an inhibitory central nervous mechanism might attenuate the peripheral stimulatory effect on the sympathetic nervous system. This notion has not been tested in overweight and obese patients. We conducted a randomized, controlled clinical study in hypertensive patients with BMI > or = 27 to < 40 kg/m(2). After 4 week placebo run-in period patients were randomized to four different antihypertensive treatments or placebo. After 4 weeks of antihypertensive therapy, patients were additionally treated with sibutramine 15 mg o. d. for 3 months. Patients underwent cardiovascular autonomic reflex testing and a graded head-up tilt test at the end of each phase. Mean body weight decreased from 98.5+/-4 to 94.7+/-4 kg (p<0.05) between end of placebo run-in and end of sibutramine treatment. Supine blood pressure was 154+/-3/80+/-2, 145+/-3/76+/-2 and 150+/-3/79+/-2mmHg at the end of placebo run-in, after antihypertensive titration (ns) and end of sibutramine treatment (ns), respectively. Blood pressure was affected similarly during head up tilt testing. The systolic blood pressure response to cold pressor testing was diminished with sibutramine (p<0.01). Sibutramine decreased low frequency systolic blood pressure oscillations in the supine position (p<0.01). Resting blood pressure tends to increase with sibutramine, whereas blood pressure during sympathetic stimulation and low frequency blood pressure oscillations are decreased. These paradoxical changes are consistent with previous studies in healthy subjects and suggest a combination of peripheral and central nervous system mechanisms.

Effects of nilvadipine and amlodipine in patients with mild to moderate essential hypertension: a double blind, prospective, randomised clinical trial

ABSTRACTObjective: This double blind, prospective, randomised, parallel group clinical trial was aimed at investigating the effects of nilvadipine or amlodipine in mild to moderate hypertensive patients over a 3-month treatment period.Research design and methods: Eligible outpatients (supine DBP ≥ 90 mmHg and ≤ 110 mmHg and supine SBP ≤ 180 mmHg) entered a maximum 15-day placebo run-in period and were randomised to receive once daily nilvadipine 8 mg or amlodipine 5 mg (to be doubled in the case of lack of response at day 30). Follow-up visits with measurement of supine and orthostatic blood pressure and heart rate were performed after 15, 30, 60 and 90 days of treatment. Standard laboratory tests and 12-lead ECG were performed at study entry and at the end of treatment; adverse events were collected at any time.Results: A total number of 168 patients, 83 in the nilvadipine and 85 in the amlodipine group, took part in the study: 15 and 14 in the two groups, respectively, were prematurely withdrawn. Supine DBP at endpoint similarly decreases in the two groups (–11.0 ± 7.1 mmHg in the nilvadipine group and –12.7 ± 8.2 mmHg in the amlodipine group), with no significant differences between groups at any time point. Measurements in the orthostatic position also did not show between-groups differences. Blood pressure was normalised in 61.8% of patients in the nilvadipine group and in 63.0% in the amlodipine group; responders to therapy were 64.5% and 69.1% in the two groups, respectively. Results of SBP also did not show differences between groups at any time point, except a more marked decrease in the amlodipine group compared to nilvadipine in the supine measurements at endpoint. A total number of 30 patients (36.6%) in the nilvadipine group and 23 (27.1%) in the amlodipine group reported adverse events ( p = 0.24 between groups), which mainly consisted of vasodilatory effects (e.g. oedema, flushing and headache). A favourable lipid profile, i.e. a significant ( p = 0.002 between groups) decrease of triglycerides levels and an increase of HDL-C, was observed in the nilvadipine group, compared with an increase of triglycerides in the amlodipine group. No effects on haematology, liver and renal function were observed in either group.Conclusions: Nilvadipine or amlodipine produced comparable effects on DBP and shared a similar adverse effect profile. A favourable effect on lipid profile was observed following nilvadipine treatment.

DASH is more effective in lowering blood pressure in metabolic syndrome patients than potassium, magnesium and fiber supplements

We found that the DASH Eating Plan lowered blood pressure (BP) in obese hypertensives. The reduction in BP correlated inversely with the increase in plasma anti-oxidant capacity, although others have attributed BP changes to the high K+, Mg++ and/or Ca++ content of DASH. In this study, the BP lowering effects were examined of supplementing the usual diet with K+, Mg++, and fiber vs DASH in lean normotensives and obese, metabolic syndrome patients. Seven obese [BMI 37.2±5.3] volunteers, 38.7±9.2 [SD] years old, 2:AA, 5:C, 3:M, 4:F, with the metabolic syndrome and 8 lean healthy subjects [BMI 22.3±1.4, age 35.5±7.7 yrs, 2:AA, 6:C, 2:M, 6:F]. All subjects initially followed a standardized usual diet (low anti-oxidant) for 3 weeks. They were randomized to follow either the same diet supplemented with K+, Mg++, and fiber to match the content of DASH or the DASH Eating Plan for 3 weeks each followed by a 3-week crossover to the other diet. All 3 diets were isocaloric and matched for Na+ and Ca++ content. Subjects prepared their own meals. Dietary adherence was determined by digital photographs of meals and beverages and food records. At the end of each 3-weeks, 6 resting supine BP readings were taken by mercury sphygmomanometry on the left arm; the first value was deleted and last five were averaged. Compared to the usual diet, BP did not decline significantly in either group when the usual diet was supplemented with ∼2000 mg K+ and 300 mg Mg++ daily to match DASH but declined on DASH in metabolic syndrome (−5.3/−4.6 mmHg, p=0.02/0.03) but not control subjects (−3.2/−2.2 mmHg, NS/NS). The data suggest the DASH Eating Plan lowers BP more effectively in obese, metabolic syndrome patients than supplementing the usual diet with K+, Mg++ and fiber to match DASH. These findings raise the possibility that other components of the diet, e.g., antioxidant / bioflavonoids, contribute to the BP benefits of the DASH Eating Plan. See Table 1.

Functional adrenergic receptor polymorphisms and idiopathic orthostatic intolerance

Idiopathic orthostatic intolerance (IOI) is a common disorder that is characterized by chronic orthostatic symptoms and substantial increases in heart rate and plasma norepinephrine concentrations that are disproportionately high while standing. Several features of the syndrome, including the tachycardia, tremulousness, and exaggerated norepinephrine have been considered potentially due to hypoactive or hyperactive states of adrenergic receptors of the sympathetic nervous system. The aim of this study was therefore to ascertain whether genotypes at eight polymorphic loci within five relevant adrenergic receptor genes (alpha2A, alpha2B, alpha2C, beta1 and beta2) influence the risk for IOI. We studied 80 young men in military service (20 patients with IOI and 60 age-matched controls). All participants underwent a tilt table test including monitoring of blood pressure, heart rate and plasma catecholamines, in the supine position and during 30 min of standing. Genotyping at the eight loci (alpha2ALys251, alpha2BDel301-303, alpha2CDel322-325, beta1Gly49, beta1Arg389, beta2Arg16, beta2Glu27, beta2Ile164) was performed in all participants. Chi-square tests of independence were used to test for associations between IOI and genotype. In addition, an association of the polymorphisms with haemodynamic variables (heart rate, supine and upright blood pressure) was ascertained using one-way variance analysis. For the beta1Gly49 polymorphism we found a decrease in the risk of IOI among persons who were homozygous (odds ratio, 0.88; 95% confidence interval, 0.81-0.97). In addition, we found an association between beta1Gly49 and decreased heart rate in the upright position, regardless of IOI diagnosis. There were no associations with the other studied polymorphisms and IOI. Our current results suggest that the beta1Gly49 polymorphism is protective for IOI. This is likely one of several common genetic loci that may represent modifiers of IOI phenotypes.

Short-term blood pressure and heart rate variability in congenital central hypoventilation syndrome (Ondine's curse)

The effect of CCHS (congenital central hypoventilation syndrome, or Ondine's curse) on short-term BP (blood pressure) and HR (heart rate) variability was evaluated in 16-year-old subjects presenting a form of CCHS requiring night ventilatory assistance. The 12 patients were compared with 12 age- and gender-matched healthy volunteers. Recordings were obtained during daytime while the subjects were breathing spontaneously. Continuous BP was measured with a Finapres device in the supine, head-up tilt and standing positions. The manoeuvre of actively standing was also analysed. HR levels were elevated in CCHS subjects at supine rest (+23%) with a reduced HR overall variability (-88%). The low- and high-frequency components of HR variability were affected. BP levels were preserved at rest, but the manoeuvres demonstrated a limited capacity to elevate BP. There was no overshoot in BP during the manoeuvre of actively standing, and steady standing BP levels in patients were not higher than supine BP levels as usually observed in healthy controls. The spontaneous baroreflex sensitivity estimated using the sequence technique or the cross-spectral analysis fell in the patients to approx. one-third of the sensitivity estimated in the healthy controls whatever the position. This cardiovascular profile suggests a predominant vagal dysfunction with signs of vagal withdrawal and baroreflex failure, and relative preservation of the cardiac and vascular sympathetic function. It is likely that the impaired ontogeny of the visceral reflexes, considered now to cause CCHS syndrome, includes the baroreceptive pathway and mainly its vagal component.

Different accumulation of temocapril and enalapril during repeated dosing in elderly patients

Angiotensin-converting enzyme (ACE) inhibitors, temocapril and enalapril, are prodrugs that are converted to the active metabolites, temocaprilat and enalaprilat, respectively. Temocaprilat is eliminated by renal and biliary routes, while enalaprilat is mainly excreted in urine [1, 2]. This difference explains a 2-fold increase in plasma temocaprilat and a 13-fold increase in plasma enalaprilat in patients with renal insufficiency [3]. Because renal function is physiologically decreased with age, it is hypothesized that, compared with temocaprilat, accumulation of enalaprilat during repeated dosing is greater and blood pressure (BP)-lowering effect is enhanced in elderly hypertensive patients. In this study, temocapril or enalapril was given once daily for 14 days to elderly hypertensive patients. Pharmacokinetic profiles and BP-lowering effects after single and repeated dosings of these drugs were determined.

Comparison of the systemic pharmacodynamic effects and pharmacokinetics of salmeterol delivered by CFC propellant and non-CFC propellant metered dose inhalers in healthy subjects

This was a randomised, double-blind, placebo-controlled, cross-over study comparing the systemic pharmacodynamic effects (heart rate and serum potassium) and pharmacokinetics of salmeterol delivered by the non-CFC hydrofluoralkane (HFA) propellant 134a and the CFC propellant (propellant 11/12) metered dose inhalers (MDI) in healthy subjects. At the therapeutic dose (50 microg), salmeterol-mediated systemic pharmacodynamics were equivalent for the HFA and CFC MDIs. Higher doses of salmeterol (150 and 300 microg) produced dose-related beta-agonist pharmacodynamic effects irrespective of the propellant. However, these effects were lower with salmeterol HFA MDI than with the salmeterol CFC MDI at all dose levels. Overall, salmeterol Cmax and AUC(0-t) values were lower for salmeterol HFA compared with salmeterol CFC MDI. At the highest dose (300 microg), where a full pharmacokinetic profile was obtained, exposure to salmeterol delivered by the HFA MDI compared with the salmeterol CFC MDI was 27% and 30% lower for Cmax and AUC(0-t), respectively. Maximum plasma concentrations were generally seen in the first plasma samples taken 5 min after the start of dosing. Salmeterol HFA was well-tolerated. At supratherapeutic doses, adverse events were typical for high-dose salmeterol with fewer adverse events occurring with the HFA compared with the CFC formulation. These data indicate that the salmeterol HFA MDI would not be associated with a significantly different pharmacodynamic, safety and tolerability profile compared with the salmeterol CFC MDI.