Hormone replacement in postmenopausal women: impact of progestogens on autonomic tone and blood pressure regulation

OBJECTIVE: Depressed heart rate variability (HRV) reflects an imbalance of autonomic tone and independently predicts increased cardiovascular risk in patients with congestive heart failure or after acute myocardial infarction. While hormone replacement therapy (HRT) with estrogens beneficially modulates autonomic tone and blood pressure (BP) regulation in postmenopausal women, the impact of concomitant treatment with progestogens remains unclear. DESIGN: In this cross-sectional study, HRV and BP were examined in 62 healthy women (ages 48-71 years) using digital beat-to-beat interval recordings of heart rate and 24-hour ambulatory BP measurements. RESULTS: Demographic parameters did not differ among women without HRT (n = 23), on estrogen (n = 17; ERT), or on progestogen-estrogen containing HRT (n = 22; PERT). Total power of HRV was significantly lower, whereas mean heart rate (HR) was significantly higher among women on PERT group versus controls and ERT (total power: 1611 +/- 146 vs. 2497 +/- 308 and 2472 +/- 348 ms(2); heart rate: 80.7 +/- 1.2 vs. 75.0 +/- 1.4 and 74.0 +/- 2.2 bpm; p < 0.05). In addition, low-frequency power and time-dependent parameters of HRV were lower among women on PERT group versus controls and ERT (p < 0.05). ERT use was associated with reduced systolic and diastolic daytime BP, whereas no significant differences were evident PERT users compared with controls. CONCLUSIONS: Progestogen-containing replacement therapy was associated with increased HR and an attenuation of HRV in postmenopausal women. BP was lower in women on ERT, whereas this effect was offset in the PERT group. These observations could at least partially explain the ambiguous results of progestogen-containing HRT on cardiovascular risk in the Heart and Estrogen/Progestin Replacement Study (HERS).     

Validation of a new noninvasive method to measure blood pressure and assess baroreflex sensitivity in preterm infants during sleep

STUDY OBJECTIVES: Accuracy and precision of a noninvasive device for continuously measuring blood pressure (BP) (Finometer, FMS, The Netherlands) during sleep was assessed in preterm infants. DESIGN: Absolute BP beat-to-beat values, interbeat changes, measurement precision, and baroreflex sensitivity were compared with BP measurements from intraarterial catheters. PARTICIPANTS: Ten preterm infants (gestational age 27-36 weeks; birth weight 964-2620 gm) were studied in the neonatal intensive care unit. MEASUREMENTS AND RESULTS: The 2 modes of BP measurement were compared in 2-minute epochs (n = 10-12/infant). Mean arterial pressure, systolic arterial pressure, and diastolic arterial pressure were analyzed beat to beat, and baroreflex sensitivity was assessed using spontaneous sequence analysis. Mean differences for absolute BP (mm Hg) were as follows: mean arterial pressure, 3 (limits of agreement, -1 to 8); systolic arterial pressure, -4 (-8 to 1); and diastolic arterial pressure, 7 (4 to 10). Mean differences and limits of agreement for interbeat changes were essentially 0 for mean arterial pressure, systolic arterial pressure, and diastolic arterial pressure. Precision (+/- 95% confidence intervals, mm Hg) for the Finometer were mean arterial pressure +/- 7, systolic arterial pressure +/- 8, and diastolic arterial pressure +/- 6. Precision was greater for the arterial catheter (mean arterial pressure +/- 3, systolic arterial pressure +/- 4, and diastolic arterial pressure +/- 4). Baroreflex sensitivity calculated from the Finometer BP was (mean +/- SEM, ms/mm Hg) 1.74 +/- 0.23 and, from the catheter system, BP was 1.56 +/- 0.21 (p value NS). CONCLUSIONS: The Finometer provides accurate measurements of beat-to-beat BP and baroreflex sensitivity. The ability to continuously measure BP and baroreflex sensitivity during sleep in infants may provide vital clues into pathologic conditions associated with impaired autonomic control during sleep.     

The effects of antihypertensive therapy on left ventricular mass in elderly patients

Left ventricular mass sometimes decreases during treatment of hypertension, but this response is inconsistent and its effects on left ventricular function are unknown. In a six-month randomized trial, we studied the ability of verapamil and atenolol to reduce left ventricular mass in 42 elderly patients with hypertension and the effects of this reduction in mass on cardiac function. The mean blood pressure (+/- SE) decreased in both the group that received verapamil (from 171.4 +/- 3.2/93.0 +/- 2.5 mm Hg to 142.9 +/- 2.8/79.0 +/- 2.0 mm Hg) and the group that received atenolol (from 179.6 +/- 4.6/98.5 +/- 2.4 mm Hg to 148.1 +/- 3.3/83.4 +/- 1.2 mm Hg), but the atenolol-treated patients more frequently required the addition of chlorthalidone to achieve blood-pressure reduction (P less than 0.01). Verapamil resulted in a reduction in the left-ventricular-mass index from 104 +/- 5 g per square meter of body-surface area to 85 +/- 5 g per square meter (P less than 0.01). Atenolol did not produce a reduction in the left-ventricular-mass index (109 +/- 9 g per square meter before treatment vs. 112 +/- 10 g per square meter after treatment). Two weeks after the withdrawal of antihypertensive therapy, blood pressure returned to pretreatment values. Nevertheless, in patients whose left ventricular mass had decreased, two measures of diastolic filling, the peak diastolic filling rate to the peak ejection rate, were significantly higher than before treatment (2.42 +/- 0.2 vs. 3.31 +/- 0.4 [P less than 0.05] and 0.61 +/- 0.03 to 0.85 +/- 0.05 [P less than 0.05], respectively). Diastolic filling was unchanged in the group that had no reduction in left ventricular mass. Cardiac output and the ejection fraction at rest and during mild exercise were unchanged in both groups as compared with baseline values. We conclude that left ventricular mass can be reduced in elderly patients with hypertension and mild ventricular hypertrophy who receive antihypertensive therapy. Reduction occurs more frequently with verapamil than with atenolol therapy, increases diastolic filling, and does not impair systolic function.     

The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis. Dutch Renal Artery Stenosis Intervention Cooperative Study Group

BACKGROUND: Patients with hypertension and renal-artery stenosis are often treated with percutaneous transluminal renal angioplasty. However, the long-term effects of this procedure on blood pressure are not well understood. METHODS: We randomly assigned 106 patients with hypertension who had atherosclerotic renal-artery stenosis (defined as a decrease in luminal diameter of 50 percent or more) and a serum creatinine concentration of 2.3 mg per deciliter (200 micromol per liter) or less to undergo percutaneous transluminal renal angioplasty or to receive drug therapy. To be included, patients also had to have a diastolic blood pressure of 95 mm Hg or higher despite treatment with two antihypertensive drugs or an increase of at least 0.2 mg per deciliter (20 micromol per liter) in the serum creatinine concentration during treatment with an angiotensin-converting-enzyme inhibitor. Blood pressure, doses of antihypertensive drugs, and renal function were assessed at 3 and 12 months, and patency of the renal artery was assessed at 12 months. RESULTS: At base line, the mean (+/-SD) systolic and diastolic blood pressures were 179+/-25 and 104+/-10 mm Hg, respectively, in the angioplasty group and 180+/-23 and 103+/-8 mm Hg, respectively, in the drug-therapy group. At three months, the blood pressures were similar in the two groups (169+/-28 and 99+/-12 mm Hg, respectively, in the 56 patients in the angioplasty group and 176+/-31 and 101+/-14 mm Hg, respectively, in the 50 patients in the drug-therapy group; P=0.25 for the comparison of systolic pressure and P=0.36 for the comparison of diastolic pressure between the two groups); at the time, patients in the angioplasty group were taking 2.1+/-1.3 defined daily doses of medication and those in the drug-therapy group were taking 3.2+/-1.5 daily doses (P<0.001). In the drug-therapy group, 22 patients underwent balloon angioplasty after three months because of persistent hypertension despite treatment with three or more drugs or because of a deterioration in renal function. According to intention-to-treat analysis, at 12 months, there were no significant differences between the angioplasty and drug-therapy groups in systolic and diastolic blood pressures, daily drug doses, or renal function. CONCLUSIONS: In the treatment of patients with hypertension and renal-artery stenosis, angioplasty has little advantage over antihypertensive-drug therapy.     

Association between G-308A polymorphism of the tumor necrosis factor-alpha gene and 24-hour ambulatory blood pressure values in type 1 diabetic adolescents

Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine, which also influences blood pressure (BP). The G-308A polymorphism of the TNF-alpha gene is associated with altered TNF-alpha production. The prevalence of the TNF-alpha-308A allele is reportedly higher among patients with type 1 diabetes mellitus (T1DM) than in the healthy population. In this study we investigated whether this genetic polymorphism might correlate with BP values in diabetic adolescents. Ambulatory BP monitoring (ABPM) was performed in 126 adolescents with T1DM (mean age: 14 +/- 2.4 years). The TNF-alpha G-308A genotype was determined by using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methodologies. ABPM results were related to healthy reference values and are given as standard deviation score (SDS). The prevalence of the -308A allele was higher in diabetic adolescents than the Hungarian reference population (0.26 vs 0.14, p < 0.01). TNF-alpha genotype was associated both with systolic and diastolic BP values (p < 0.01 and p < 0.01, respectively). In patients with TNF-alpha-308GG and -308GA/AA genotypes, the 24-h systolic BP average values were 0.37 +/- 1.33 and -0.38 +/- 1.28 SDS, while 24-h diastolic BP average values were 0.09 +/- 1.30 and -0.67 +/- 1.31 SDS. Hence, the TNF-alpha-308A allele carrier state appears to be associated with lower systolic and diastolic BP values.     

Relationship of blood pressure and pump flow in an implantable centrifugal blood pump during hypertension

The purpose of this study was to evaluate the real time relationship between pump flow and pump differential pressure (D-P) during experimentally induced hypertension (HT). Two calves (80 and 68 kg) were implanted with the EVA-HEART centrifugal blood pump (SunMedical Technology Research Corp., Nagano, Japan) under general anesthesia. Blood pressure (BP) in diastole was increased to 100 mm Hg by norepinephrine to simulate HT. Pump flow, D-P, ECG, and BP were measured at pump speeds of 1,800, 2,100, and 2,300 rpm. All data were separated into systole and diastole, and pump flow during HT was compared with normotensive (NT) conditions at respective pump speeds. Diastolic BP was increased to 99.3+/-4.1 mm Hg from 66.5+/-4.4 mm Hg (p<0.01). D-P in systole was under 40 mm Hg (range of change was 10 to 40 mm Hg) even during HT. During NT, the average systolic pump flow volume was 60% of the total pump flow. However, during HT, the average systolic pump flow was 100% of total pump flow volume, although the pump flow volume in systole during HT decreased (33.1+/-5.7 vs. 25.9+/-4.0 ml/systole, p<0.01). In diastole, the average flow volume through the pump was 19.6+/-6.9 ml/diastole during NT and -2.2+/-11.1 ml/diastole during HT (p<0.01). The change in pump flow volume due to HT, in diastole, was greater than the change in pump flow in systole at each pump speed (p<0.001). This study suggests that the decrease of mean pump flow during HT is mainly due to the decrease of the diastolic pump flow and, to a much lesser degree, systolic pump flow.     

Response to exercise and ambulatory blood pressure monitoring in essential hypertension

To evaluate the relationship of ambulatory blood pressure (ABP) recording and blood pressure response to exercise, 58 essential hypertensive patients, not taking any drugs, had symptom-limited treadmill stress test (TST) within 48-96 hours of ABP, TST time, blood pressure increase, decrease, mode of increase and decrease, were independent of ABP systolic (SBP) and diastolic blood pressure (DBP) over 24 hours, day time and night time (p = ns). SBP decrease immediately after exercise were independent of ABP data. TST achieved heart rate was related to both 24 hours SBP (r = -0.64, p = 0.00005) and DBP (r = -0.55, p = 0.00001) in both day (r = -0.64, p = 0.00001 and r = -0.54, p = 0.002) and night (r = -0.52, p = 0.0001 and r = -0.46, p = 0.003) time periods. Therefore patients with achieved heart rate < 100% (n = 18) had higher 24 hour SBP (148 vs 132 +/- 2 mm Hg, p = 0.0006) and DBP (92.4 +/- 6.4 vs 84 +/- 6.2 mm Hg, P = 0.006) day and night. It is concluded that there is no overlap of diagnostic information using blood pressure. Values in TST or ABP although achieved heart rate in exercise is inversely related to severity of hypertension.     

Relationship between erythrocyte GLUT1 function and membrane glycation in type 2 diabetes

This paper investigates the effect of glycation on glucose transport in erythrocytes. Glucose transporter function, numbers and erythrocyte phosphorylation rates are simultaneously studied using 30 Caucasian patients with diabetes and 30 Caucasian control volunteers (mean +/- SD where P < or = 0.05; age 48 +/- 8 vs. 45 +/- 8 years [ns]; body mass index [BMI] 31 +/- 7 vs. 27 +/- 5 [P=0.035]; blood glucose 12 +/- 7 vs. 5 +/- 0.6 mmol/L [P=0.001]; HbA1c 8 +/- 2 vs. 5 +/- 0.3% [P=0.0001]; fructosamine 336 +/- 64 vs. 237 +/- 16 micromol/L [P=0.0001]; disease duration 13 +/- 11 years, respectively). Significant differences were found for glucose transporter function, with 3-O-methylglucose uptake rates (108 +/- 49 vs. 146 +/- 55 micromol/L/sec/10(12) cells [P=0.010]); D-glucose influx (64 +/- 30 vs. 117 +/- 45 micromol/L/sec/10(12) cells [P=0.0001]); and D-glucose net transport (31 +/- 22 vs. 74 +/- 55 micromol/L/sec/ 10(12) cells [P = 0.0001]). No differences were found for phosphorylation rates using 2-deoxyglucose (33 +/- 17 vs. 38 +/- 12 micromol/L/sec/10(12) cells [P=0.194]). The number of functional transporters using cytochalasin B studies measured via B(max), was not found to be significantly different between the groups (195 +/- 139 vs. 264 +/- 174 [P=0.206]). However, K(d) was lower for those with diabetes, suggesting higher binding affinity (12 +/- 11 vs. 32 +/- 25 nmol/L [P=0.006]). A negative correlation between HbAlc and D-glucose influx involving both groups was found (r=-0.670, P=0.0001). Glucose transport is shown to be decreased in people who have diabetes compared to normoglycaemic volunteers, whereas the number of glucose transporters is apparently unchanged; however, affinity for binding is increased.     

An open clinical trial of benazepril--a new ACE inhibitor in mild-moderate hypertension

Benazepril hydrochloride, a new non-sulfhydryl ACE inhibitor (ACEI) was studied in a titrated dose of 10 mg-20 mg once a day for 6 weeks in 42 mild to moderate adult hypertensive patients with sitting diastolic blood pressure (SDBP) 95-114 mm Hg. The pre-drug SDBP(mean +/- SE) of 102.5 +/- 0.8 mm Hg showed a significant reduction to 87.5 +/- 0.93 mm Hg at the end of treatment. BP was controlled (SDBP < or = 90 mm Hg) in 34 (81%) patients and a drop of at least 10 mm Hg from the pre-treatment SDBP value was noted in 34 (81%) patients. Common adverse reaction was cough in 8(19%) patients. Clinically significant changes in laboratory evaluations were not seen in any patient. Study showed that benazepril in a dose range of 10 to 20 mg per day is an effective agent for treatment of mild to moderate hypertension.     

Acute and chronic stress influence blood pressure variability in mice

There is evidence that alterations in heart rate and blood pressure variability (BPV) are associated with cardiovascular disease. We used a mice model to investigate the effects of acute and chronic stress on blood pressure variability (BPV) and heat rate variability (HRV). Shaker stress was given acutely (5 min, 150 cycles/min) and chronically (3 days, 2 min stress, 150 cycles/min, 45 sessions/day) in male C57BLJ mice. Systolic arterial pressure (SAP) and pulse interval (PI) time series were submitted to autoregressive spectral analysis with variability measured in the low-frequency (LF, 0.1-1.0 Hz) and high-frequency (HF, 1-5 Hz) ranges. In the acute experiment, MAP was increased significantly in the first 10 min poststress period (99+/-2 vs. 113+/-2 mm Hg) and returned to control levels 30 min poststress. HR was significantly higher in the initial poststress period (537+/-12 vs. 615+/-20 bpm). These alterations were associated with a marked increase in BPV (21+/-4 vs. 55+/-11 mm Hg2) and in power of LF oscillations (18+/-3 vs. 42+/-7 mm Hg2). On the other hand, chronic stress exposure produced a reduction in BPV (16+/-4 vs. 6+/-1 mm Hg2) and LF oscillations (11+/-3 vs. 3+/-1 mm Hg2). HRV was not altered after either acute or chronic stress. Spontaneous baroreflex sensitivity (SBS), determined by cross-spectral analysis between PI and BP, was reduced significantly in acute stress (-50%), but unchanged in chronic stress. Our results show that acute stress produced changes in BPV that may be associated with increased sympathetic activity and a reduction in blood pressure buffering. Under chronic conditions, there is no alteration in baroreflex sensitivity while BPV is reduced. This is likely related to the combination of sympathetic activation in the face of vasculature alterations.     

Human renin gene BglI dimorphism associated with hypertension in two independent populations

The renin (REN) gene is a good candidate that could underlie an individual's genetic susceptibility to human essential hypertension (EHT). We describe here a polymerase chain reaction-based assay for detection of a BglI dimorphic site located in the first intron of the REN gene. In this retrospective, case-control, association study, we investigated BglI allele and genotype distributions in 554 subjects (280 hypertensives and 274 normotensives) from the United Arab Emirates (UAE) - a genetically homogeneous ethnic population with no history of smoking or alcohol consumption - and in 485 hypercholesterolemic, US Caucasian subjects (250 hypertensives and 235 normotensives). A statistically significant association was found between alleles on which the BglI site is present [BglI(+)] and clinical diagnosis of EHT in the UAE sample group (odds ratio = 2.69, p = 0.0006), and a similar trend was observed in the US group (odds ratio = 1.97, p = 0.01). BglI(+) homozygous status was also investigated in the US group and found to be associated with elevated systolic and diastolic blood pressure values (respectively, 144.8+/-26.1 vs. 134.1+/-23.0 mm Hg, p = 0.04; and 91.0+/-12.5 vs. 82.2+/-12.7 mm Hg, p = 0.009). In conclusion, variations of the REN (or of a nearby) gene that may be in linkage disequilibrium with the REN BglI(+) marker could play a role in contributing to an increased individual's genetic susceptibility to EHT in the UAE population and amongst US hypercholesterolemic Caucasians. Such a genetic influence, which seems to show a recessive mode of inheritance, could also be implicated in raising both systolic and diastolic blood pressures.     

Effect of hormone therapy on BP in normotensive and hypertensive postmenopausal women

High blood pressure (BP) ranks as the greatest risk factor for cardiovascular disease. The increased cardiovascular risk determined in recent interventional studies has led the health authorities in some countries to re-ignite the discussion about whether hypertension should be listed as a contraindication for hormone replacement therapy (HRT). We reviewed papers published since 1960 and listed in MEDLINE, EMBASE and Biosis, on studies that monitored the course of BP during HRT. We found that both primarily normotensive and hypertensive postmenopausal women actually run only a very low risk of BP increase during HRT, indeed, BP was often lowered. In one of our own studies 1397 hypertensive women with BP diastolic >95 mmHg received transdermal HRT regimens; BP was lowered by an average of 7 mmHg systolic and 9 mmHg diastolic. The results of the more recent 24-h ambulatory BP studies are particularly conclusive. At least 19 such studies have been performed, 13 placebo-controlled and 10 cross-over; 5 found no effect on BP and 14 studies demonstrated BP reductions. BP was lowered by treatment with transdermal estradiol in 11 of 13 studies and by oral estrogen in 4 of 11 studies. The effects were not consistent with regard to systolic or diastolic BP nor to action on day- and night-time BP. It cannot be ruled out that some women with a particular predisposition exhibit an abnormal reaction to the vasoactive effects of HRT, and there is a paucity of long-term data on risk populations, specifically on the progestogenic effects in patients with pre-existing arteriosclerotic lesions. In conclusion, the risk of developing hypertension during HRT is very low, but hormone therapy should always be appropriately indicated and during therapy BP should be checked regularly.     

Lateral sleeping position reduces severity of central sleep apnea / Cheyne-Stokes respiration

INTRODUCTION: The influence of sleeping position on obstructive sleep apnea severity is well established. However, in central sleep apnea with Cheyne Stokes respiration (CSA-CSR) in which respiratory-control instability plays a major pathophysiologic role, the effect of position is less clear. STUDY OBJECTIVES: To examine the influence of position on CSA-CSR severity as well as central and mixed apnea frequency. METHODS: Polysomnograms with digitized video surveillance of 20 consecutive patients with heart failure and CSA-CSR were analyzed for total apnea-hypopnea index, mean event duration, and mean oxygen desaturation according to sleep stage and position. Position effects on mixed and central apnea index, mean apnea duration, and mean desaturation were also examined in non-rapid eye movement sleep. RESULTS: Data are presented as mean +/- SEM unless otherwise indicated. Group age was 59.9 +/- 2.3 years, and total apnea-hypopnea index was 26.4 +/- 3.0 events per hour. Compared with supine position, lateral position reduced the apnea-hypopnea index in all sleep stages (Stage 1, 54.7 +/- 4.2 events per hour vs 27.2 +/- 4.1 events per hour [p < .001]; Stage 2, 43.3 +/- 6.1 events per hour vs 14.4 +/- 3.6 events per hour [p < .001]; slow-wave sleep, 15.9 +/- 6.4 events per hour vs 5.4 +/- 2.9 events per hour [p < .01]; rapid eye movement sleep, 38.0 +/- 7.3 events per hour vs 11.0 +/- 3.0 events per hour [p < .001]). Lateral position attenuated apnea and hypopnea associated desaturation (supine 4.7% +/- 0.3%, lateral 3.0% +/- 0.4%; p < .001) with no difference in event duration (supine 25.7 +/- 2.8 seconds, lateral 26.9 +/- 3.4 seconds; p = .921). Mixed apneas were longer than central (29.1 +/- 2.1 seconds and 19.3 +/- 1.1 seconds; p < .001) and produced greater desaturation (6.1% +/- 0.5% and 4.5% +/- 0.5%, p = .003). Lateral position decreased desaturation independent of apnea type (supine 5.4% +/- 0.5%, lateral 3.9% < or = 0.4%; p = .003). CONCLUSIONS: Lateral position attenuates severity of CSA-CSR. This effect is independent of postural effects on the upper airway and is likely to be due to changes in pulmonary oxygen stores. Further studies are required to investigate mechanisms involved.     

Left heart hypertrophy in arterial hypertension in relation to hemodynamic and humoral factors

In patients with arterial hypertension hemodynamic as well as humoral factors may influence the development of left ventricular hypertrophy. We therefore investigated in 23 patients with long standing hypertension (11 females, 12 males, age 50 +/- 13 years) wether left ventricular mass as determined by echocardiography interrelates with hemodynamic or humoral parameters. Left ventricular mass measured 161 +/- 51 g/m2 and correlated significantly with patients' age (r = 0.55, p less than 0.05) and systolic blood pressure (159 +/- 21 mm Hg, r = 0.51, p less than 0.05) but not with diastolic blood pressure (99 +/- 15 mm Hg, r = 0.23, not significant). Plasma renin activity was 0.6 +/- 0.6 ng/ml/h and plasma norepinephrine levels measured 371 +/- 168 ng/l. Neither of these humoral parameters correlated significantly with left ventricular mass. It is concluded that in long standing hypertension left ventricular hypertrophy is determined predominantly by the elevation of systolic blood pressure and the patients' age.     

Evidence of prostacyclin deficiency in the syndrome of hyporeninemic hypoaldosteronism

Hyporeninemic hypoaldosteronism is an important cause of hyperkalemia and is characterized by low renin secretion. We found that prostacyclin, a potent vasodilator and renin secretagogue, was markedly reduced--as reflected by its stable urinary metabolite 6-keto-prostaglandin F1 alpha--in seven patients with hyporeninemic hypoaldosteronism as compared with seven matched controls with renal insufficiency and as compared with 12 normal volunteers (mean +/- SE, 42 +/- 7 vs. 185 +/- 37 and 164 +/- 20 ng per gram of creatinine, respectively; P less than 0.001). In contrast, renal prostaglandin E2 excretion was similar in all three groups. A low-dose infusion of calcium or norepinephrine (known stimulants of prostacyclin) increased renal prostacyclin release in normal subjects and controls with renal insufficiency. Neither agonist, however, increased the low basal prostacyclin excretion in the patients (49.6 +/- 11 [basal] vs. 62 +/- 20 [norepinephrine] and 47.5 +/- 16 [calcium]; P greater than 0.8). To evaluate the functional importance of the altered prostacyclin production, we studied the responses of renal blood flow and blood pressure to the calcium infusion. The calcium infusion did not alter blood pressure or renal blood flow in the normal subjects or the controls with renal insufficiency. In contrast, the same dose of calcium in the patients with hyporeninemic hypoaldosteronism produced a rise in mean blood pressure (from 91 +/- 6 to 104 +/- 8 mm Hg, P less than 0.05) and a fall in renal blood flow (from 673 +/- 58 to 560 +/- 42 ml per minute per 1.73 m2, P less than 0.05). These results indicate that a deficiency of prostacyclin could explain the low active-renin concentration and altered vasomotor tone seen in hyporeninemic hypoaldosteronism.     

Effects of hormonal replacement therapy in postmenopausal hypertensive patients.

OBJECTIVE: To evaluate the effect of hormonal replacement therapy (HRT) on blood pressure (BP) in postmenopausal hypertensive women. METHODS: Sixty women affected by hypertension were enrolled and randomized in two groups of treatment: transdermal continuous HRT in a sequential regimen (group A) and placebo (group P). At baseline, after 3 and 6 months of treatment, the BP with standard sphygmomanometer and with 24-h ambulatory recording method was evaluated in two periods (from day 10 through day 16 of the cycle and from day 20 through day 27 of the cycle). At the same time, we also evaluated total cholesterol, LDL-c, HDL-c, triglycerides, and fibrinogen levels. RESULTS: After 3 and 6 months of treatment, no significant variations of systolic and diastolic BP measured with standard sphygmomanometer were detected in both groups. On the contrary, in group A in comparison with basal values and group P, and without difference between the two phases of treatment, the 24-h recording showed a significant (P<0.05) decrease in BP. No significant variations were detected in group P versus baseline. In particular, we observed in group A at 3 months of treatment a significant (P<0.05) decrease only in daytime BP in comparison with basal values and group P, without difference between the two phases of treatment. Indeed, the decrease in daytime BP was significant (P<0.05) for both systolic and diastolic BP. At 3 and 6 months a significant (P<0.05) decrease in total cholesterol, LDL-c and fibrinogen levels was detected in group A versus baseline and group P. HDL-c and triglyceride concentrations showed no significant variations. CONCLUSIONS: The transdermal HRT induces a significant reduction of BP values and a favorable metabolic action in postmenopausal hypertensive patients.     

Sleep apnea syndrome: a possible contributing factor to resistant

STUDY OBJECTIVES: There is evidence supporting an association between sleep apnea and hypertension. However, it is not clear if sleep apnea interteres with the pharmacotherapy of hypertension. To investigate this question, we studied the relationship between the effectiveness of anti-hypertensive treatment in reducing blood pressure, and severity of sleep apnea in a large group of apneic patients referred to a sleep disorders centre at St. Michael's Hospital at the University of Toronto. DESIGN: N/A SETTING: N/A PARTICIPANTS: 1,485 adult patients with sleep apnea, as defined by the apnea/hypopnea index (AHI) >10 events/hr, were analyzed. There were 393 who reported using anti-hypertensive medications on a regular basis for more than 6 months. One hundred and eighty-three patients were treated "effectively" (i.e. blood pressure lower than 140/90 mm Hg in the morning and in the evening). Seventy-four patients were treated "ineffectively," defined as blood pressure >140/90 mm Hg in the morning or in the evening. Both groups were compared with respect to clinical and demographic data using analysis of covariance with gender, age, body mass index (BMI), and neck circumference (NC) as covariates. INTERVENTIONS: N/A MEASUREMENTS AND RESULTS: Ineffectively and effectively treated patients were similar in age (57 +/- 9) vs. 57 +/- 10 years, respectively), and had similar body mass index (33.8 +/- 7.4 vs. 33.4 +/- 7.3 kg/m2, respectively). However, ineffectively treated patients had significantly higher apnea/hypopnea index (44 +/- 29 vs. 33 +/- 25 events/hr, p<.0005), despite having similar nocturnal oxygenation (percent of total sleep time spent with oxygen desaturation lower than 90% was 36 +/- 34 vs. 29 +/- 30% in the ineffective and effective groups, respectively). The difference in AHI persisted even after adjusting for age, gender, and body mass index. CONCLUSIONS: Our results demonstrate that hypertensive patients with sleep apnea whose blood pressure responds beneficially to treatment have less severe sleep apnea than those patients whose blood pressure remains elevated despite anti-hypertensive therapy. Since neither obesity nor nocturnal hypoxemia appear to be important determinants of ineffective treatment, we suggest that resistant hypertension may be caused by frequent intermittent sympathetic stimulation.     

An evaluation of the effects of renal artery stenting in renovascular hypertension

Renal artery stenosis is a common cause (1-6%) of secondary hypertension. Renal artery stenting has recently been employed as an adjunct to antihypertensive medication. We evaluated 92 patients who underwent renal angiography of whom 30 were stented. There was a reduction (p < 0.01) in blood pressure immediately post renal artery stenting--systolic BP from 157 +/- 20 to 140 +/- 21 mmHg and diastolic BP from 81 +/- 13 to 72 +/- 12 mmHg was sustained at 6 months follow up (148 +/- 20/76 +/- 12 mmHg) in the outpatients' clinic. The amount of antihypertensive medication did not differ post stenting--2.7 +/- 1.2 pre vs 2.7 +/- 1.2 drugs post procedure. Renal artery stenting did not provide a 'cure' for any patient with atherosclerotic renovascular hypertension and until the results of randomized studies are known we believe use should be restricted.     

Combination effects of normobaric hyperoxia and edaravone on focal cerebral ischemia-induced neuronal damage in mice

We evaluated the potential neuroprotective effects of combination treatment with normobaric hyperoxia (NBO) and edaravone, a potent scavenger of hydroxyl radicals, on acute brain injuries after stroke. Mice subjected to 2-h filamental middle cerebral artery occlusion were treated with NBO (95% O2, during the ischemia) alone, with edaravone (1.5 mg/kg, intravenously after the ischemia) alone, with both of these treatments (combination), or with vehicle. The histological and neurological score were assessed at 22-h after reperfusion. Infarct volume was significantly reduced in the combination group [36.3+/-6.7 mm3 (n=10) vs. vehicle: 65.5+/-5.9 mm3 (n=14) P<0.05], but not in the two monotherapy-groups [NBO: 50.5+/-5.8 mm3 (n=14) and edaravone: 56.7+/-5.8 mm3 (n=10)]. The combination therapy reduced TUNEL-positive cells in the ischemic boundary zone both in cortex [6.0+/-1.4 x 10(2)/mm2 (n=5) vs. vehicle: 18.9+/-2.4 x 10(2)/mm2 (n=5), P<0.01] and subcortex [11.6+/-1.5 x 10(2)/mm2 (n=5) vs. vehicle: 22.5+/-2.1 x 10(2)/mm2 (n=5), P<0.01]. NBO and combination groups exhibited significantly reduced neurological deficit scores at 22-h after reperfusion (vs. vehicle, P<0.05). Combination therapy with NBO plus edaravone prevented the neuronal damage after focal cerebral ischemia and reperfusion in mice, compared with monotherapy of NBO or edaravone.     

Cardiovascular and metabolic responses to fasting and thermoneutrality in Ay mice

Several lines of evidence support a role for reduced melanocortin signaling in the regulation of metabolic rate and cardiovascular function during negative energy balance. We tested the hypothesis that agouti yellow (B6.Cg-A(y)) mice would exhibit blunted physiologic responses to fasting and thermoneutrality. Male B6.Cg-A(y) mice (A(y); n=11, 34+/-2 g) and lean B6 littermates (B6; n=7, 26+/-2 g) were implanted with telemetry devices and housed in metabolic chambers (T(a)=23 degrees C) to determine the effects of a 24-h fasting and exposure to thermoneutrality (T(a)=30 degrees C) on mean arterial pressure (MAP), heart rate (HR), AP and HR variability (time and frequency domain), oxygen consumption (VO(2)), and locomotor activity. A(y) mice exhibited elevated baseline light-period MAP (A(y): 113+/-4; B6: 99+/-3 mm Hg) and VO(2) (A(y): 1.82+/-0.08 vs. B6: 1.45+/-0.13 ml/min) with no difference in HR (A(y): 530+/-12 vs. B6: 548+/-19 bpm). At 12-24 h after food removal, A(y) mice displayed normal fasting-induced bradycardia (A(y): -106+/-12; B6: -117+/-19 bpm) and reduction in VO(2) (A(y): -0.19+/-0.04 vs. B6: -0.28+/-0.05 ml/min), but with augmented hypotension (A(y): -9+/-2 vs. B6: -0.5+/-2 mm Hg) and blunted hyperactivity (A(y): 27+/-23 vs. B6: 122+/-42 m/11 h). Fasting was associated with increased HR variability in both time and frequency domain in B6 but not A(y) mice. Exposure to thermoneutrality produced comparable reductions in MAP, HR, and VO(2) in both strains. We conclude that inhibition of melanocortin signaling is not requisite for, but participates in, the metabolic and cardiovascular responses to negative energy balance.