Roland E. Schmieder

A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension

PURPOSE Antihypertensive medications have different effects on left ventricular mass. We conducted a meta-analysis of double-blind trials that measured the effects of antihypertensive therapy on left ventricular mass. METHODS Medical databases and review articles were screened for double-blind, randomized controlled trials (through September 2002) that reported the effects of diuretics, beta-blockers, calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor antagonists on echocardiographic left ventricular mass in essential hypertension. Treatment arms of the same drug class, weighted for the number of patients, were combined. Analysis of covariance was performed to detect differences among drug classes in effects on left ventricular structure. RESULTS Eighty trials with 146 active treatment arms (n = 3767 patients) and 17 placebo arms (n = 346 patients) were identified. Adjusted for treatment duration and change in diastolic blood pressure, there was a significant difference (P = 0.004) among medication classes: left ventricular mass index decreased by 13% with angiotensin II receptor antagonists (95% confidence interval [CI]: 8% to 18%), by 11% with calcium antagonists (95% CI: 9% to 13%), by 10% with ACE inhibitors (95% CI: 8% to 12%), by 8% with diuretics (95% CI: 5% to 10%), and by 6% with beta-blockers (95% CI: 3% to 8%). In pairwise comparisons, angiotensin II receptor antagonists, calcium antagonists, and ACE inhibitors were more effective at reducing left ventricular mass than were beta-blockers (all P <0.05 with Bonferroni correction). CONCLUSIONS Antihypertensive drug classes have different effects on left ventricular mass reduction. Whether a greater reduction of left ventricular mass results in better clinical outcomes remains to be determined.

Obesity as a determinant for response to antihypertensive treatment.

OBJECTIVE--To test the hypothesis that beta blockers lower blood pressure more effectively than calcium entry blockers in obese hypertensive patients and that calcium entry blockers are more effective in lean patients. DESIGN--Double blind, randomised controlled trial of treatment over six weeks. SETTING--Tertiary referral centre. SUBJECTS--42 white men with uncomplicated mild to moderate essential hypertension (World Health Organisation stage I or II); 36 completed the study. INTERVENTION--Patients were randomised to metoprolol 50-100 mg twice daily or isradipine 2.5-5.0 mg twice daily for six weeks after a two week run in phase. MAIN OUTCOME MEASURE--Blood pressure after six weeks of treatment. RESULTS--When stratified according to treatment and presence of obesity (body mass index < or = 27 kg/m2), the mean (SD) fall in blood pressure in the beta blocker group was 24 (13)/18 (10) mm Hg in obese patients and 18 (19)/12 (13) mm Hg in lean patients. In the calcium entry blocker group, the fall in blood pressure was 21 (15)/17 (6) mm Hg in lean patients and 18 (11)/8 (10) mm Hg in obese patients. After taking age and blood pressure before treatment into account there was a significant interaction between obesity and drug therapy (p = 0.019) with a better diastolic blood pressure response to calcium entry blockers in lean patients and to beta blockers in obese hypertensive patients. CONCLUSION--Obesity affects the efficacy of metoprolol and isradipine in reducing blood pressure.

The First Cyclodiasteromeric [3]Rotaxane

A mechanically linked molecule, consisting of an axle and two equivalent wheels, shows an analogous stereochemistry to the classical example tartaric acid. Though the components are not chiral themselves, a (cyclo)diastereomeric species is obtained, the enantiomers (shown schematically) and the meso form of which were completely separated and chiroptically characterized.

Disparate hemodynamic responses to mental challenge after antihypertensive therapy with beta blockers and calcium entry blockers

The hemodynamic response to mental challenge was studied in 40 male outpatients with mild essential hypertension. The patients were treated randomly either with a beta adrenoreceptor blocker (oxprenolol) or with a calcium entry blocker (nitrendipine). Cardiovascular reactivity was evaluated with two different mental arithmetic tasks before and six months after treatment by continuously measuring systolic and diastolic pressure (ultrasonic Doppler device), heart rate (electrocardiography), and stoke volume (impedance cardiography). Patients in both treatment groups had equal decreases in arterial pressure and the same pressures at rest. In patients receiving calcium entry blockers, mental challenge provoked an increase in stroke volume and a decrease in total peripheral resistance similar to results in the pretreatment phase. In contrast, beta adrenoreceptor blockade reversed the hemodynamic response pattern to a distinct decrease in stroke volume (p less than or equal to 0.05) and an increase in total peripheral resistance (p less than or equal to 0.05). In addition, an attenuated heart rate response (p less than or equal to 0.01) and a larger increase in diastolic pressure (p less than or equal to 0.01) were found in the beta blocker group compared with the calcium entry blocker group. Although beta blockers and calcium blockers produce equal decreases in arterial pressure, beta blockers evoke an abnormal hemodynamic response to mental challenge, whereas calcium entry blockers preserve the physiologic reactivity pattern of the untreated state.

From rotaxanes to knots. Templating, hydrogen bond patterns, and cyclochirality

Rotaxanes of the amide type have been accessible in preparative yields by a variety of reactions. Beneath SN2- and SN2t-mechanisms we developed a synthesis of [2]rotaxanes that comes off a Michael addition. The motif of the attractive interactions between an axle-shaped and a macrocyclic wheel part to form rotaxanes consists of multiple hydrogen bonds in the nonionic strategy (threading), as well as in a new high yield anionic template synthesis (trapping). We introduce new synthetic routes for the preparation of [n]rotaxanes using nonionic as well as anionic templates. Furthermore, we report on the latest results of the statistical synthesis (slipping) by melting together axle and wheel to form rotaxanes. The chiroptical properties of a homologous series of cycloenantiomeric [1]rotaxanes as well as a cyclodiastereomeric [3]rotaxane have been described. The differences in the Cotton effects obtained show that small structural changes have an impact on the chiroptical properties of rotaxanes. The first X-ray structures obtained of cycloenantiomerically chiral amide-based [2]- and [1]rotaxanes as well as of the first topologically chiral amide-based knot compound were solved which show networks of H-bonds between the entities of the rotaxanes and the segments of the knot-shaped molecule. Our investigations in template effects based on hydrogen bonding for the synthesis of supramolecular structures open up a variety of strategies for the preparation of catenanes, rotaxanes andrecentlyeven molecular knots.

Predictors for hypertensive nephropathy: results of a 6-year follow-up study in essential hypertension.

Objective and design To identify predictors for the development of early hypertensive nephropathy, 88 previously untreated patients with mild-to-moderate essential hypertension (World Health Organization stage I or II) were re-examined after 6 years of follow-up. According to previous results, protein excretion, urinary excretion of N-acetyl-β-glucosaminidase (NAG), serum NAG concentration and glomerular filtration rate (creatinine clearance) may predict the change in renal function. Results Serum creatinine level increased significantly, but none of the patients developed serum creatinine of > 1.3 mg/dl. An elevated protein excretion between 200 and 500 mg/day at baseline (microproteinuria), urinary NAG excretion, serum NAG concentration and blood pressure control during treatment were not related to serum creatinine level at follow-up or change in serum creatinine level throughout the 6 years of follow-up. In contrast, a high creatinine clearance at baseline was related to a marked rise in serum creatinine level after 6 years. The patients with a clear-cut increase in serum creatinine level of > 0.2 mg/dl (n = 23) were characterized by a significantly higher pretreatment blood pressure at the worksite and a significantly greater initial creatinine clearance than the patients with no significant change in serum creatinine level. In the two groups age, blood pressure level during therapy, and the intensity and duration of blood pressure control were not different. Conclusion In patients with uncomplicated essential hypertension, microproteinuria, NAG parameters and treatment blood pressure level did not predict the change in serum creatinine level in the first 6 years of follow-up. A high creatinine clearance (suggesting glomerular hyperfiltration) emerged as a clinical diagnostic marker of early hypertensive nephropathy.

Effects of Bromocriptine on Cardiovascular Regulation in Healthy Humans

Bromocriptine, a dopamine agonist with central nervous system actions, may reduce sympathetic nervous system activity. We tested this hypothesis by measuring arterial blood pressure, central venous pressure, heart rate, muscle sympathetic nerve activity, and forearm blood flow before and after unloading the arterial baroreceptors with sodium nitroprusside (0.5 to 1.5 mcg/kg per minute IV), before and after unloading the cardiopulmonary baroreceptors with incremental lower body negative pressure (0 to -15 mm Hg), and before and after immersion of the hand in ice-cold water for 2 minutes (cold pressor test). After obtaining basal responses to provocative maneuvers, we gave 20 healthy subjects either 5 mg oral bromocriptine (n = 10) or placebo (n = 10) in a randomized, double-blind fashion. Bromocriptine did not affect resting mean arterial pressure, heart rate, or forearm blood flow. Bromocriptine decreased resting central venous pressure by 1.2 mm Hg (P < .05) and tended to increase total integrated muscle sympathetic nerve activity (from 151 +/- 44 to 212 +/- 82 U/min, P = NS). The reflex increases in muscle sympathetic nerve activity to nitroprusside infusion and lower body negative pressure were unchanged by bromocriptine; however, vascular responsiveness to both maneuvers was impaired after bromocriptine administration compared with control. Without bromocriptine, the reflex increase in muscle sympathetic nerve activity after nitroprusside-induced hypotension maintained forearm blood flow at a constant level, whereas with bromocriptine the forearm blood flow increased from 1.9 +/- 0.3 to 2.8 +/- 0.6 mL/min per 100 mL (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Stress response pattern in obesity and systemic hypertension

Under resting conditions obese hypertensive patients have been described as having a greater cardiac output and lower total peripheral resistance than lean hypertensive patients. To evaluate the hemodynamic patterns under stress conditions, we determined the hemodynamic response to mental stress (first study) and during isometric exercise (second study) in hypertensive patients with a body mass index > 27 kg/m2 (obese) and < 27 kg/m2 (lean). The cohort exposed to mental stress comprised 54 white male patients (30 were lean, 24 were obese) with untreated stage I or II essential hypertension according to the World Health Organization. Obese subjects responded with a higher increase in total peripheral resistance (p < 0.02) and lower increases in heart rate (p < 0.01), cardiac output (p < 0.01) and stroke volume (p < 0.02) when compared with their lean counterparts. This was independent of any differences in chemical or baseline hemodynamic characteristics at rest. The cohort exposed to isometric stress consisted of 57 patients (30 were lean, 27 were obese) with World Health Organization stage I or II essential hypertension. Obese subjects responded with exaggerated increases in systolic (p < 0.04) and diastolic (p < 0.01) pressures, and heart rate (p < 0.04) when compared with lean patients. Body mass index emerged as an independent determinant of the increase in systolic (r = 0.03) and diastolic (r = 0.01) pressure as well as of heart rate (r = 0.03). These results indicate that obese hypertensive patients respond to (1) mental stress with vasoconstriction instead of the expected vasodilation, and to (2) isometric stress with an exaggerated increase in arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

The Role of Fixed-Dose Combination Therapy with Drugs that Target the Renin-Angiotensin System in the Hypertension Paradigm

Most patients with hypertension require two or more agents from different classes to achieve BP control. Several fixed-dose combinations are available, often combining agents that target the renin angiotensin system (angiotensin-converting enzyme [ACE] inhibitors or an angiotensin receptor blockers [ARBs]) plus either thiazide diuretics or calcium channel blockers (CCBs). At low doses, these combinations may have greater efficacy and better tolerability than the respective high dose monotherapies. Combining an ARB (instead of an ACE inhibitor) with the CCB amlodipine offers efficacy with improved tolerability. This review aims to highlight the simplicity, tolerability, and convenience of fixed-dose combinations targeting the renin-angiotensin system, which can lead to improved compliance and more patients achieving BP goals.

Chiral Amide Rotaxanes with Glucose Stoppers – Synthesis, Chiroptical Properties and Wheel-Axle Interactions

In this paper we report on amide rotaxanes with tetrabenzoylglucose stoppers. When acetyl groups are used instead of benzoyl groups, merely a pseudo-rotaxane 5 is obtained. The circular dichroism measurements of the rotaxanes 6a and 6b differ significantly from that one of the free axle 7. Similarly, the Cotton effects of the mixtures of achiral wheels 2a and 2b and chiral axle indicate intermolecular host-guest interactions, likewise. After an addition of a solution of NaOMe the wheel is slipping off immediately and quantitatively by hydrolysis, as the benzoylglucose stoppers decrease in size by hydrolysis.