Rainer Düsing

A new oscillometric method for assessment of arterial stiffness: comparison with tonometric and piezo-electronic methods.

Introduction Pulse wave velocity (PWV) and augmentation index (AIx) are parameters of arterial stiffness and wave reflection. PWV and AIx are strong indicators for cardiovascular risk and are used increasingly in clinical practice. Previous systems for assessment of PWV and AIx are investigator dependent and time consuming. The aim of this study was to validate the new oscillometric method (Arteriograph) for determining PWV and AIx by comparing it to two clinically validated, broadly accepted tonometric and piezo-electronic systems (SphygmoCor and Complior). Design and method PWV and AIx were measured up to five times in 51 patients with the SphygmoCor, Complior and Arteriograph. In 35 patients, the measurements were repeated after 1 week in a second session using the same protocol. Results The correlations of the PWV as assessed with the Arteriograph with the values obtained using the SphygmoCor (r = 0.67, P < 0.001) and the Complior (r = 0.69, P < 0.001) were highly significant. Variability and reproducibility for PWV were best for the Arteriograph, followed by Complior and SphygmoCor. AIx (SphygmoCor versus Arteriograph) were very closely correlated (r = 0.92, P < 0.001). Perspectives The Arteriograph is a new, easy-to-use and time-effective method for assessing arterial stiffness and wave reflection.

Dietary administration of eicosapentaenoic and linolenic acid increases arterial blood pressure and suppresses vascular prostacyclin synthesis in the rat

Abstract The role of the ‘prostacyclin-thromboxane system’ in the regulation of arterial blood pressure was investigated in rats receiving diets which contained different amounts of eixosapentaenoic (EPA) and linolenic acid (LNA). Forty rats were divided into five groups of 8 animals, each group receiving 25 energy (en) % as fat. All diets contained equal amounts of linoleic acid (5 en%) and oleic acid (5 en%). In the control group I, the remaining 15 en% of fat were given as saturated fat. Two groups of animals received cod liver oil as a source for EPA in amounts of 2.5 (group II)_and 5 en% (group III) while the two remaining groups were given diets supplemented with linseed oil as a source for LNA in amounts of 2.5 (group IV) and 5 en% (group V), respectively. After six weeks of feeding period the animals were sacrificed and portions of their isolated aorta incubated in Tris buffer (pH 9.3) for determination of prostacyclin (PGI2)-like activity. Arterial blood pressure was uncharged in group I animals, but significantly increased in all rats receiving dietary EPA or LNA supplements. This rise is arterial blood pressure was associated with a marked suppression of the appearance of PGI2-like activity in the incubation buffer while platelet thromboxane release during blood clotting was unchanged. Our results show that dietary adminis- tration of EPA and LNA increases arterial blood pressure in the rat and that this effect is associated with a suppressed generation of vasodilator prostacyclin by vascular tissue.

The converting enzyme inhibitor captopril stimulates prostacyclin synthesis by isolated rat aorta

In the present study, pretreatment of rats with captopril significantly stimulated prostacyclin (PGI2) synthesis by their isolated aorta. This effect was maximal at captopril doses of 1.0 mumol/kg body weight. When added directly into the incubation buffer, captopril at final concentrations of 50 and 500 nM also increased the synthesis of PGI2 by isolated rat aorta. Our results show that captopril stimulates PGI2 synthesis in vascular tissue and that this effect may be due at least in part to a direct action of this substance.

Lysophosphatidic acid and intracellular signalling in vascular smooth muscle cells

Growth of vascular smooth muscle cells (VSMC) plays an important role in the pathogenesis of atherosclerosis and hypertension. Lysophosphatidic acid (LPA), a natural phospholipid is thought to be an important VSMC mitogen and has recently been suggested to play an important role in the development of vascular disease. In the present study, we describe the effects of LPA on intracellular signalling pathways in VSMC. LPA (5 micrograms/ml) induced an increase of cytosolic free calcium concentration ([Ca2+]i) in the presence and absence of extracellular Ca2+ and markedly stimulated the Na+/H+ exchanger. LPA dose-dependently caused a stimulation of the 42-kDa mitogen-activated protein kinase (MAP kinase) isoform with a maximum at 5 min. Also, LPA induced a 5-fold increase in [3H]thymidine incorporation into cell DNA above the basal value, as well as a 42% increase in cell number. Pretreatment of VSMC with pertussis toxin (PTX) (100 ng/ml) for 24 h markedly blunted the LPA-dependent intracellular signalling transduction including the increase in [Ca2+]i, activation of the Na+/H+ exchanger, activation of MAP kinase and the increase in cell DNA synthesis. These findings demonstrate that the effects of LPA on intracellular signalling transduction pathway as well as on VSMC growth are mediated by PTX-sensitive guanosine triphosphate (GTP) binding protein (Gi protein).

Novel Description of the 24-Hour Circadian Rhythms of Brachial Versus Central Aortic Blood Pressure and the Impact of Blood Pressure Treatment in a Randomized Controlled Clinical Trial: The Ambulatory Central Aortic Pressure (AmCAP) Study

&NA; Elevated brachial blood pressure (BP) is associated with increased cardiovascular risk and predicts morbidity and mortality in humans. Recently, 24-hour ambulatory BP monitoring and assessment of central aortic BP have been introduced to improve BP phenotyping. The Ambulatory Central Aortic Pressure (AmCAP) study combines these approaches and describes, for the first time, the diurnal patterns of simultaneously measured 24-hour ambulatory brachial and central pressures in a prespecified substudy embedded within a clinical trial of BP lowering in patients with hypertension. Twenty-four–hour ambulatory brachial and central pressure measurements were acquired using a tonometer mounted into the articulating strap of a wristwatch-like device (BPro) in 171 participants with hypertension recruited into the ASSERTIVE (AliSkiren Study of profound antihypERtensive efficacy in hyperTensIVE patients) trial. Participants were randomly assigned to BP lowering with either aliskiren 300 mg QD or telmisartan 80 mg QD for 12 weeks. Ambulatory brachial and central BP was measured in all participants both at baseline and at study end. Brachial and central BP both demonstrated typical diurnal patterns with lower pressures at night. However, night time was associated with smaller reductions in central relative to brachial pressure and decreased pulse pressure amplification (P<0.0001 for both). These effects were not modulated after BP lowering and were maintained after adjustment for day and night-time BP and heart rate (P=0.02). This study demonstrates that brachial and central pressure show different diurnal patterns, which are not modulated by BP-lowering therapy, with relatively higher night-time central pressures. These novel data indicate that night-time central BP may provide prognostic importance and warrants further investigation. Clinical Trial Registration– URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865020.

Optimizing blood pressure control through the use of fixed combinations

The majority of hypertensive patients need ≥2 antihypertensive agents to reach goal blood pressure. As an estimate, one-third of unselected hypertensive patients may be successfully treated with monotherapy, one-third may require 2 and the remaining one-third of patients will need ≥3 antihypertensive agents for effective blood pressure control. However, doctors are often hesitant to expand therapy in treated patients whose blood pressure is not lowered to goal (therapeutic inertia). Multiple-drug therapy in the majority of hypertensive patients may also represent one of several factors responsible for the low rates of adherence with chronic antihypertensive treatment. As a consequence, both US and European guidelines recommend single pill combinations to lower the number of pills needed in order to increase medication adherence and, possibly, reduce therapeutic inertia. For 2 drug combinations, the recently revised European (ESC/ESH) guidelines recommend the following options: diuretic plus either calcium channel blocker (CCB) or renin–angiotensin system (RAS) blocker (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker) or CCB plus RAS-blocker. In the absence of substantial evidence, neither JNC-7 (from 2003) nor the European guidelines from 2007 give any meaningful advice on triple combination treatment. It is therefore of interest that the 2009 reappraisal of the European guidelines gives preference to the combination of a RAS blocker and a CCB plus a diuretic. On the background of the substantial number of patients requiring ≥3 drugs for blood pressure control, the recent approval of a single-pill 3-drug combination composed in accordance with the above mentioned ESC/ESH recommendations should be appreciated.

Biotransformation of glyceryl trinitrate by blood platelets as compared to vascular smooth muscle cells

The present study investigated the metabolism of glyceryl trinitrate by washed human platelets as compared to that by rat vascular smooth muscle cells. Possible changes in metabolism after induction of nitrate tolerance were also studied in both systems. Incubation of the cells with glyceryl trinitrate (0.1 mM) resulted in a time-dependent release of nitrite (NO2-) amounting to 6.30 +/- 0.63 nmol mg protein-1 h-1 in vascular smooth muscle cells and 0.61 +/- 0.08 nmol mg protein-1 h-1 for platelets, respectively. The nitric oxide (NO) scavenger, oxyhemoglobin (10 microM), significantly reduced NO2- generation in both cell types studied. Nitrate tolerance was induced by incubation of the cells with glyceryl trinitrate (2 mM) for 2 h. In tolerant vascular smooth muscle cells as well as in tolerant platelets, NO2- release was significantly reduced. The inhibitory capacity of glyceryl trinitrate on ADP (6 microM)-induced platelet aggregation and on intracellular Ca2+ signals was significantly reduced in tolerant platelets. The data show a direct metabolism of glyceryl trinitrate by human blood platelets which is subject to a type of tolerance development similar to that in vascular smooth muscle cells.

Normal values of blood pressure self-measurement in view of the 1999 World Health Organization-International Society of Hypertension guidelines.

New guidelines for the management of hypertension have been published in 1999 by the World Health Organization (WHO) and the International Society of Hypertension (ISH). The WHO/ISH Committee has adopted in principle the definition and classification of hypertension provided by the JNC VI (1997). The new classification defines a blood pressure of 120/80 mm Hg as optimal and of 130/85 mm Hg as the limit between normal and high-normal blood pressure. It is unclear which self-measured home blood pressure values correspond to these office blood pressure limits. In this study we reevaluated data from our Dübendorf study to determine self-measured blood pressure values corresponding to optimal and normal office blood pressure using the percentiles of the (office and home) blood pressure distributions of 503 individuals (age, 20 to 90 years; mean age, 46.5 years; 265 men, 238 women). Self-measured blood pressure values corresponding to office values of 130/85 mm Hg and 120/80 mm Hg were 124.1/79.9 mm Hg and 114.3/75.1 mm Hg. Thus, we propose 125/80 mm Hg as a home blood pressure corresponding to an office blood pressure of 130/85 mm Hg (WHO 1999: normal) and 115/75 mm Hg corresponding to 120/80 mm Hg (optimal).

Antihypertensive drug treatment and fibrinolytic function

Thromboembolic complications such as ischemic stroke and myocardial infarction are significantly more frequent in patients with arterial hypertension. From the available intervention studies, it appears that pharmacologic treatment of hypertension-at least with diuretics and beta-blockers-may more effectively protect against cerebrovascular as compared to coronary thromboembolic events. Whether other antihypertensive substances provide a more effective protection with respect to cardiac morbidity and mortality is the subject of numerous studies presently underway. These studies will help to answer the question of whether the extent of protection from coronary events during antihypertensive treatment depends on factors beyond blood pressure control. The fibrinolytic system is crucially involved in the pathogenesis of thromboembolic events. One determinant of this system is the balance between plasminogen activators (tissue-type plasminogen activator [t-PA]) and inhibitors (plasminogen activator inhibitor 1 [PAI-1]). Experimental and clinical evidence suggests that at least some of the drugs used in the treatment of hypertension may alter the activity of the fibrinolytic system. Scarce and controversial data with respect to such an interaction exist with respect to diuretics, beta-blockers, and calcium antagonists. In addition, experimental evidence demonstrates that PAI-1 is stimulated by angiotensin II (A II), whereas t-PA is activated by bradykinin. Thus, antihypertensive drugs acting within the renin angiotensin system should exert effects also within the fibrinolytic system. However, results from clinical studies with angiotensin converting enzyme (ACE) inhibitors and A II receptor antagonists do not unequivocally support such a concept. The discrepancy in the results may, at least in part, be explained by studies performed in healthy volunteer subjects showing that ACE inhibition profoundly affected fibrinolysis only during stimulation of the renin angiotensin system by NaCL restriction.

Prostaglandins and renal function in acute extracellular volume expansion.

Mechanisms determining the natriuresis in ECV-expansion are not yet completely understood. The present study was therefore undertaken to investigate if prostaglandins (PG) are involved in the natriuresis of acute ECV-expansion and by which mechanisms PG may affect renal Na-absorption. In non-expanded rats the PG synthetase inhibitor indomethacin (INDO) had no effect on renal function. In 37 Sprague-Dawley rats ECV-expansion with isotonic saline corresponding to an increase in b.wt. of 10% was induced. Twenty-one animals received an oral dose of 10 mg/kg b.wt. of INDO prior to ECV-expansion. Sixteen animals served as ECV-expanded controls (C). GFR (INDO: 12.5 +/- 1.0; C: 10.5 +/- 0.9 ml/min/kg b.wt.) did not significantly differ in both groups. However, total renal plasma flow (RPF) (INDO: 22.9 +/- 1.8; C: 30.1 +/- 2.7 ml/min/kg b.wt.), urinary flow rate (INDO: 1.11 +/- 0.20; C: 1.93 +/- 0.21 ml/min/kg b.wt.) and urinary excretion of sodium (INDO: 141 +/- 26; C: 267 +/- 46 muEq/min/kg b.wt.) and potassium (INDO: 13.0 +/- 0.9; C: 19.8 +/- 1.7 muEq/min/kg b.wt.) markedly decreased in animals pretreated with INDO. The results indicate that PG are involved in the natriuresis of acute ECV-expansion and suggest, that PG may inhibit the intrinsic capacity for Na-absorption in more proximal parts of the nephron possibly via intrarenal physical factors.