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Biomedical subjects

R Düsing

Publications and source records attributed to R Düsing.

At least 55 records · Page 3Linked to original sources
PubMed2000

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).

Adult↗
PubMed2000

Fibrinolytic function in diuretic-induced volume depletion.

Accumulating evidence suggests that the renin-angiotensin system (RAS) may participate in the regulation of fibrinolytic function. In clinical studies, however, angiotensin-converting enzyme (ACE) inhibitors and the angiotensin II receptor antagonist losartan have failed to consistently affect endogenous fibrinolysis. Because such an effect may depend on the degree of prestimulation of the RAS, we have studied parameters of fibrinolytic function in 15 healthy volunteer subjects during baseline (day 1) and after 10 days of treatment with 25 mg of hydrochlorothiazide (HCT)/day (day 11). On the last day of the study (day 12), a single oral dose of 50 mg of losartan was given to the volunteers in addition to HCT and fibrinolytic function was assessed at the peak effect of losartan (5 h later). Plasma renin activity (PRA) was significantly stimulated during diuretic treatment (1.35 +/- 0.21 v 0.34 +/- 0.06 ng mL(-1) x h(-1) [P < .001]) and further increased after losartan (6.39 +/- 1.16 ng mL(-1) x h(-1) [P < .001]). No effects of either the diuretic or losartan could be observed on tissue-type plasminogen activator (t-PA) antigen concentration and activity. However, 10 days of treatment with HCT significantly increased plasminogen activator inhibitor-1 (PAI-1) antigen (26.8 +/- 5.8 v 21.1 +/- 3.4 ng/mL [p = .037]). In addition, PAI-1 activity was also tentatively raised by HCT treatment (5.48 +/- 1.82 v 3.88 +/- 0.79 IU/mL [P = .067]). In spite of the marked further rise in PRA after losartan, the stimulation of PAI-1 antigen and activity was blunted by losartan (24.4 +/- 3.6 ng/mL and 4.55 +/- 0.99 IU/mL, respectively). Our results demonstrate that volume depletion induced by HCT treatment is associated with a rise in PAI-1. Acute administration of losartan is capable of blunting this effect, suggesting that the angiotensin II type 1 receptor may participate in this effect of angiotensin II.

Adult↗
PubMed2000

Effects of the mineralocorticoid fludrocortisone on fibrinolytic function in healthy subjects.

Recent evidence suggests that the renin-angiotensin-aldosterone system (RAAS) may participate in the regulation of fibrinolytic function. Angiotensin II (Ang II) is the primary candidate to mediate this inter-relationship, since this peptide is capable of stimulating plasminogen activator inhibitor-1 (PAI-1) in vitro and in vivo. It has been suggested that aldosterone may also modulate fibrinolysis, possibly by interacting with Ang II. The present study therefore investigates the effect of short-term treatment with the synthetic mineralocorticoid fludrocortisone (F) on fibrinolytic function. Ten healthy male volunteers, aged 25 to 30 years, on a constant intake of 160-180 mmol Na(+) and 60-80 mmol K(+), were studied on a control day (C1), after two days of oral administration of F (0.1 mg b.d.), and again three days after cessation of F (C2). F was associated with a marked decrease in plasma renin activity (PRA) from 0.91 +/- 0.45 ng ml(-1) h(-1) to 0.34 +/- 0.29 ng ml(-1) h(-1) (p=0.005), which returned to the baseline range at C2 (0.65 +/- 0.45 ng ml(-1) h(-1); p=0.032). The experimental protocol was not associated with significant changes in the activity or antigen concentration of tissue plasminogen activator (t-PA). PAI-1 exhibited a circadian rhythm with highest values at 0800 hours (41.8 +/- 9.1 ng/ml), decreasing by 1230 hours (22.6 +/- 5.9 ng/ml), with a further decrease at 1630 hours (12.3 +/- 3.1 ng/ml). At all three time points, PAI-1 remained unchanged by the mineralocorticoid. Our results therefore do not support a major mineralocorticoid effect on PAI-1. However, our study does not exclude a modulatory role of F, since unchanged PAI-1 could be observed in spite of a marked suppression of the RAAS.

Adult↗
PubMed1999

Effects of captopril on fibrinolytic function in healthy humans.

Several lines of evidence point to an interrelation of the renin angiotensin system (RAS) with the endogenous fibrinolytic system. In the present study, we have therefore investigated the effect of the ACE-inhibitor captopril on various parameters of the fibrinolytic system in healthy volunteer subjects. 10 male subjects aged 28-38 years were given captopril 25 mg b.i.d. over 2 weeks. Venous blood was drawn before and at the end of the treatment period at 09.00 AM, after the volunteers had received their last dose of captopril by 07. 30 AM. Blood samples were processed for the determination of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Both parameters were determined with respect to their abundance (as antigen concentrations) and function (activity). In addition, the concentration and activity of the von Willebrand factor were also determined. Two weeks of captopril treatment had no significant effect on any of the above mentioned parameters. Our results thus show that short-term treatment with the ACE-inhibitor captopril, at least in healthy subjects on an unrestricted NaCl intake, does not affect the fibrinolytic balance between t-PA and PAI-1 or the von Willebrand factor.

Adult↗
PubMed1998

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.

Adrenergic Antagonists↗
PubMed1998

Changes in antihypertensive therapy--the role of adverse effects and compliance.

In a German multicentre study (1603 patients, 320 private practices), adverse effects and patient compliance during antihypertensive therapy were investigated using standardized questionnaires for both patient and physician. Patients with a change in antihypertensive therapy during the last six months were included in this study. The single most important reason for the change in therapy was inadequate blood pressure control (48.4%), followed by adverse effects (30.1%), patient dissatisfaction (20.0%), non-compliance (16.8%) and cost (4.9%). The most frequent adverse effects noted by the doctors were cough (51.9%), oedema (36.9%), flush (36.6) and dizziness (27.8%). In comparing the answers of the physicians and patients, it becomes obvious that compliance may be overestimated by the doctors (good: 41.7%; medium: 57.3%; bad: 1.0%), since only 32.3% of the patients stated that they never missed a dose, 54.8% were occasionally non-compliant and 12.9% admitted missing a dose frequently. The predominant reasons for non-compliance (assessed by the patients) were forgetfulness (40.4%), followed by adverse effects (9.6%) and irregular lifestyle (6.5%). Thus, lack of effectiveness and adverse effects/patient dissatisfaction/non-compliance contributed roughly equally to the decision to change therapy. In addition, forgetfulness was shown to be an important contributor to suboptimal compliance. Lastly, physicians may still underestimate the extent of non-compliance.

Adult↗
PubMed1997

Angiotensin type-1 (AT1) receptor gene expression in primarily cultured human arterial umbilical endothelial cells.

The aim of this study was to investigate the interaction of angiotensin II (Ang II) and human umbilical arterial endothelial cells (HUAEC). Specific binding of 125I-ANG II to primarily cultured HUAEC showed a K(D) of 1.98 +/- 0.53 x 10(-9) M (n = 5) with a maximum binding site of 2.84 +/- 1.07 x 10(-13) mol/mg protein (n = 5). In later passages (third and fifth subculture), this binding site was no longer detectable. Gene expression analysis revealed a strong expression of the angiotensin type-I receptor (AT1-R) in the primarily cultured HUAEC, with a decrease in additional passages. In primarily cultured HUAEC, Ang II (10(-10)-10(-6) M) induced a concentration-dependent increase in intracellular free calcium ([Ca2+]i) that could be blocked by a preincubation with candesartan (TCV-112) but not by PD123319. These data show the expression of the AT1-R in primary cultures of HUAEC. The Ang II-induced increase in [Ca2+]i seems to be mediated by this receptor.

Angiotensin II↗
PubMed1997

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).

Animals↗
PubMed1997

Acute saline infusion induces extracellular acidification and activation of the Na+/H+ exchanger in man.

The effect of acute expansion of the extracellular fluid volume (ECV) with isotonic (0.9%) saline on the activity of the lymphocyte Na+/H+ antiport (NHE) was studied in a total of 18 healthy volunteers. Saline was infused at a constant rate so that 4 mmol kg-1 b.w. was administered over 2 h. NHE activity was measured by quantifying cytosolic pH (pHi) recovery following acidification of the cells with propionic acid and by pH clamping at various pHi values between 7.2 and 5.8 using nigericin. Both methods demonstrate NHE activation associated with intravenous saline infusion, the kinetic difference being a marked decrease in the Hill coefficient n from 3.28 +/- 0.21 (SEM) to 2.22 +/- 0.11 in the absence of changes in baseline pHi (7.14 +/- 0.02 vs. 7.08 +/- 0.02; P = 0.15), Vmax (42.8 +/- 2.7 vs. 48.1 +/- 2.8 mmol L-1 min-1; P = 0.08) and pK (6.32 +/- 0.04 vs. 6.35 +/- 0.02). NHE activation was associated with significant decreases in serum chloride (P = 0.016), calcium (P = 0.008), total cholesterol (P = 0.008), low-density lipoproteins (P = 0.016) and high-density lipoproteins (P = 0.008). Moreover, saline infusion induced extracellular acidification with a decrease in pH from 7.39 +/- 0.01 to 7.37 +/- 0.01 (P = 0.016), HCO3- from 23.3 +/- 0.43 mmol L-1 to 21.3 +/- 0.25 mmol L-1 (P = 0.008) and base excess from -1.03 +/- 0.38 mmol L-1 to -3.00 +/- 0.31 mmol L-1 (P = 0.008). Our results show for the first time that acute ECV expansion with isotonic saline is followed by an activation of the lymphocyte NHE. The underlying mechanism(s) remain to be investigated. However, the demonstration in our study of marked changes in acid-base balance induced by acute saline points to a possible inter-relationship of antiporter activation and extracellular acidification.

Acid-Base Equilibrium↗
PubMed1996

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.

Animals↗
PubMed1996

Oligodeoxynucleotides directed to early growth response gene-1 mRNA inhibit DNA synthesis in the smooth muscle cell.

Vascular smooth muscle cell proliferation plays a central role in the pathophysiology of cardiovascular diseases. The induction of the early growth response gene-1 (egr-1) mRNA is associated with different cellular processes such as cell proliferation. Antisense oligodeoxynucleotides seem to provide a promising new pharmaceutical tool for effective modification of the expression of specific genes. Hence, in the present study, the effect of 15-mer antisense oligodeoxynucleotides (targeted to the initial codon region of the egr-1 mRNA) on the angiotensin II- and platelet-derived growth factor-BB-induced growth promoting effects of aortic smooth muscle cells was evaluated. Angiotensin II- and platelet-derived growth factor-BB induced egr-1 mRNA (3.4 kb) and Egr-1 protein (80 kDa) in a time- and concentration-dependent fashion. No effects of the sense and antisense oligodeoxynucleotides on the agonist-induced elevation of the egr-1 mRNA and on the Egr-1 protein could be demonstrated. However, they effectively inhibited the angiotensin II- and the platelet-derived growth factor-BB-induced DNA synthesis. Our findings provide evidence that the oligodeoxynucleotides inhibit vascular smooth muscle cell growth via nonantisense mechanism(s).

Angiotensin II↗
PubMed1996

CV-11974, the active metabolite of TCV-116 (Candesarten), inhibits the synergistic or additive effect of different growth factors on angiotensin II-induced proliferation of vascular smooth muscle cells.

Many previous studies have demonstrated that angiotensin II (AII) type I (ATI) receptor antagonists remarkably reduced intimal lesions in rats following balloon injury. Using vascular smooth muscle cells (VSMC) in culture, we tested the hypothesis that other classical growth factors may enhance AII effects on VSMC growth, and ATI receptor antagonists may inhibit these effects. AII, platelet-derived growth factor-BB (PDGF-BB), and epidermal growth factor (EGF) caused a 3426 +/- 262%, 277 +/- 69%, and 1568 +/- 62% increase in [3H]thymidine incorporation in VSMC (mean +/- SD, n = 3), respectively. The exposure of the cells to AII in combination with PDGF-BB or EGF resulted in an approximately 2-fold or 1.5-fold elevation of the AII-dependent effect, respectively. 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimi dazole-7- carboxylic acid (CV-11974), the active metabolite of the specific nonpeptide AT1 receptor antagonist (+/-)-1-cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimi dazole- 7-carboxylate (TCV-116, Candesartan), suppressed the effect of AII down to basal values, as well as reducing the synergistic effect of PDGF or the additive effect of EGF on AII-induced [3H]thymidine incorporation. AII and PDGF-BB per se induced 57 +/- 19 and 70 +/- 14% increase in VSMC number. Combination of both agonists resulted in a 2-fold increase of the AII effect on cell number. Again, CV-11974 blocked the effect of AII, as well as the additive effect of PDGF-BB on cell number. From these findings, it may be concluded that AT1 receptor antagonists may reduce or prevent the development of intimal lesions following vascular injury through inhibition of direct and indirect growth-promoting effects of AII in VSMC.

Angiotensin II↗
PubMed1996

Effect of the Na+/H+ antiport inhibitor Hoe 694 on the angiotensin II-induced vascular smooth muscle cell growth.

1. Hoe 694 (3-methylsulphonyl-4-piperidinobenzoyl)guanidine methanesulphonate) was characterized as a new, potent, non-amiloride inhibitor of the Na+/H+ exchanger. In order to elucidate the role of the Na+/H+ exchanger isoform 1 (NHE-1) in the regulation of vascular smooth muscle cell growth, we investigated the effects of different amiloride analogues and of Hoe 694 on angiotensin II-induced cell growth. Since intracellular pH, the intracellular free Ca2+ concentration and the expression of the transcription factor c-fos seem to be involved in the regulation of cell growth, the effects of the amiloride analogues and Hoe 694 on the angiotensin II-induced changes in these three parameters were examined. 2. Measurement of cytosolic Ca2+ and pH in cell monolayers was performed using fura-2/AM and BCECF/AM, respectively. The effect of angiotensin II on cell growth was examined using (1) [3H]-thymidine incorporation, (2) the bromo-2-deoxyuridine (BrdU) immunfluorescence assay, (3) the colorimetric determination of cell mitochondrial dehydrogenase activity and (4) determination of cell number. Total RNA was extracted from cells by the guanidinium isothiocyanate/CsCl procedure. The expression of c-fos was quantitated by Northern blotting. 3. Various amiloride analogues inhibited the angiotensin II-induced stimulation of the Na+/H+ exchanger, the increase in cytosolic Ca2+ and cell growth but not the induction of c-fos mRNA. Hoe 694 (1-25 microM) dose-dependently inhibited the angiotensin II-induced stimulation of the Na+/H+ exchanger but had no significant effects on cytosolic Ca2+, c-fos mRNA levels or cell growth. 4. Our findings support the concept that activation of the Na+/H+ exchanger is not essential for angiotensin II-induced vascular smooth muscle cell growth.

Angiotensin II↗
PubMed1995

Effects of TCV-116 and CV-11974 on angiotensin II-induced responses in vascular smooth muscle cells.

(+/-)-1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylate (TCV-116, Candesartan) and its active metabolite 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylic acid (CV-11974) are specific nonpeptide angiotensin AT1 receptor antagonists. In the present study, the inhibitory potency of these two antagonists on the angiotensin II-induced responses in aortic vascular smooth muscle cells from Wystar Kyoto rats was investigated. The specific binding of 125I-angiotensin II to cells was inhibited by CV-11974 and TCV-116 with a half-maximal inhibitory concentration (IC50) of 3 x 10(-11) M and 1 x 10(-9) M, respectively. CV-11974 and TCV-116 inhibited the angiotensin II-induced increase in [3H]thymidine incorporation with an IC50 of 3 x 10(-10) and 5 x 10(-9) M, respectively. Both CV-11974 and TCV-116 (10(-7) M) completely blocked the angiotensin II-induced increase in c-fos mRNA. The inhibitory potency of the metabolite CV-11974 was about 30-100-fold higher than that of the prodrug TCV-116.

Angiotensin II↗
PubMed1995

[Orthostatic hypotension].

We report about a 67-year-old woman presenting with progressive orthostatic vertigo, urinary incontinence and clinical signs of Parkinson's disease. The Schellong test revealed deficient sympathetic orthostatic pressure response without an increase of plasma norepinephrine; therefore, a Shy-Drager syndrome was diagnosed. Because of inefficiency of the general measures (compressive pantyhose), the sympathomimetic agonists, and the centrally active alpha-2-antagonists, norepinephrine was administered via a miniature dosing pump. By this therapeutic regimen a marked improvement of orthostatic hypotension was achieved.

Aged↗