Calcium antagonist induced vasodilation in peripheral, coronary and cerebral vasculature as important factors in the treatment of elderly hypertensives

Increased arteriolar tone is the pathophysiological hallmark of essential hypertension and is determined by the intracellular free calcium concentration in the vascular smooth muscle cell. Calcium influx is an important determinant of vasoconstriction and excess calcium influx-dependent vasoconstriction has been shown by plethysmographical studies in patients with essential hypertension. Calcium antagonists acutely lower BP by reducing calcium influx, calcium concentration and peripheral resistance. The degree of the attendant sympathetic nerve reflex activation and counter-regulatory mechanisms determines the antihypertensive response of the individual. Chronic monotherapy with a calcium antagonist results in an antihypertensive response, which is directly related to the patient's age and pretreatment BP and indirectly related to plasma renin levels. The resulting reduction in after-load neither leads to reduced cerebral blood flow in hypertensive patients, nor aggravates congestive heart failure. Calcium antagonists are a useful alternative to diuretics, primarily in older patients with low renin levels, either alone or combined with any other antihypertensive drug, and provide effective and safe control of blood pressur

Comparative Effects of Haemodialysis and Haemofiltration on Plasma Atrial Natriuretic Peptide

The effects of 4 h haemodialysis (15 patients) or 4 h haemofiltration (five patients) on plasma concentrations of atrial natriuretic peptide (ANP) were compared by means of a sensitive radioreceptor binding assay, and related to accompanying changes in body weight, blood pressure and plasma renin activity. Before dialysis, plasma ANP concentrations were considerably elevated: haemodialysis group 10-484 pmol/l (mean 156 pmol/l); haemofiltration group 72-320 pmol/l (mean 170 pmol/l). Although plasma concentrations of ANP fell markedly with treatment in both groups: post-haemodialysis 2-187 pmol/l (mean 67 pmol/l); post-haemofiltration 47-135 pmol/l (mean 79 pmol/l), after treatment it remained above the normal range in 14 of the 20 patients. Pretreatment plasma ANP was related to systolic blood pressure (r=0.459; P<0.05) but bore no relationship to mean or diastolic blood pressure, or plasma renin activity. The fall in plasma ANP concentration during treatment correlated with the postural blood pressure drop after dialysis (r=0.505; P<0.05), but was unrelated to changes in weight or plasma renin activity with haemodialysis or haemofiltration. Plasma ANP concentrations rose rapidly again in the 60 min after dialysis treatment, without change in body weight. These results show that high levels of biologically active ANP circulate in end-stage renal disease. The fact that these are not reduced to normal by haemodialysis or haemofiltration, despite restoration to normovolaemic or hypovolaemic state, suggests that the increased levels of ANP in end-stage renal failure are due to both hypervolaemia and other factors, which may include occult cardiac dysfunction and loss of renal clearanc

Angiotensin II-receptor subtypes in human atria and evidence for alterations in patients with cardiac dysfunction

Angiotensin II (All) has been implicated as an important factor in the pathophysiology of heart diseases. Following the recent identification of two subtypes of the All receptor in cardiac tissue of animals, we investigated the possible occurrence of these, or similar, subtypes in human atrial tissue. In right-atrial tissue from patients undergoing heart surgery, we determined the All-receptor profile in receptor binding studies, using [125I]-angiotensin as radioligand and All as well as two compounds selective for the receptor subtypes to identify and quantify All-receptor subpopulations. In 35 patients (23 requiring coronary bypasses, 10 vaivular surgery and two combined coronary and valvular surgery), the left-ventricular ejection fraction was determined in the preoperative phase, and right- and left-atrial pressure during surgery. In membranes of human right atria, All receptors are present in high density (median: Bmax= 294 fmol. mg−1 protein, range: 111-2073) and two different subtypes can be distinguished. Type-1 receptors (AT1) accounted for 33 ± l0% of the population whereas type-2 receptors (AT2) made up 67 ± 10% of the population. There was no correlation between any of the measured cardiac functions and total All-receptor density or receptor affinity. However, the percentage of AT1 receptors was higher in the atria of patients with normal right-atrial pressure; left-ventricular ejection fraction was positively and right-atrial pressure inversely correlated with the percentage of AT1 receptors (r=0·740 and -0·901, respectively; P<0·001, for both). Moreover, the percentage of AT receptors was directly correlated with the levels of left-atrial pressure (r=0·853; P<0·001). It is concluded that the ratio of AT1 to AT2 receptors correlates well with right-atrial pressure and left-ventricular function. This is a first indication of a possible involvement of All-receptor subtypes in the pathophysiology of cardiac dysfunction

Is pretreatment with Beta-blockers beneficial in patients with acute coronary syndrome?

OBJECTIVES: The role of beta-blockers in the treatment of hypertension is discussed controversially and the data showing a clear benefit in acute coronary syndromes (ACS) were obtained in the thrombolysis era. The goal of this study was to analyze the role of pretreatment with beta-blockers in patients with ACS. METHODS: Using data from the Acute Myocardial Infarction in Switzerland (AMIS Plus) registry, we analyzed outcomes of patients with beta-blocker pretreatment in whom they were continued during hospitalization (group A), those without beta-blocker pretreatment but with administration after admission (group B) and those who never received them (group C). Major adverse cardiac events defined as composed endpoint of re-infarction and stroke (during hospitalization) and/or in-hospital death were compared between the groups. RESULTS: A total of 24,709 patients were included in the study (6,234 in group A, 12,344 in group B, 6,131 in group C). Patients of group B were younger compared to patients of group A and C (62.5, 67.6 and 68.4, respectively). In the multivariate analysis, odds ratio for major adverse cardiac events was 0.59 (CI 0.47-0.74) for group A and 0.66 (CI 0.55-0.83) for group B, while group C was taken as a reference. CONCLUSIONS: beta-Blocker therapy is beneficial in ACS and they should be started in those who are not pretreated and continued in stable patients who had been on chronic beta-blocker therapy before

Renale Denervation: Schweizer Erfahrungen im Langzeitverlauf

Despite great advances in pharmacological and non-pharmacological treatment of patients with arterial hypertension, a significant proportion of patients do not reach the target values suggested by the guidelines. A therapy-resistant hypertension is defined as a blood pressure above the suggested target values despite an antihypertensive therapy with three medications at maximal dosis, including a diuretic. The renal denervation is a new and promising method for the treatment of refractory arterial hypertension. An optimal selection of the patients undergoing a renal denervation is extremely important, and this intervention should be performed in highly specialized centers only

Identification of plant-derived alkaloids with therapeutic potential for myotonic dystrophy type I

Myotonic dystrophy type I (DM1) is a disabling neuromuscular disease with no causal treatment available. This disease is caused by expanded CTG trinucleotide repeats in the 3 UTR of the dystrophia myotonica protein kinase gene. On the RNA level, expanded (CUG)n repeats form hairpin structures that sequester splicing factors such as muscleblind-like 1 (MBNL1). Lack of availableMBNL1leads to misregulated alternative splicing of many target pre-mRNAs, leading to the multisystemic symptoms in DM1. Many studies aiming to identify small molecules that target the (CUG)n-MBNL1 complex focused on synthetic molecules. In an effort to identify new small molecules that liberate sequesteredMBNL1from (CUG)n RNA, we focused specifically on small molecules of natural origin. Natural products remain an important source for drugs and play a significant role in providing novel leads and pharmacophores for medicinal chemistry. In a new DM1 mechanism-based biochemical assay, we screened a collection of isolated natural compounds and a library of over 2100 extracts from plants and fungal strains. HPLC-based activity profiling in combination with spectroscopic methods were used to identify the active principles in the extracts. The bioactivity of the identified compounds was investigated in a human cell model and in a mouse model of DM1.We identified several alkaloids, including the -carboline harmine and the isoquinoline berberine, that ameliorated certain aspects of theDM1pathology in these models. Alkaloids as a compound class may have potential for drug discovery in other RNA-mediated diseases

Association of calcemia and serum vitamin D with 24H-urinary calcium excretion in a swiss population-based study

Background: Elevated urinary calcium excretion is associated with reduced bone mineral density. Population-based data on urinary calcium excretion are scarce. We explored the association of serum calcium and circulating levels of vitamin D (including 25(OH)D2 and 25(OH)D3) with urinary calcium excretion in men and women in a population-based study. Methods: We used data from the "Swiss Survey on Salt" conducted between 2010 and 2012 and including people aged 15 years and over. Twenty-four hour urine collection, blood analysis, clinical examination and anthropometric measures were collected in 11 centres from the 3 linguistic regions of Switzerland. Vitamin D was measured centrally using liquid chromatography - tandem mass spectrometry. Hypercalciuria was defined as urinary calcium excretion &gt;0.1 mmol/kg/24h. Multivariable linear regression was used to explore factors associated with 24-hour urinary calcium excretion (mmol/24h) squared root transformed, taken as the dependant variable. Vitamin D was divided into monthspecific tertiles with the first tertile having the lowest value and the third tertile having the highest value. Results: The 669 men and 624 women had mean (SD) age of 49.2 (18.1) and 47 (17.9) years and a prevalence of hypercalciuria of 8.9% and 8.0%, respectively. In adjusted models, the association of urinary calcium excretion with protein-corrected serum calcium was (β coefficient &#x81;} standard error, according to urinary calcium squared root transformed) 1.125 &#x81;} 0.184 mmol/L per square-root (mmol/24h) (P&lt;0.001) in women and 0.374 &#x81;} 0.224 (P=0.096) in men. Men in the third month-specific vitamin D tertile had higher urinary calcium excretion than men in the first tertile (0.170 &#x81;} 0.05 nmol/L per mmol/24h, P=0.001) and the corresponding association was 0.048 &#x81;} 0.043, P= 0.272 in women. Conclusion: About one in eleven person has hypercalciuria in the Swiss population. The positive association of serum calcium with urinary calcium excretion was steeper in women than in men, independently of menopausal status. Circulating vitamin D was associated positively with urinary calcium excretion only in men. The reasons underlying the observed sex differences in the hormonal control of urinary calcium excretion need to be explored in further studies

Comparison of office, home and ambulatory blood pressure measurements in hypertensive and suspected hypertensive SWICOS participants.

PURPOSE Hypertension should be confirmed with the use of home BP measurement (HBPM) or 24h ambulatory BP measurement (ABPM). The aim of our study was to compare measurements obtained by OBPM, HBPM and ABPM in individuals with elevated OBPM participating in the population-based Swiss Longitudinal Cohort Study (SWICOS). MATERIAL AND METHODS Participants with OBPM ≥140/90 mmHg assessed their BP using HBPM and ABPM. The cut-off for hypertension was ≥135/85 mmHg for HBPM, ≥130/80 mmHg for ABPM. White-coat hypertension (WCH) was defined as normal HPBM and ABPM in participants not taking antihypertensive drugs. Uncontrolled hypertension was defined as hypertension in HBPM or ABPM despite antihypertensive treatment. RESULTS Of 72 hypertensive subjects with office BP ≥140/90 mmHg and valid measurements of HBPM and ABPM, 39 were males (aged 62.8 ± 11.8y), 33 were females (aged 57.4 ± 14.2y). Hypertension was confirmed with HBPM and ABPM in 17 participants (24%), with ABPM only in 24 further participants (33%), and with HBPM only in 2 further participants (3%). Participants who had hypertension according to ABPM but not HBPM were younger (59 ± 11 y versus 67 ± 16 y; p < 0.001) and more frequently still working (83% versus 23%; p < 0.001). The prevalence of WCH was 28%. Among the 32 subjects taking antihypertensive drugs, uncontrolled hypertension was found in 49%. CONCLUSION This population-based study found a high prevalence of WCH and potential uncontrolled hypertension among individuals with elevated OBPM. This study, therefore, supports the ESH recommendations of complementing OBPM by ABPM or HBPM. The use of HBPM instead of ABPM for the confirmation of hypertension in individuals with elevated OBPM might lead to underdiagnosis and uncontrolled hypertension, in particular in the younger working population. In these individuals, this study suggests using ABPM instead of HBPM