[The treatment of arterial hypertension: is it a simple routine?].
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France↗
Biomedical subjects
B Waeber
Publications and source records attributed to B Waeber.
[7th symposium d'Ouchy: "How to and use appropriate medical measures for managing low back pain in general practice?"].
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Family Practice↗
Blood pressure measuring devices: recommendations of the European Society of Hypertension.
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Blood Pressure Monitors↗
Cardiovascular effects of fentanyl in conscious rats.
The polymicrobial sepsis induced by cecal ligation and puncture (CLP) in the rat is widely used in shock research. For ethical reasons, narcotic analgesics are often administered in this model, with the potential risk of confounding effects. In conscious non-septic rats, we investigated the cardiovascular effects of a continuous i.v. infusion of fentanyl (20 microg/kg per h) administered with fluid loading (10 ml/kg per h) for 24 h, a regimen commonly applied in rat CLP. Animals were randomly allocated to receive analgesia with fluid loading (Fentanyl group), or fluid loading alone (Control). All endpoints were assessed after 24 h of infusion. At that time, Control animals had mild respiratory alkalosis, which was essentially abolished by fentanyl. Analgesia mildly elevated the plasma norepinephrine levels [median (interquartile range): Control 232 pg/ml (0-292), Fentanyl 302 pg/ml (234-676), P=0.045] but was devoid of any effect on blood pressure, heart rate, cardiac output (mean +/-SD: Control 388+/-61 ml/kg per min, Fentanyl 382+/-62 ml/kg per min, P=0.87) and indices of left ventricular function derived from high-fidelity recordings of left ventricular pressure (dP/dtmax: Control 11782+/-2324 mmHg/s, Fentanyl 12107+/-2816 mmHg/s, P=0.77). In ex vivo experiments carried out immediately after animal sacrifice, no differences were noted between the Control and Fentanyl groups in the sensitivity of endothelium-intact aortic rings to norepinephrine-induced vasoconstriction (-logEC50: Control 8.78+/-0.28, Fentanyl 8.83+/-0.26, P=0.52) or acetylcholine-induced vasodilatation (-logEC50: Control 7.00+/-0.37, Fentanyl 7.06+/-0.26+/-0.53, P=0.75). In conclusion, the present data provide no contraindication, and even some support for the ethical use of a high dose i.v. infusion of fentanyl in cardiovascular studies of conscious catheterized rats undergoing CLP or other painful procedures.
Acetylcholine↗
Is nitric oxide overproduction the target of choice for the management of septic shock?
Sepsis is a heterogeneous class of syndromes caused by a systemic inflammatory response to infection. Septic shock, a severe form of sepsis, is associated with the development of progressive damage in multiple organs, and is a leading cause of patient mortality in intensive care units. Despite important advances in understanding its pathophysiology, therapy remains largely symptomatic and supportive. A decade ago, the overproduction of nitric oxide (NO) had been discovered as a potentially important event in this condition. As a result, great hopes arose that the pharmacological inhibition of NO synthesis could be developed into an efficient, mechanism-based therapeutic approach. Since then, an extraordinary effort by the scientific community has brought a deeper insight regarding the feasibility of this goal. Here we present in summary form the present state of knowledge of the biological chemistry and physiology of NO. We then proceed to a systematic review of experimental and clinical data, indicating an up-regulation of NO production in septic shock; information on the role of NO in septic shock, as provided by experiments in transgenic mice that lack the ability to up-regulate NO production; effects of pharmacological inhibitors of NO production in various experimental models of septic shock; and relevant clinical experience. The accrued evidence suggests that the contribution of NO to the pathophysiology of septic shock is highly heterogeneous and, therefore, difficult to target therapeutically without appropriate monitoring tools, which do not exist at present.
Animals↗
Connexins 40 and 43 are differentially regulated within the kidneys of rats with renovascular hypertension.
BACKGROUND: Connexin 40 (Cx40) is a gap junction protein expressed in endothelial cells of vessels, endocardium, and conducting cells of the His-Purkinje system of heart. Its distribution in the kidney remains to be fully investigated. METHODS: To address this distribution, we generated rabbit antibodies directed to a polypeptide comprising amino acids 231 to 330 of the carboxy-terminal domain of rodent Cx40, which specifically recognizes this protein at gap junctions. RESULTS: Immunolabeling and in situ hybridization of kidney sections showed that Cx40 and its transcript were coexpressed by most endothelial cells of vessels and glomeruli, as well as by renin-secreting cells. This distribution contrasted with that of Cx43, which was expressed in some tubules of medulla and sparse endothelial cells. Cx40 and Cx43 expression were investigated further in a renin-dependent model of hypertension, in which rats showed an increase in arterial mean blood pressure four weeks after clipping one renal artery [two kidney, one-clip (2K1C) model]. Northern blot analysis of polyA+ RNA demonstrated that, compared with sham-operated animals, the hypertensive 2K1C animals featured an increase in Cx40 mRNA expression in both left (clipped) and right (unclipped) kidneys. In contrast, Cx43 mRNA expression was only increased in the latter organ. Antibodies confirmed that the levels of Cx40 were actually increased in the kidneys of hypertensive animals (Western blots) and this was caused, at least in part, by enhanced expression of this protein in the renin-secreting cells of the afferent arteriole (immunofluorescence). CONCLUSIONS: Cell-to-cell communication mediated by Cx40 may be implicated in the function of renin-secreting cells, hence participating in the control of blood pressure.
Animals↗
Beta-blockade with nebivolol enhances the acetylcholine-induced cutaneous vasodilation.
Nebivolol is a selective beta(1)-adrenoceptor blocker that has a vasorelaxant activity thought to be the result of a facilitation of the release of nitric oxide from the endothelium. This study was undertaken in 12 healthy male volunteers to assess whether this compound increases the vasodilatory response to acetylcholine when administered orally at a dose commonly recommended for the treatment of cardiovascular diseases. The subjects were randomly allocated to an 8-day treatment with nebivolol (5 mg once a day) and atenolol (50 mg once a day) according to a cross-over design. The two treatments were separated by a 1-week washout period. On the first and the last day of each treatment phase, both before drug administration and 3 hours after drug administration, the forearm skin blood flow response to acetylcholine applied by iontophoresis was determined with the use of a laser Doppler scanner imaging system. The reactivity to acetylcholine was significantly increased 3 hours after the administration of nebivolol on both the first and the last day of treatment, whereas atenolol had no effect on this parameter. These data therefore indicate that nebivolol, but not atenolol, enhances the vasorelaxant activity of acetylcholine in the skin vascular bed; this is compatible with a facilitation by this beta-blocker of the endothelium-dependent vasodilation.
Acetylcholine↗
Treatment strategy to control blood pressure optimally in hypertensive patients.
Pharmacological treatment of hypertension significantly reduces the incidence of cardiovascular diseases. Unfortunately, only a fraction of hypertensive patients benefit maximally from the protection afforded by the blood pressure lowering, mainly because the blood pressure control achieved during antihypertensive therapy remains often insufficient. One way to improve this situation is to individualize the treatment in determining for each patient the most simple drug regimen, which is at the same time efficacious and well tolerated. To this end, combining small doses of drugs acting by different mechanisms is often required. It is also essential that physicians develop skills to motivate their patients to comply lifelong with the treatment.
Antihypertensive Agents↗
Achieving blood pressure targets in the management of hypertension.
The 1999 World Health Organization-International Society of Hypertension guidelines state that the goal of antihypertensive therapy should be to restore blood pressure to a level defined as normal (<130/85 mmHg). Yet, despite significant efforts in diagnosing and treating hypertension, blood pressure is normalized in less than one-third of hypertensive patients worldwide. Inadequate blood pressure control is most likely to occur when treatment is ineffective, intolerable or both. Hypertension is a heterogeneous disease involving several pressor systems. It is therefore not surprising that a single drug normalizes blood pressure in only a fraction of hypertensive patients. Co-administering two medications that lower blood pressure by different mechanisms generally increases antihypertensive efficacy. The angiotensin II receptor antagonist (AIIRA) class represents a new therapeutic option: a class of agents that provide blood pressure reduction similar to other classes of antihypertensives with the additional advantage of an excellent tolerability profile. The AIIRA irbesartan has demonstrated dose-related efficacy in reducing blood pressure as monotherapy and augmented efficacy in combination with low doses of the diuretic hydrochlorothiazide. Efforts should be directed to normalize blood pressure in every hypertensive patient by finding a drug regimen that is simultaneously effective and well tolerated.
Angiotensin Receptor Antagonists↗
Diabetes and hypertension.
The incidence of hypertension is increased in individuals with diabetes mellitus. This is especially true in patients with type 2 diabetes. In these patients high blood pressure is common at the time of diagnosis of diabetes, but the development of diabetes is often preceded by a period during which hyperinsulinemia and insulin resistance is already present. Diabetes represents by itself a major risk of cardiovascular morbidity and mortality. This risk is considerably enhanced by the co-existence of hypertension. One of the main complications of type 2 diabetes is nephropathy, which manifests initially by microalbuminuria, then by clinical proteinuria, leading to a progressive chronic renal failure and end-stage renal disease. Microalbuminuria is considered today as an indicator of renal endothelial dysfunction as well as an independent predictor of the cardiovascular risk. During recent years a number of studies have shown that tight blood pressure control is essential in diabetic patients in order to provide maximal protection against cardiovascular events and the deterioration of renal function. Of note, there is recent evidence indicating that blockade of the renin-angiotensin system with angiotensin II antagonists has marked nephroprotective effects in patients with hypertension and type 2 diabetes, both at early and late stages of renal disease.
Antihypertensive Agents↗
The return of increased blood pressure after discontinuation of antihypertensive treatment is associated with an impaired post-ischemic skin blood flow response.
OBJECTIVE: To assess the post-ischemic skin blood flow response after withdrawal of antihypertensive therapy in hypertensive patients with normal blood pressure during treatment. DESIGN AND METHODS: Twenty hypertensive patients (group A) with a normal clinic blood pressure (<140/ 90 mmHg) receiving antihypertensive treatment (any monotherapy; one pill per day for at least 6 months) had their treatment discontinued. Before medication withdrawal and 2, 4, 12 and 24 weeks thereafter, the following measurements were made: clinic blood pressure, home blood pressure (three times per week, morning and evening) and skin blood flow response to a 5 min forearm arterial occlusion (using laser Doppler flowmetry). The patients were asked to perform an ambulatory blood pressure recording at any time if home blood pressure was > or =160/95 mmHg on two consecutive days, and treatment was initiated again, after determination of the skin hyperemic response, if daytime ambulatory blood pressure was > or =140/90 mmHg. The same studies were performed in 20 additional hypertensive individuals in whom antihypertensive treatment was not withdrawn (group B). The allocation of patients to groups A and B was random. RESULTS: The data fom 18 patients in group A who adhered strictly to the procedure were available for analysis. Seven of them had to start treatment again within the first 4 weeks of follow-up; four additional patients started treatment again during the next 8 weeks (group A1). The seven other patients remained untreated (group A2). The skin hyperemic response decreased significantly in patients in group A1 and returned to baseline values at the end of the study, when there were again receiving antihypertensive treatment. In patients in group A2 a significant attenuation of the hyperemic response was also observed. This impaired response was present even at the end of the 6 month follow-up, at which time the patients were still untreated but exhibited a significantly greater blood pressure than before drug discontinuation. The hyperemic response of patients who did not stop treatment (group B) did not change during the course of the study. CONCLUSIONS: Our findings show a decrease in the postischemic skin blood flow response after withdrawal of antihypertensive treatment in hypertensive patients. This impaired response may be due to the development of endothelial dysfunction, vascular remodeling, or both, and might contribute to the return of blood pressure to hypertensive values after withdrawal of antihypertensive therapy.
Adult↗
Combination of hydrochlorothiazide or benazepril with valsartan in hypertensive patients unresponsive to valsartan alone.
OBJECTIVE: The aim of this open multicentric study was to investigate the efficacy and safety of the addition of an angiotensin converting enzyme (ACE) inhibitor (benazepril, 10 mg/day) or a diuretic (hydrochlorothiazide, 12.5 mg/day) for 4 weeks in patients with mild to moderate essential hypertension having been treated for 4 weeks by an angiotensin II antagonist (valsartan, 80 mg/day) but still having a diastolic blood pressure (BP) > 90 mmHg on this medication given alone. METHODS: A total of 327 patients were included in the trial and 153 patients (46%) had their diastolic BP </= 90 mmHg after 4 weeks of valsartan monotherapy. These patients continued the same treatment regimen for the next 4 weeks, but no further blood pressure reduction was observed. The remaining patients were randomized to either the valsartan-hydrochlorothiazide or the valsartan-benazepril combination. RESULTS: The two combinations induced an additional significant BP reduction, which was of similar magnitude for diastolic BP (-4.5 during valsartan-hydrochlorothiazide treatment and -3.3 mmHg during valsartan-benazepril treatment), but of greater magnitude for systolic BP during valsartan-hydrochlorothiazide (-6.77 mmHg) than during valsartan-benazepril co-administration (-3.2 mmHg). At the end of the trial, the BP of the responders to the valsartan monotherapy was lower than that of patients having required a combination therapy. Valsartan given alone or in association with hydrochlorothiazide or benazepril was well tolerated. CONCLUSION: These data therefore show that in patients not responding sufficiently to angiotensin II receptor blockade BP can be further and safely lowered by adding a small dose of a diuretic or an ACE inhibitor, with the diuretic-containing combination tending to being more effective in controlling systolic BP.
Aged↗
Does the activation of poly (ADP-ribose) synthetase mediate tissue injury in the sepsis induced by cecal ligation and puncture?
Poly (ADP-ribose) synthetase (PARS) is a DNA protective enzyme activated by single-strand breakage. It is suspected that exaggerated PARS activation related to biochemical stress by reactive oxygen and nitrogen species contributes to cellular injury in sepsis. The main hypothesis is that PARS activation leads to massive ATP and NAD consumption and consequent cellular energy depletion. The PARS inhibitor 3-amino-benzamide (3AB) is protective in rodents challenged with either endotoxin or intraperitoneal zymozan. The present experiment was designed to test the effect of 3AB in a more clinically relevant model of sepsis, namely polymicrobial sepsis induced by cecal ligature and puncture (CLP). Adult male Wistar rats were anesthetized, instrumented with catheters in the jugular vein and in the carotid artery, and then randomized into three groups: Sham (no laparotomy, n = 13), CLP (n = 15), and CLP/3AB (n = 18). All animals were allowed to recover and they received a continuous intravenous infusion of saline (20 mL/kg/h) and fentanyl (20 microg/kg/h). 3AB was administered to the CLP/3AB group as an intravenous bolus (10 mg/kg) followed by a continuous intravenous infusion (10 mg/kg/h). After 24 h, blood was drawn for the determination of biological indicators of organ injury. Rats were then anesthetized and biopsies of the liver were quickly frozen into liquid nitrogen for the subsequent determination of NAD and ATP levels. Further organ samples were collected for the assay of myeloperoxidase (MPO) to indicate tissue infiltration by leukocytes, and nitrotyrosine to indicate the level of biochemical stress by reactive nitrogen species. Twenty-four-hour mortality was 0/13 (Sham), 1/15 (CLP), and 5/18 (CLP/3AB; p = NS). In the surviving rats, CLP induced a clear elevation of liver enzymes, bilirubin, and pancreatic lipase, but not creatinine in the plasma, as well as a marked increase of MPO activity in liver, jejunum, and lung, but not kidney or heart. None of these variables was affected by treatment with 3AB. Furthermore, CLP did not cause depletion of NAD or ATP in the liver, nor any change in the nitrotyrosine content of any organ. These data argue against a general role of PARS activation in the pathogenesis of sepsis-induced tissue injury.
Adenosine Triphosphate↗
The multifactorial nature of hypertension: the greatest challenge for its treatment?
Essential hypertension is a polygenic disease involving a major contribution of various environmental factors. It is therefore not surprising that antihypertensive medications, whatever their mechanism(s) of action, only normalize the blood pressure for a fraction of hypertensive patients when administered as monotherapies. It is unfortunately not possible to predict with any degree of certainty which type of blood pressure-lowering agent is the most appropriate for a given patient. Although very attractive, genetic mapping is not really helpful in selecting a treatment for any individual patient. In most patients the association of two medications having different impacts on the cardiovascular system is necessary to normalize blood pressure. Fixed-low-dose combinations are becoming increasingly popular as first line treatment as they increase the probability of bringing the patient's blood pressure under control while minimizing the incidence of dose-dependent adverse effects.
Angiotensin-Converting Enzyme Inhibitors↗
Rationale for the use of very-low-dose combinations as first-line treatment of hypertension.
The management of hypertension remains a difficult task, despite the availability of an increasing number of medications that decrease blood pressure by different mechanisms. In order to achieve a blood pressure less than 140/90 mmHg, most hypertensive patients require the co-administration of two or more drugs from different therapeutic classes. This explains why fixed-dose combinations are becoming increasingly popular. Combining drugs with different impacts on the cardiovascular system makes it possible to maximise the antihypertensive efficacy of the treatment regimen. The combination of very low doses of drugs that exhibit dose-dependent side effects leads to a marked gain in efficacy, with indiscernible side effects. During recent years, very-low-dose combinations have been developed. These combinations are very promising because of their excellent efficacy and tolerance profile. This has led to the recognition that such combinations might be a valuable option with which to initiate treatment in hypertensive patients.
Antihypertensive Agents↗
[Changes in medications acting on the cardiovascular system during hospitalization].
The present study was conducted to assess the extent to which the treatment of patients who take one or more cardiovascular drugs regularly is changed during hospitalisation and over the course of the subsequent two months after release from hospital. In order to elucidate the question more exactly, data was collected on 107 patient after a hospital stay on the internal medicine ward of a university hospital and on 107 patients who had been hospitalised in two non-university hospitals. The average number of changes in medication in patients in the university setting was 2.7 and in patients in the non-university setting it was 2.2. The treatment of patients who were hospitalised for cardiovascular complications was switched more often than that of patients whose circulation was stable at admission. Over the course of the subsequent two months after release, the attending general practitioners (GP) switched the medication at a much lower frequency than the hospitals had done. Within one specific drug class there was no more frequent changes in medication during the hospital stay as afterwards. A drug was discontinued in 107 patients in the university setting and in 124 cases in the two non-university hospitals. The same drug was prescribed again by the treating GP in 30 and 40 patients, respectively, after release. The results of the study show that treatment with drugs that have an effect on the patient's understanding of his illness with regard to its severity may be likely to cause doubts about the effectiveness of the drug and whether the therapeutic decisions that were made by the doctors for medical or other reasons were correct. Therefore, it makes more sense to avoid unnecessary changes in medication whenever possible and only then in unavoidable cases with a clear medical indication.
Adult↗
[Vasopeptidase inhibition: a new mechanism of action--a new antihypertensive drug].
The novel principle of vaso-peptidase inhibition is based on the simultaneous inhibition of two enzymes, the angiotensin converting enzyme (ACE) and the neutral endopeptidase (NEP) by a single drug. NEP participates in metabolism of various natriuretic and vasodilatating peptides produced by atria and ventricles of the heart and endothelium (arterial natriuretic peptide, brain natriuretic peptide and C-Type natriuretic peptide). The orally effective vaso-peptidase inhibitor omapatrilate has recently become available. This substance reduced blood pressure in hypertensive patients in a dose-dependent fashion. It is tolerated as well as ACE inhibitors and seems to ameliorate mainly systolic pressure.
Angiotensin-Converting Enzyme Inhibitors↗
[Evidence-based medicine in routine clinical practice].
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Evidence-Based Medicine↗