Hypertension: Hoyer J

Klaus D, Böhm M, Halle M, Kolloch R, Middeke M, Pavenstädt H, Hoyer J. · Medizinische Klinik, Klinikum Dortmund. · Dtsch Med Wochenschr. · Pubmed #19418415 No free full text.

Abstract: Restricting salt intake not only leads to a decrease of blood pressure and a reduction in the incidence of arterial hypertension but also to a fall in cardiovascular morbidity and mortality. But high sodium intake is not only a risk factor for hypertension but also for cardiovascular diseases. Moderate reduction of daily salt intake in the entire population of Germany from the present level of 8-10 mg to 5-6 mg is of great benefit for disease load and to the economy. Any possible risk for a few groups of persons is predictable and can be coped with. General sodium reduction cannot be achieved only by individual advice, instruction or information campaigns but requires a reduction in the sodium content of industrially processed foods, in fast-food chains, restaurants and canteens because they supply 80% of total daily sodium intake. To achieve the target of restricting the sodium intake of the whole population it is recommended that an interdisciplinary and interprofessional task force, "Less salt for all" be established. This is to bring together the expertise of scientific societies and institutions that see their main task in the reduction of cardiovascular mortality and morbidity by primary prevention. Individual prevention in patients at risk can be very significantly improved by population-related preventive measures. These include, in addition to general limitation of sodium intake, continuing change in lifestyle.

Lenz T, Kuhlmann U, Hoyer J. · KfH Nierenzentrum Ludwigshafen. · Dtsch Med Wochenschr. · Pubmed #19353465 No free full text.

This publication has no abstract.

Kuhlmann U, Hoyer J. · Innere Medizin und Nephrologie, Philipps-Universität Marburg, Marburg. · MMW Fortschr Med. · Pubmed #19149310 No free full text.

This publication has no abstract.

Köhler R, Hoyer J. · Department of Internal Medicine-Nephrology, Philipps-University, Marburg, Germany. · Kidney Int. · Pubmed #17457372 No free full text.

Abstract: In the late eighties, several studies revealed the existence of a third vasodilating factor next to nitric oxide (NO) and prostacyclin (PGI2). As the action of this third factor is closely related to smooth muscle hyperpolarization, this factor was termed endothelium-derived hyperpolarizing factor (EDHF). The story of its investigation is a confusing one and several different candidate molecules and pathways have been proposed to account for the EDHF phenomenon. Major candidate molecules/mediators of EDHF signalling are K+, electrical coupling through gap junctions, cytochrome P450 metabolites, and endothelial small- and intermediate Ca2+-activated K+ channels (SK(Ca) and IK(Ca)). In this mini review, we wish to convey that EDHF is as powerful as NO and PGI2 in terms of blood pressure regulation and that deficiency in EDHF signalling contribute to several cardiovascular pathologies such as hypertension, chronic renal failure, and diabetes. In addition, we focus on recent insight into the EDHF phenomenon provided by novel genetic animal models, such as mice deficient of either endothelial SK(Ca) or IK(Ca) and the impact of channel deficiency on endothelial function, EDHF signalling, and arterial blood pressure.

Maier T, Hoyer J. · Klinik für Innere Medizin und Nephrologie, Universitätsklinikum Giessen und Marburg. · Dtsch Med Wochenschr. · Pubmed #17096307 No free full text.

This publication has no abstract.

Maier T, Grgic I, Busch C, Hoyer J, Köhler R. · Zentrum für Innere Medizin--Schwerpunkt Nephrologie, Universitätsklinikum der Philipps-Universität Marburg. · Dtsch Med Wochenschr. · Pubmed #16281159 No free full text.

Abstract: Endothelial cation channel are important regulators of vascular tone by modulating intracellular Ca(2+)-signaling and thus adequate synthesis of vasodilating factors. The overall importance of these ion channels suggests that they may represent novel pharmacotherapeutic targets in addition to the well-known voltage-gated calcium channels in vascular smooth muscle. In this short overview we summarize the current knowledge about endothelial ion channels and their roles for endothelium-dependent vasodilatation. Furthermore, we perspectively discuss the usefulness of specific openers of endothelial Ca(2+)-activated K(+)-channels and TRPV-channels as novel antihypertensive drugs.

Brakemeier S, Eichler I, Hoyer J. · Abteilung für Nephrologie, Universitätsklinikum Benjamin Franklin, FU-Berlin, Germany. · Dtsch Med Wochenschr. · Pubmed #12422298 No free full text.

This publication has no abstract.

Zidek W, Schrader J, Lüders S, Matthaei S, Hasslacher C, Hoyer J, Bramlage P, Sturm CD, Paar WD. · Medical Department IV, University Hospital Charité, Campus Benjamin-Franklin, Berlin, Germany. · Cardiovasc Diabetol. · Pubmed #18652658 links to  free full text

Abstract: BACKGROUND: Recent clinical trials reported conflicting results on the reduction of new-onset diabetes using RAS blocking agents. Therefore the role of these agents in preventing diabetes is still not well defined. Ramipril is an ACE inhibitor (ACEi), that has been shown to reduce cardiovascular events in high risk patients and post-hoc analyses of the HOPE trial have provided evidence for its beneficial action in the prevention of diabetes. METHODS: The ADaPT investigation ("ACE inhibitor-based versus diuretic-based antihypertensive primary treatment in patients with pre-diabetes") is a 4-year open, prospective, parallel group phase IV study. It compares an antihypertensive treatment regimen based on ramipril versus a treatment based on diuretics or betablockers. The primary evaluation criterion is the first manifestation of type 2 diabetes. The study is conducted in primary care to allow the broadest possible application of its results. The present article provides an outline of the rationale, the design and baseline characteristics of AdaPT and compares these to previous studies including ASCOT-BLPA, VALUE and DREAM. RESULTS: Until March 2006 a total of 2,015 patients in 150 general practices (general physicians and internists) throughout Germany were enrolled. The average age of patients enrolled was 67.1 +/- 10.3 years, with 47% being male and a BMI of 29.9 +/- 5.0 kg/m2. Dyslipidemia was present in 56.5%. 37.8% reported a family history of diabetes, 57.8% were previously diagnosed with hypertension (usually long standing). The HbA1c value at baseline was 5.6 %. Compared to the DREAM study patients were older, had more frequently hypertension and patients with cardiovascular disease were not excluded. CONCLUSION: Comparing the ADaPT design and baseline data to previous randomized controlled trial it can be acknowledged that AdaPT included patients with a high risk for diabetes development. Results are expected to be available in 2010. Data will be highly valuable for clinical practice due to the observational study design.

Kuhlmann U, Hoyer J. · Medizinische Klinik III, Gesundheit Nord, Klinikum Bremen-Mitte gGmbH, St.-Jürgen-Str. 1, 28177 Bremen. · Urologe A. · Pubmed #19590915 No free full text.

Abstract: Chronic renal failure does not only involve the risk for the patient of becoming dependent on hemodialysis, but also increases the risk of premature death due to cardiovascular events. In most renal diseases, progressive chronic loss of renal function develops once a critical extent of renal damage has occurred, independent of the course of the underlying renal disease. The key factors driving the progressive loss of renal function are, apart from the underlying nephrological disease, arterial hypertension and diabetes mellitus. The loss of renal function is also promoted by other factors, such as increased intake of dietary proteins, chronic inflammation, smoking, and anemia. With the help of a multimodal therapeutic concept, the progression of chronic renal failure can be delayed effectively. This approach comprises strict blood pressure control with a target blood pressure of 130/80 mmHg in patients with micro-albuminuria and of 120/75 mmHg in patients with proteinuria of >1 g/d. The preferred drugs for the treatment of hypertension are ACE inhibitors and angiotensin receptor blockers. In diabetics with renal insufficiency, target HbA1c levels below 7% are to be aimed for. Dietary protein intake should be restricted to 0.8-1 g/kg body weight/d. Additional therapeutic targets include nicotine abstinence, early treatment of renal anemia, weight reduction, and, if indicated, lipid-lowering therapy.

Brähler S, Kaistha A, Schmidt VJ, Wölfle SE, Busch C, Kaistha BP, Kacik M, Hasenau AL, Grgic I, Si H, Bond CT, Adelman JP, Wulff H, de Wit C, Hoyer J, Köhler R. · Department of Internal Medicine/Nephrology, Philipps University, Marburg, Germany. · Circulation. · Pubmed #19380617 No free full text.

Abstract: BACKGROUND: It has been proposed that activation of endothelial SK3 (K(Ca)2.3) and IK1 (K(Ca)3.1) K+ channels plays a role in the arteriolar dilation attributed to an endothelium-derived hyperpolarizing factor (EDHF). However, our understanding of the precise function of SK3 and IK1 in the EDHF dilator response and in blood pressure control remains incomplete. To clarify the roles of SK3 and IK1 channels in the EDHF dilator response and their contribution to blood pressure control in vivo, we generated mice deficient for both channels. METHODS AND RESULTS: Expression and function of endothelial SK3 and IK1 in IK1(-/-)/SK3(T/T) mice was characterized by patch-clamp, membrane potential measurements, pressure myography, and intravital microscopy. Blood pressure was measured in conscious mice by telemetry. Combined IK1/SK3 deficiency in IK1(-/-)/SK3(T/T) (+doxycycline) mice abolished endothelial K(Ca) currents and impaired acetylcholine-induced smooth muscle hyperpolarization and EDHF-mediated dilation in conduit arteries and in resistance arterioles in vivo. IK1 deficiency had a severe impact on acetylcholine-induced EDHF-mediated vasodilation, whereas SK3 deficiency impaired NO-mediated dilation to acetylcholine and to shear stress stimulation. As a consequence, SK3/IK1-deficient mice exhibited an elevated arterial blood pressure, which was most prominent during physical activity. Overexpression of SK3 in IK1(-/-)/SK3(T/T) mice partially restored EDHF- and nitric oxide-mediated vasodilation and lowered elevated blood pressure. The IK1-opener SKA-31 enhanced EDHF-mediated vasodilation and lowered blood pressure in SK3-deficient IK1(+/+)/SK3(T/T) (+doxycycline) mice to normotensive levels. CONCLUSIONS: Our study demonstrates that endothelial SK3 and IK1 channels have distinct stimulus-dependent functions, are major players in the EDHF pathway, and significantly contribute to arterial blood pressure regulation. Endothelial K(Ca) channels may represent novel therapeutic targets for the treatment of hypertension.

Sankaranarayanan A, Raman G, Busch C, Schultz T, Zimin PI, Hoyer J, Köhler R, Wulff H. · Department of Pharmacology, University of California, Davis, California 95616, USA. · Mol Pharmacol. · Pubmed #18955585 No free full text.

Abstract: Small-conductance (KCa2.1-2.3) and intermediate-conductance (KCa3.1) calcium-activated K(+) channels are critically involved in modulating calcium-signaling cascades and membrane potential in both excitable and nonexcitable cells. Activators of these channels constitute useful pharmacological tools and potential new drugs for the treatment of ataxia, epilepsy, and hypertension. Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC(50) values of 430 nM and 2.9 microM, KCa2.2 with an EC(50) value of 1.9 microM, KCa2.3 with EC(50) values of 1.2 and 2.9 microM, and KCa3.1 with EC(50) values of 115 and 260 nM. Likewise, SKA-20 and SKA-31 activated native KCa2.3 and KCa3.1 channels in murine endothelial cells, and the more "drug-like" SKA-31 (half-life of 12 h) potentiated endothelium-derived hyperpolarizing factor-mediated dilations of carotid arteries from KCa3.1(+/+) mice but not from KCa3.1(-/-) mice. Administration of 10 and 30 mg/kg SKA-31 lowered mean arterial blood pressure by 4 and 6 mm Hg in normotensive mice and by 12 mm Hg in angiotensin-II-induced hypertension. These effects were absent in KCa3.1-deficient mice. In conclusion, with SKA-31, we have designed a new pharmacological tool to define the functional role of the KCa2/3 channel activation in vivo. The blood pressure-lowering effect of SKA-31 suggests KCa3.1 channel activation as a new therapeutic principle for the treatment of hypertension.

Klaus D, Middeke M, Hoyer J. · Medizinische Klinik, Klinikum Dortmund. · Dtsch Med Wochenschr. · Pubmed #18528801 No free full text.

This publication has no abstract.

Kuhlmann U, Hoyer J. · Klinik für Innere Medizin, Schwerpunkt Nephrologie, Universitätsklinikum Giessen und Marburg GmbH, Standort Marburg, Baldingerstrasse, 35043, Marburg, Germany. · Internist (Berl). · Pubmed #18305916 No free full text.

Abstract: Chronic renal failure does not only involve the risk for the patient of becoming dependent on hemodialysis, but also increases the risk of premature death due to cardiovascular events. In most renal diseases, progressive chronic loss of renal function develops once a critical extent of renal damage has occurred, independent of the course of the underlying renal disease. The key factors driving the progressive loss of renal function are, apart from the underlying nephrological disease, arterial hypertension and diabetes mellitus. The loss of renal function is also promoted by other factors, such as increased intake of dietary proteins, chronic inflammation, smoking, and anemia. With the help of a multimodal therapeutic concept, the progression of chronic renal failure can be delayed effectively. This approach comprises strict blood pressure control with a target blood pressure of 130/80 mmHg in patients with micro-albuminuria and of 120/75 mmHg in patients with proteinuria of >1 g/d. The preferred drugs for the treatment of hypertension are ACE inhibitors and angiotensin receptor blockers. In diabetics with renal insufficiency, target HbA1c levels below 7% are to be aimed for. Dietary protein intake should be restricted to 0.8-1 g/kg body weight/d. Additional therapeutic targets include nicotine abstinence, early treatment of renal anemia, weight reduction, and, if indicated, lipid-lowering therapy.

Köhler R, Grundig A, Brakemeier S, Rothermund L, Distler A, Kreutz R, Hoyer J. · Department of Nephrology, University Hospital Benjamin Franklin, Freie Universität Berlin, Germany. · Am J Hypertens. · Pubmed #11465659 No free full text.

Abstract: The pressure-activated cation channel (PAC), a novel type of mechanosensitive channel, has been suggested to act as a mechanosensor in aortic endothelium. In experimental hypertension, PAC function was up-regulated in the established phase of high blood pressure. This association of altered PAC function and elevated arterial pressure suggests that PAC function is regulated by alterations in blood pressure. In the present study, we electrophysiologically investigated PAC function in intact endothelium of aorta (EA) and mesenteric artery (EMA) from stroke-prone spontaneously hypertensive rats (SHRSP), SHRSP after 4 weeks of treatment with quinaprilat (10 mg/kg/day), and normotensive Wistar-Kyoto (WKY) rats. In untreated SHRSP and WKY rats, systolic blood pressure (SBP) was 201+/-3 mm Hg and 142+/-3 mm Hg, respectively. In quinaprilat-treated SHRSP, SBP was lowered to 135+/-5 mm Hg. Apparent PAC density (percentage of patches with PAC activity) in EA of untreated SHRSP (63.7%+/-7.3%) was 2.4-fold higher than in WKY rats (26.0%+/-5.0%). In contrast, no significant PAC up-regulation was detected in EMA of SHRSP (15.7%+/-4.2%) compared with WKY rats (12.0%+/-3.9%). In EA of quinaprilat-treated normotensive SHRSP, PAC density (27.1%+/-5.2%) was lowered to levels found in normotensive WKY rats. Unitary conductance and pressure sensitivity of PAC were not altered in either hypertensive or normotensive rats. Taken together, hypertension-induced increases of endothelial PAC density can be completely reversed by antihypertensive therapy. The PAC up-regulation in EA was interpreted as a compensatory mechanism to enhance Ca2+-influx and subsequently the synthesis of vasodilatory factors. This mechanism is missing in EMA of SHRSP, which might contribute to high blood pressure in this rat model of severe genetic hypertension.

Köhler R, Kreutz R, Grundig A, Rothermund L, Yagil C, Yagil Y, Pries AR, Hoyer J. · Department of Nephrology, Freie Universität Berlin, Berlin, Germany. · J Am Soc Nephrol. · Pubmed #11461934 links to  free full text

Abstract: Mechanosensitive ion channels have been suggested to act as endothelial mechanosensors for hemodynamic forces. The present study tested the hypothesis that the pressure-activated cation channel (PAC), a novel type of endothelial mechanosensitive ion channel, is involved in salt sensitivity in the Sabra rat model of hypertension. Groups of Sabra salt-sensitive (SBH/y) and salt-resistant (SBN/y) rats were loaded with deoxycorticosterone-acetate (DOCA)-salt for 8 wk or were fed a regular diet. Single channel function of PAC in SBH/y and SBN/y rats was investigated in intact endothelium of mesenteric artery using the patch-clamp technique. After DOCA-salt treatment, the SBH/y rats showed a full hypertensive response, whereas SBN/y rats were normotensive. Rats of both strains that received a regular diet were normotensive. In endothelium of both Sabra rats, Ca(2+) permeable PAC that was activated by positive pipette pressures was identified. Apparent PAC density (percentage of patches with PAC activity) was reduced in hypertensive SBH/y rats that were loaded with DOCA-salt compared with salt-loaded normotensive SBN/y rats (6 +/- 2% versus 24 +/- 8%, respectively; P < 0.05). In normotensive SBH/y and SBN/y rats that received a regular diet, PAC density was not altered. Mechanosensitivity and unitary conductance of endothelial PAC were similar in both strains under a regular diet as well as salt loading with DOCA-salt. In conclusion, the decreased density of PAC in mesenteric endothelium from hypertensive SBH/y rats indicates an impaired ion channel regulation. The defective PAC function presumably leads to an impaired mechanosensitive Ca(2+) entry and might contribute to endothelial dysfunction and high BP in this type of salt-sensitive genetic hypertension.

Pokojski S, Busch C, Grgic I, Kacik M, Salman W, Preisig-Müller R, Heyken WT, Daut J, Hoyer J, Köhler R. · Department of Internal Medicine-Nephrology, Philipps-University, Baldingerstrasse, 35033 Marburg, Hessen, Germany. · Cardiovasc Res. · Pubmed #18339646 links to  free full text

Abstract: AIMS: Potassium channels are essential elements of endothelial function. Recently, evidence emerged that the TWIK (tandem of P domains in a weak inwardly rectifying K+ channel)-related K+ channel (TREK-1) of the two-pore domain potassium channel gene family (K2P) may be involved in the regulation of vascular tone. However, the functional and molecular characterization of vascular TREK-1 is incomplete. In this study, we therefore analysed the functional expression of TREK-1 in the endothelium. Moreover, we hypothesized that changes in channel expression may contribute to altered endothelial vasodilator response under conditions of elevated blood pressure. METHODS AND RESULTS: Gene expression and function of endothelial TREK-1 were analysed by single-cell RT-PCR, the patch-clamp technique and pressure myography in murine carotid arteries (CA). K+ outward currents displaying the characteristics of TREK-1 were observed following various TREK-1-activating stimuli such as membrane stretch, intracellular acidosis, polyunsaturated fatty acids, isoflurane (ISOFL), riluzole, and acetylcholine (ACh). In K(Ca)3.1(-/-) mice exhibiting elevated blood pressure, endothelial TREK-1 currents and TREK-1 mRNA expression were enhanced as compared with normotensive control mice. TREK-1-mediated vasodilator responses to alpha-linolenic acid, ISOFL, or ACh were increased. A similar up-regulation of endothelial TREK-1 was observed in spontaneously hypertensive rats. CONCLUSION: We have found that TREK-1 is an endothelial K+ channel capable of producing hyperpolarization and vasodilation. A correlation between hypertension and up-regulation of TREK-1 was observed in two different animal models of elevated blood pressure. Thus, TREK-1 may play a protective role in the cardiovascular system by providing a novel type of endothelial hyperpolarization-mediated vasodilator response.