Novel functions of the anion exchanger AE4 (SLC4A9).

The kidney plays a crucial role in acid-base homeostasis. In the distal nephron, α-intercalated cells contribute to urinary acid (H+) secretion and ß-intercalated cells accomplish urinary base (HCO3-) secretion. ß-intercalated cells regulate the acid base status through modulation of the apical Cl-/HCO3- exchanger pendrin (SLC26A4) activity. In this review, we summarize and discuss our current knowledge of the physiological role of the renal transporter AE4 (SLC4A9). The AE4, as cation-dependent Cl-/HCO3- exchanger, is exclusively expressed in the basolateral membrane of ß-intercalated cells and is essential for the sensing of metabolic acid-base disturbances in mice, but not for renal sodium reabsorption and plasma volume control. Potential intracellular signaling pathways are discussed that might link basolateral acid-base sensing through the AE4 to apical pendrin activity.

Deficiency of Complement C3a and C5a receptors Does Not Prevent Angiotensin II-Induced Hypertension and Hypertensive End-Organ Damage.

BACKGROUND: Complement may drive the pathology of hypertension through effects on innate and adaptive immune responses. Recently an injurious role for the anaphylatoxin receptors C3aR (complement component 3a receptor) and C5aR1 (complement component 5a receptor) in the development of hypertension was shown through downregulation of Foxp3+ (forkhead box protein 3) regulatory T cells. Here, we deepen our understanding of the therapeutic potential of targeting both receptors in hypertension. METHODS: Data from the European Renal cDNA Bank, single cell sequencing and immunohistochemistry were examined in hypertensive patients. The effect of C3aR or C3aR/C5aR1 double deficiency was assessed in two models of Ang II (angiotensin II)-induced hypertension in knockout mice. RESULTS: We found increased expression of C3aR, C5aR1 and Foxp3 cells in kidney biopsies of patients with hypertensive nephropathy. Expression of both receptors was mainly found in myeloid cells. No differences in blood pressure, renal injury (albuminuria, glomerular filtration rate, glomerular and tubulointerstitial injury, inflammation) or cardiac injury (cardiac fibrosis, heart weight, gene expression) between control and mutant mice was discerned in C3aR-/- as well as C3aR/C5aR1-/- double knockout mice. The number of renal Tregs was not decreased in Ang II as well as in DOCA salt induced hypertension. CONCLUSIONS: Hypertensive nephropathy in mice and men is characterized by an increase of renal regulatory T cells and enhanced expression of anaphylatoxin receptors. Our investigations do not corroborate a role for C3aR/C5aR1 axis in Ang II-induced hypertension hence challenging the concept of anaphylatoxin receptor targeting in the treatment of hypertensive disease.

Bridging vascular physiology to vascular medicine: an integrative laboratory class.

Vascular diseases of the legs are highly prevalent and constitute an important part of medical curricula. The understanding of these diseases relies on strongly interwoven aspects of vascular physiology and vascular medicine. We aimed to connect these within a horizontally integrated laboratory class on vascular physiology of the leg that was designed in cooperation between the departments of physiology and vascular surgery. Conceptually, we applied examination techniques of vascular medicine to visualize physiological parameters that are altered by the most frequent diseases. This facilitates integrative discussions on malfunctions, trains diagnostic skills, and bridges to vascular medicine. In four experiments, we use oscillometry and impedance venous occlusion plethysmography to address key aspects of the arterial and venous system of the legs: 1) arterial pulse wave, 2) arterial systolic blood pressure, 3) venous capacitance and venous outflow, and 4) reactive hyperemia. After the experiments, physiological vascular function, the associated diseases, their impact on the recorded parameters, and diagnostic options are discussed. To allow reproduction, we describe the course structure and the experimental setup in detail. We present the experimental data of a cohort of medical students and document learning success and student satisfaction. All experiments were feasible and provided robust data on physiologically and clinically relevant vascular functions. The activity was perceived positively by the students and led to a substantial improvement of knowledge. With this work, we offer a template for reproduction or variation of a proven concept of horizontally integrated teaching of vascular physiology of the leg.NEW & NOTEWORTHY This article presents an integrative laboratory class on vascular physiology bridging to vascular medicine. The four experiments rely on oscillometry and venous occlusion plethysmography. We describe in detail this new class regarding structure, experimental setup, and experimental procedure, and we give insight into the applied materials. Moreover, we present the experimental data of 74 students and a quantitative evaluation of the students' learning success and acceptance.

The baroreceptor reflex brought to life outside the classroom - an e-learning based asynchronous laboratory class using a non-supervised modified Active Standing Test.

BACKGROUND: E-learning based laboratory classes can replace or enhance in-classroom laboratories. They typically offer temporal flexibility, self-determined learning speed, repeatability and do not require supervision or face-to-face contact. The aim of this feasibility study was to investigate whether the established in-classroom laboratory class on the baroreceptor reflex (BRR) can be transformed into a new e-learning based asynchronous laboratory class for untrained, non-supervised students without medical equipment. The BRR is a fundamental cardiovascular process which is regularly visualized in physiology during in-classroom laboratories by a student-performed Active Standing Test (AST). During this voluntary provocation of orthostatic stress, the BRR reliably causes a solid rise in heart rate (HR) and a stabilization or even increase in blood pressure (BP). METHODS: The conventional AST was modified by omission of BP measurements which would require medical devices and was embedded into a framework of interactive digital material allowing independent student performance. With specific adaptions, this instrument was implemented to 1st and 2nd year curricula of human medicine, dental medicine, midwifery and pharmacy. An audience response system was used to collect the students' data on HR, epidemiology, technical problems, satisfaction and orthostatic symptoms. As primary outcome, we investigated the students' correct performance of the modified AST regarding textbook conformity of the HR data. Secondary outcomes included technical feasibility, the students' satisfaction and consistency of HR data within predefined subgroups (e.g., gender, curricula). Descriptive statistics are reported. RESULTS: The class was completed by 217 students (mean age: 23 ± 8 [SD], 81% female, 19% male). Mean reported rise of HR during standing was ~ 20 bpm (~ 30%) which is highly concordant to textbooks. Reported feasibility (~ 80% negated any technical issues) and students' satisfaction (4.4 on 5-point Likert-scale) were high. The HR data were consistent within the subgroups. CONCLUSION: This study demonstrates that the highly relevant BRR can be successfully addressed in an e-learning based asynchronous laboratory class implementing a non-supervised AST restricted to HR measurements embedded in digital material. The robust HR response and the adjustable complexity allow an application to different healthcare-related curricula. This class, therefore, provides a broad audience access to a fundamental concept of cardiovascular physiology.

Medullary and Hypothalamic Functional Magnetic Imaging During Acute Hypoxia in Tracing Human Peripheral Chemoreflex Responses.

[Figure: see text].

Immune mechanisms in arterial hypertension. Recent advances.

Increasing evidence indicates that hypertension and hypertensive end-organ damage are not only mediated by hemodynamic injury. Inflammation also plays an important role in the pathophysiology and contributes to the deleterious consequences of this disease. Cells of the innate immune system including monocyte/macrophages and dendritic cells can promote blood pressure elevation via effects mostly on kidney and vascular function. Moreover, convincing evidence shows that T and B cells from the adaptive immune system are involved in hypertension and hypertensive end-organ damage. Skin monocyte/macrophages, regulatory T cells, natural killer T cells, and myeloid-derived suppressor cells have been shown to exert blood pressure controlling effects. Sodium intake is undoubtedly indispensable for normal body function but can be detrimental when taken in excess of dietary requirements. Sodium levels also modulate the function of monocyte/macrophages, dendritic cells, and different T cell subsets. Some of these effects are mediated by changes in the microbiome and metabolome that can be found after high salt intake. Modulation of the immune response can reduce severity of blood pressure elevation and hypertensive end-organ damage in several animal models. The purpose of this review is to briefly summarize recent advances in immunity and hypertension as well as hypertensive end-organ damage.

B6.Rag1 Knockout Mice Generated at the Jackson Laboratory in 2009 Show a Robust Wild-Type Hypertensive Phenotype in Response to Ang II (Angiotensin II).

A key finding supporting a causal role of the immune system in the pathogenesis of hypertension is the observation that RAG1 knockout mice on a C57Bl/6J background (B6.Rag1-/-), which lack functional B and T cells, develop a much milder hypertensive response to Ang II (angiotensin II) than control C57Bl/6J mice. Here, we report that we never observed any Ang II resistance of B6.Rag1-/- mice purchased directly from the Jackson Laboratory as early as 2009. B6.Rag1-/- mice displayed nearly identical blood pressure increases monitored via radiotelemetry and hypertensive end-organ damage in response to different doses of Ang II and different levels of salt intake (0.02%, 0.3%, and 3% NaCl diet). Similarly, restoration of T-cell immunity by adoptive cell transfer did not affect the blood pressure response to Ang II in B6.Rag1-/- mice. Full development of the hypertension-resistant phenotype in B6.Rag1-/- mice appears to depend on the action of yet unidentified nongenetic modifiers in addition to the absence of functional T cells.

Testing individual baroreflex responses to hypoxia-induced peripheral chemoreflex stimulation.

INTRODUCTION: Baroreflexes and peripheral chemoreflexes control efferent autonomic activity making these reflexes treatment targets for arterial hypertension. The literature on their interaction is controversial, with suggestions that their individual and collective influence on blood pressure and heart rate regulation is variable. Therefore, we applied a study design that allows the elucidation of individual baroreflex-chemoreflex interactions. METHODS: We studied nine healthy young men who breathed either normal air (normoxia) or an air-nitrogen-carbon dioxide mixture with decreased oxygen content (hypoxia) for 90 min, with randomization to condition, followed by a 30-min recovery period and then exposure to the other condition for 90 min. Multiple intravenous phenylephrine bolus doses were applied per condition to determine phenylephrine pressor sensitivity as an estimate of baroreflex blood pressure buffering and cardiovagal baroreflex sensitivity (BRS). RESULTS: Hypoxia reduced arterial oxygen saturation from 98.1 ± 0.4 to 81.0 ± 0.4% (p < 0.001), raised heart rate from 62.9 ± 2.1 to 76.0 ± 3.6 bpm (p < 0.001), but did not change systolic blood pressure (p = 0.182). Of the nine subjects, six had significantly lower BRS in hypoxia (p < 0.05), two showed a significantly decreased pressor response, and three showed a significantly increased pressor response to phenylephrine in hypoxia, likely through reduced baroreflex buffering (p < 0.05). On average, hypoxia decreased BRS by 6.4 ± 0.9 ms/mmHg (19.9 ± 2.0 vs. 14.12 ± 1.6 ms/mmHg; p < 0.001) but did not change the phenylephrine pressor response (p = 0.878). CONCLUSION: We applied an approach to assess individual baroreflex-chemoreflex interactions in human subjects. A subgroup exhibited significant impairments in baroreflex blood pressure buffering and BRS with peripheral chemoreflex activation. The methodology may have utility in elucidating individual pathophysiology and in targeting treatments modulating baroreflex or chemoreflex function.

Augmentation of myocardial If dysregulates calcium homeostasis and causes adverse cardiac remodeling.

HCN channels underlie the depolarizing funny current (If) that contributes importantly to cardiac pacemaking. If is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic mice (HCN4tg/wt) to assess functional consequences of HCN4 overexpression-mediated If increase in cardiomyocytes to levels observed in human heart failure. HCN4tg/wt animals exhibit a dilated cardiomyopathy phenotype with increased cellular arrhythmogenicity but unchanged heart rate and conduction parameters. If augmentation induces a diastolic Na+ influx shifting the Na+/Ca2+ exchanger equilibrium towards 'reverse mode' leading to increased [Ca2+]i. Changed Ca2+ homeostasis results in significantly higher systolic [Ca2+]i transients and stimulates apoptosis. Pharmacological inhibition of If prevents the rise of [Ca2+]i and protects from ventricular remodeling. Here we report that augmented myocardial If alters intracellular Ca2+ homeostasis leading to structural cardiac changes and increased arrhythmogenicity. Inhibition of myocardial If per se may constitute a therapeutic mechanism to prevent cardiomyopathy.

Human iPS cell-derived engineered heart tissue does not affect ventricular arrhythmias in a guinea pig cryo-injury model.

Human iPSC-derived engineered heart tissue (hEHT) has been used to remuscularize injured hearts in a guinea pig infarction model. While beneficial effects on cardiac remodeling have been demonstrated, the arrhythmogenic potential of hEHTs is a major concern. We investigated whether hiPSC-derived hEHTs increase the incidence of ventricular arrhythmias. HEHTs were created from human iPSC-derived cardiomyocytes and endothelial cells. Left-ventricular cryo-injury was induced in guinea pigs (n = 37) and telemetry sensors for continuous ECG monitoring were implanted. 7 days following the cryo-injury, hEHTs or cell-free constructs were transplanted into the surviving animals (n = 15 and n = 9). ECGs were recorded over the following 28 days. 10 hEHT animals and 8 control animals survived the observation period and were included in the final analysis. After implantation of hEHTs or cell-free constructs, ventricular arrhythmias (premature ventricular contractions, couplets, triplets and non-sustained ventricular tachycardia) were observed in animals of both groups. The fraction of animals with the respective arrhythmias as well as the rate of arrhythmic events did not differ between groups. Following hEHT implantation, no clinically relevant sustained ventricular tachycardia or ventricular fibrillation was detected. Our telemetric data provides first evidence for the electrical safety of human iPSC-derived EHTs in this experimental model, thereby supporting further development of this approach.

The heterotopic heart transplantation in mice as a small animal model to study mechanical unloading - Establishment of the procedure, perioperative management and postoperative scoring.

BACKGROUND: Unloading of failing hearts by left ventricular assist devices induces an extensive cardiac remodeling which may lead to a reversal of the initial phenotype-or to its deterioration. The mechanisms underlying these processes are unclear. HYPOTHESIS: Heterotopic heart transplantion (hHTX) is an accepted model for the study of mechanical unloading in rodents. The wide variety of genetically modified strains in mice provides an unique opportunity to examine remodeling pathways. However, the procedure is technically demanding and has not been extensively used in this area. To support investigators adopting this method, we present our experience establishing the abdominal hHTX in mice and describe refinements to the technique. METHODS: In this model, the transplanted heart is vascularised but implanted in series, and therefore does not contribute to systemic circulation and results in a complete mechanical unloading of the donor heart. Training followed a systematic program using a combination of literature, video tutorials, cadaveric training, direct observation and training in live animals. RESULTS: Successful transplantation was defined as a recipient surviving > 24 hours with a palpable, beating apex in the transplanted heart and was achieved after 20 transplants in live animals. A success rate of 90% was reached after 60 transplants. Operative time was shown to decrease in correlation with increasing number of procedures from 200 minutes to 45 minutes after 60 operations. Cold/warm ischemia time improved from 45/100 to 10/20 minutes. Key factors for success and trouble shootings were identified. CONCLUSION: Abdominal hHTX in the mouse may enable future examination of specific pathways in unloading induced myocardial remodeling. Establishment of the technique, however, is challenging. Structured training programs utilising a variety of training methods can help to expedite the process. Postoperative management, including daily scoring increases animal wellbeing and helps to predict survival.

Analysis of fibrosis in control or pressure overloaded rat hearts after mechanical unloading by heterotopic heart transplantation.

Mechanical unloading (MU) by implantation of left ventricular assist devices (LVAD) has become clinical routine. This procedure has been shown to reverse cardiac pathological remodeling, with the underlying molecular mechanisms incompletely understood. Most studies thus far were performed in non-standardized human specimens or MU of healthy animal hearts. Our study investigates cardiac remodeling processes in sham-operated healthy rat hearts and in hearts subjected to standardized pathological pressure overload by transverse aortic constriction (TAC) prior to MU by heterotopic heart transplantation (hHTx/MU). Rats underwent sham or TAC surgery. Disease progression was monitored by echocardiography prior to MU by hHTx/MU. Hearts after TAC or TAC combined with hHTx/MU were removed and analyzed by histology, western immunoblot and gene expression analysis. TAC surgery resulted in cardiac hypertrophy and impaired cardiac function. TAC hearts revealed significantly increased cardiac myocyte diameter and mild fibrosis. Expression of hypertrophy associated genes after TAC was higher compared to hearts after hHTx/MU. While cardiac myocyte cell diameter regressed to the level of sham-operated controls in all hearts subjected to hHTx/MU, fibrotic remodeling was significantly exacerbated. Transcription of pro-fibrotic and apoptosis-related genes was markedly augmented in all hearts after hHTx/MU. Sarcomeric proteins involved in excitation-contraction coupling displayed significantly lower phosphorylation levels after TAC and significantly reduced total protein levels after hHTx/MU. Development of myocardial fibrosis, cardiac myocyte atrophy and loss of sarcomeric proteins was observed in all hearts that underwent hHTX/MU regardless of the disease state. These results may help to explain the clinical experience with low rates of LVAD removal due to lack of myocardial recovery.

Novel Approach to Elucidate Human Baroreflex Regulation at the Brainstem Level: Pharmacological Testing During fMRI.

Introduction: Brainstem nuclei govern the arterial baroreflex, which is crucial for heart rate and blood pressure control. Yet, brainstem function is difficult to explore in living humans and is therefore mostly studied using animal models or postmortem human anatomy studies. We developed a methodology to identify brainstem nuclei involved in baroreflex cardiovascular control in humans by combining pharmacological baroreflex testing with functional magnetic resonance imaging. Materials and Methods: In 11 healthy men, we applied eight repeated intravenous phenylephrine bolus doses of 25 and 75 µg followed by a saline flush using a remote-controlled injector during multiband functional magnetic resonance imaging (fMRI) acquisition of the whole brain including the brainstem. Continuous finger arterial blood pressure, respiration, and electrocardiogram (ECG) were monitored. fMRI data were preprocessed with a brainstem-specific pipeline and analyzed with a general linear model (GLM) to identify brainstem nuclei involved in central integration of the baroreceptor input. Results: Phenylephrine elicited a pressor response followed by a baroreflex-mediated lengthening of the RR interval (25 µg: 197 ± 15 ms; 75 µg: 221 ± 33 ms). By combining fMRI responses during both phenylephrine doses, we identified significant signal changes in the nucleus tractus solitarii (t = 5.97), caudal ventrolateral medulla (t = 4.59), rostral ventrolateral medulla (t = 7.11), nucleus ambiguus (t = 5.6), nucleus raphe obscurus (t = 6.45), and several other brainstem nuclei [p < 0.0005 family-wise error (few)-corr.]. Conclusion: Pharmacological baroreflex testing during fMRI allows characterizing central baroreflex regulation at the level of the brainstem in humans. Baroreflex-mediated activation and deactivation patterns are consistent with previous investigations in animal models. The methodology has the potential to elucidate human physiology and mechanisms of autonomic cardiovascular disease.

Salt, inflammation, IL-17 and hypertension.

Traditionally, arterial hypertension and subsequent end-organ damage have been attributed to haemodynamic factors, but increasing evidence indicates that inflammation also contributes to the deleterious consequences of this disease. The immune system has evolved to prevent invasion of foreign microorganisms and to promote tissue healing after injury. However, this beneficial activity comes at a cost of collateral damage when the immune system overreacts to internal injury, such as prehypertension. Over the past few years, important findings have revolutionized hypertension research. Firstly, in 2007, a seminal paper showed that adaptive immunity is involved in the pathogenesis of hypertension. Secondly, salt storage in the skin and its consequences for cardiovascular physiology were discovered. Thirdly, after the discovery that salt promotes the differentiation of CD4+ T cells into TH 17 cells, it was demonstrated that salt directly changes several cells of the innate and adaptive immune system and aggravates autoimmune disease but may improve antimicrobial defence. Herein, we will review pathways of activation of immune cells by salt in hypertension as the framework for understanding the multiple roles of salt and immunity in arterial hypertension and autoimmune disease. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.

Adaptive immunity and IL-17A are not involved in the progression of chronic kidney disease after 5/6 nephrectomy in mice.

BACKGROUND AND PURPOSE: The adaptive immune response and IL-17A contribute to renal damage in several experimental models of renal injury. EXPERIMENTAL APPROACH: To evaluate the role of the adaptive immune response, 5/6 nephrectomy was performed in wildtype DBA/1J mice and in recombination-activating gene-1 (RAG-1) deficient mice that lack B and T-cells. To assess the role of IL-17A, we carried out 5/6 nephrectomy in IL-17A deficient mice. Flow cytometric analysis, immunohistochemistry and RT-PCR were used. KEY RESULTS: Infiltration of CD3+ T-cells in the remnant kidney was increased after 5/6 nephrectomy in wildtype mice, along with a robust induction of IL-17A production in CD4+ T and γδ T-cells. After 5/6 nephrectomy, wildtype mice developed albuminuria in the nephrotic range over 10 weeks. This was accompanied by severe glomerular sclerosis and tubulointerstitial injury, and as well as renal mRNA expression of markers of inflammation and fibrosis (the chemokine CCL2, plasminogen activator inhibitor-1; PAI-1 and neutrophil gelatinase-associated lipocalin; NGAL). Unexpectedly, RAG-1 deficient mice and IL-17A deficient mice developed renal injury, similar to that in wildtype mice. No differences were found for albuminuria, glomerular sclerosis, tubulointerstitial injury and mRNA expression of CCL2, PAI-1 and NGAL. Mortality did not differ between the three groups. CONCLUSIONS AND IMPLICATIONS: Numbers of CD3+ T-cells and IL-17A+ lymphocytes infiltrating the kidney were increased after 5/6 nephrectomy. In contrast to other experimental models of renal injury, genetic deficiency of the adaptive immune system or of IL-17A did not attenuate induction or progression of chronic kidney disease after 5/6 nephrectomy. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.

The chemokine receptor CX3CR1 reduces renal injury in mice with angiotensin II-induced hypertension.

The role of CX3CR1, also known as fractalkine receptor, in hypertension is unknown. The present study determined the role of the fractalkine receptor CX3CR1 in hypertensive renal and cardiac injury. Expression of CX3CR1 was determined using CX3CR1GFP/+ mice that express a green fluorescent protein (GFP) reporter in CX3CR1+ cells. FACS analysis of leukocytes isolated from the kidney showed that 34% of CD45+ cells expressed CX3CR1. Dendritic cells were the majority of positive cells (67%) followed by macrophages (10%), NK cells (6%), and T cells (10%). With the use of confocal microscopy, the receptor was detected in the kidney only on infiltrating cells but not on resident renal cells. To evaluate the role of CX3CR1 in hypertensive end-organ injury, an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of angiotensin II (ANG II, 1.5 ng·g-1·min-1) and a high-salt diet in wild-type ( n = 15) and CX3CR1-deficient mice ( n = 18). CX3CR1 deficiency reduced the number of renal dendritic cells and increased the numbers of renal CD11b/F4/80+ macrophages and CD11b/Ly6G+ neutrophils in ANG II-infused mice. Surprisingly, CX3CR1-deficient mice exhibited increased albuminuria, glomerular injury, and reduced podocyte density in spite of similar levels of arterial hypertension. In contrast, cardiac damage as assessed by increased heart weight, cardiac fibrosis, and expression of fetal genes, and matrix components were not different between both genotypes. Our findings suggest that CX3CR1 exerts protective properties by modulating the invasion of inflammatory cells in hypertensive renal injury. CX3CR1 inhibition should be avoided in hypertension because it may promote hypertensive renal injury.

Genetic background dominates the susceptibility to ventricular arrhythmias in a murine model of ß-adrenergic stimulation.

In cardiovascular research, several mouse strains with differing genetic backgrounds are used to investigate mechanisms leading to and sustaining ventricular arrhythmias. The genetic background has been shown to affect the studied phenotype in other research fields. Surprisingly little is known about potential strain-specific susceptibilities towards ventricular arrhythmias in vivo. Here, we hypothesized that inter-strain differences reported in the responsiveness of the ß-adrenergic pathway, which is relevant for the development of arrhythmias, translate into a strain-specific vulnerability. To test this hypothesis, we characterized responses to ß-adrenergic blockade (metoprolol) and ß-adrenergic stimulation (isoproterenol) in 4 mouse strains commonly employed in cardiovascular research (Balb/c, BS, C57Bl/6 and FVB) using telemetric ECG recordings. We report pronounced differences in the electrical vulnerability following isoproterenol: Balb/c mice developed the highest number and the most complex arrhythmias while BS mice were protected. Balb/c mice, therefore, seem to be the background of choice for experiments requiring the occurrence of arrhythmias while BS mice may give insight into electrical stability. Arrhythmias did not correlate with the basal ß-adrenergic tone, with the response to ß-adrenergic stimulation or with the absolute heart rates during ß-adrenergic stimulation. Thus, genetic factors dominate the susceptibility to ventricular arrhythmias in this model of ß-adrenergic stimulation.

A pathogenic role of complement in arterial hypertension and hypertensive end organ damage.

The self-amplifying cascade of messenger and effector molecules of the complement system serves as a powerful danger-sensing system that protects the host from a hostile microbial environment, while maintaining proper tissue and organ function through effective clearance of altered or dying cells. As an important effector arm of innate immunity, it also plays important roles in the regulation of adaptive immunity. Innate and adaptive immune responses have been identified as crucial players in the pathogenesis of arterial hypertension and hypertensive end organ damage. In line with this view, complement activation may drive the pathology of hypertension and hypertensive injury through its impact on innate and adaptive immune responses. It is well known that complement activation can cause tissue inflammation and injury and complement-inhibitory drugs are effective treatments for several inflammatory diseases. In addition to these proinflammatory properties, complement cleavage fragments of C3 and C5 can exert anti-inflammatory effects that dampen the inflammatory response to injury. Recent experimental data strongly support a role for complement in arterial hypertension. The remarkably similar clinical and histopathological features of malignant nephrosclerosis and atypical hemolytic uremic syndrome, which is driven by complement activation, suggest a role for complement also in the development of malignant nephrosclerosis. Herein, we will review canonical and noncanonical pathways of complement activation as the framework to understand the multiple roles of complement in arterial hypertension and hypertensive end organ damage.