ABSTRACT
Aging is associated with chronic, low-level inflammation which may contribute to cardiovascular pathologies such as hypertension and atherosclerosis. This chronic inflammation may be opposed by endogenous mechanisms to limit inflammation, for example, by the actions of annexin A1 (ANXA1), an endogenous glucocorticoid-regulated protein that has anti-inflammatory and pro-resolving activity. We hypothesized the pro-resolving mediator ANXA1 protects against age-induced changes in blood pressure (BP), cardiovascular structure and function, and cardiac senescence. BP was measured monthly in conscious mature (4-month) and middle-aged (12-month) ANXA1-deficient (ANXA1-/- ) and wild-type C57BL/6 mice. Body composition was measured using EchoMRI, and both cardiac and vascular function using ultrasound imaging. Cardiac hypertrophy, fibrosis and senescence, vascular fibrosis, elastin, and calcification were assessed histologically. Gene expression relevant to structural remodeling, inflammation, and cardiomyocyte senescence were also quantified. In C57BL/6 mice, progression from 4 to 12 months of age did not affect the majority of cardiovascular parameters measured, with the exception of mild cardiac hypertrophy, vascular calcium, and collagen deposition. Interestingly, ANXA1-/- mice exhibited higher BP, regardless of age. Additionally, age progression had a marked impact in ANXA1-/- mice, with markedly augmented vascular remodeling, impaired vascular distensibility, and body composition. Consistent with vascular dysfunction, cardiac dysfunction, and hypertrophy were also evident, together with markers of senescence and inflammation. These findings suggest that endogenous ANXA1 plays a critical role in regulating BP, cardiovascular function, and remodeling and delays cardiac senescence. Our findings support the development of novel ANXA1-based therapies to prevent age-related cardiovascular pathologies.
Subject(s)
Annexin A1 , Blood Pressure , Vascular Remodeling , Animals , Mice , Annexin A1/genetics , Annexin A1/metabolism , Cardiomegaly , Fibrosis , Inflammation/pathology , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
Cardiovascular ailments are a major cause of mortality where over 1.3 billion people suffer from hypertension leading to heart-disease related deaths. Snake venoms possess a broad repertoire of natriuretic peptides with therapeutic potential for treating hypertension, congestive heart failure, and related cardiovascular disease. We now describe several taipan (Oxyuranus microlepidotus) natriuretic peptides TNPa-e which stimulated cGMP production through the natriuretic peptide receptor A (NPR-A) with higher potencies for the rat NPR-A (rNPR-A) over human NPR-A (hNPR-A). TNPc and TNPd were the most potent, demonstrating 100- and 560-fold selectivity for rNPR-A over hNPR-A. In vivo studies found that TNPc decreased diastolic and systolic blood pressure (BP) and increased heart rate (HR) in conscious normotensive rabbits, to a level that was similar to that of human atrial natriuretic peptide (hANP). TNPc also enhanced the bradycardia due to cardiac afferent stimulation (Bezold-Jarisch reflex). This indicated that TNPc possesses the ability to lower blood pressure and facilitate cardiac vagal afferent reflexes but unlike hANP does not produce tachycardia. The 3-dimensional structure of TNPc was well defined within the pharmacophoric disulfide ring, displaying two turn-like regions (RMSD = 1.15 Å). Further, its much greater biological stability together with its selectivity and potency will enhance its usefulness as a biological tool.
Subject(s)
Hypertension , Natriuretic Peptides , Rats , Animals , Humans , Rabbits , Natriuretic Peptides/pharmacology , Receptors, Atrial Natriuretic Factor , Heart , Elapidae , Hypertension/drug therapyABSTRACT
AIM: Gut microbiota-derived metabolites, such as short-chain fatty acids (SCFAs) have vasodilator properties in animal and human ex vivo arteries. However, the role of the gut microbiota and SCFAs in arterial stiffness in humans is still unclear. Here we aimed to determine associations between the gut microbiome, SCFA and their G-protein coupled sensing receptors (GPCRs) in relation to human arterial stiffness. METHODS: Ambulatory arterial stiffness index (AASI) was determined from ambulatory blood pressure (BP) monitoring in 69 participants from regional and metropolitan regions in Australia (55.1% women; mean, 59.8± SD, 7.26 years of age). The gut microbiome was determined by 16S rRNA sequencing, SCFA levels by gas chromatography, and GPCR expression in circulating immune cells by real-time PCR. RESULTS: There was no association between metrics of bacterial α and ß diversity and AASI or AASI quartiles in men and women. We identified two main bacteria taxa that were associated with AASI quartiles: Lactobacillus spp. was only present in the lowest quartile, while Clostridium spp. was present in all quartiles but the lowest. AASI was positively associated with higher levels of plasma, but not faecal, butyrate. Finally, we identified that the expression of GPR43 (FFAR2) and GPR41 (FFAR3) in circulating immune cells were negatively associated with AASI. CONCLUSIONS: Our results suggest that arterial stiffness is associated with lower levels of the metabolite-sensing receptors GPR41/GPR43 in humans, blunting its response to BP-lowering metabolites such as butyrate. The role of Lactobacillus spp. and Clostridium spp., as well as butyrate-sensing receptors GPR41/GPR43, in human arterial stiffness needs to be determined.
Subject(s)
Gastrointestinal Microbiome , Vascular Stiffness , Animals , Blood Pressure Monitoring, Ambulatory , Fatty Acids, Volatile , Female , Humans , Male , RNA, Ribosomal, 16SABSTRACT
AIMS/HYPOTHESIS: We determined whether empagliflozin altered renal sympathetic nerve activity (RSNA) and baroreflexes in a diabetes model in conscious rabbits. METHODS: Diabetes was induced by alloxan, and RSNA, mean arterial pressure (MAP) and heart rate were measured before and after 1 week of treatment with empagliflozin, insulin, the diuretic acetazolamide or the ACE inhibitor perindopril, or no treatment, in conscious rabbits. RESULTS: Four weeks after alloxan administration, blood glucose was threefold and MAP 9% higher than non-diabetic controls (p < 0.05). One week of treatment with empagliflozin produced a stable fall in blood glucose (-43%) and increased water intake (+49%) but did not change RSNA, MAP or heart rate compared with untreated diabetic rabbits. The maximum RSNA to hypotension was augmented by 75% (p < 0.01) in diabetic rabbits but the heart rate baroreflex was unaltered. Empagliflozin and acetazolamide reduced the augmentation of the RSNA baroreflex (p < 0.05) to be similar to the non-diabetic group. Noradrenaline (norepinephrine) spillover was similar in untreated diabetic and non-diabetic rabbits but twofold greater in empagliflozin- and acetazolamide-treated rabbits (p < 0.05). CONCLUSIONS/INTERPRETATION: As empagliflozin can restore diabetes-induced augmented sympathetic reflexes, this may be beneficial in diabetic patients. A similar action of the diuretic acetazolamide suggests that the mechanism may involve increased sodium and water excretion. Graphical abstract.
Subject(s)
Benzhydryl Compounds/therapeutic use , Glucosides/therapeutic use , Animals , Baroreflex/drug effects , Blood Glucose/drug effects , Blood Pressure/drug effects , Body Weight/drug effects , Heart Rate/drug effects , Male , Perindopril/pharmacology , Rabbits , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Sympathetic Nervous System/drug effects , Sympathetic Nervous System/metabolismABSTRACT
Chronic kidney disease (CKD) is associated with greater sympathetic nerve activity but it is unclear if this is a kidney-specific response or due to generalized stimulation of sympathetic nervous system activity. To determine this, we used a rabbit model of CKD in which quantitative comparisons with control rabbits could be made of kidney sympathetic nerve activity and whole-body norepinephrine spillover. Rabbits either had surgery to lesion 5/6th of the cortex of one kidney by electro-lesioning and two weeks later removal of the contralateral kidney, or sham lesioning and sham nephrectomy. After three weeks, the blood pressure was statistically significantly 20% higher in conscious rabbits with CKD compared to rabbits with a sham operation, but their heart rate was similar. Strikingly, kidney nerve activity was 37% greater than in controls, with greater burst height and frequency. Total norepinephrine spillover was statistically significantly lower by 34%, and kidney baroreflex curves were shifted to the right in rabbits with CKD. Plasma creatinine and urine output were elevated by 38% and 131%, respectively, and the glomerular filtration rate was 37% lower than in sham-operated animals (all statistically significant). Kidney gene expression of fibronectin, transforming growth factor-ß, monocyte chemotactic protein1, Nox4 and Nox5 was two- to eight-fold greater in rabbits with CKD than in control rabbits. Overall, the glomerular layer lesioning model in conscious rabbits produced a moderate, stable degree of CKD characterized by elevated blood pressure and increased kidney sympathetic nerve activity. Thus, our findings, together with that of a reduction in total norepinephrine spillover, suggest that kidney denervation, rather than generalized sympatholytic treatments, may represent a preferable management for CKD associated hypertension.
Subject(s)
Renal Insufficiency, Chronic , Animals , Baroreflex , Blood Pressure , Heart Rate , Kidney , Rabbits , Sympathetic Nervous SystemABSTRACT
The precise mechanisms underlying resistant hypertension remain elusive. Reduced nitric oxide (NO) bioavailability is frequently documented in chronic kidney disease, obesity, diabetes and advanced age, all of which are risk factors for resistant hypertension. Sympathetic overactivity and chronic activation of the renin-angiotensin system are salient features of resistant hypertension. Interestingly, recent data indicate that renal sympathetic overactivity can reduce the expression of neuronal nitric oxide synthase in the paraventricular nucleus. Reduced NO levels in the paraventricular nucleus can increase sympathetic outflow and this can create a vicious cycle contributing to resistant hypertension. Angiotensin II can reduce l-arginine transport and hence NO production. Reduced NO levels may reduce the formation of angiotensin 1-7 dampening the cardio-protective effects of the renin-angiotensin system contributing to resistant hypertension. In addition, interleukin-6 (IL-6) is demonstrated to be independently associated with resistant hypertension, and IL-6 can reduce NO synthesis. Despite this, NO levels have not been quantified in resistant hypertension. Findings from a small proof of concept study indicate that NO donors can reduce blood pressure in patients with resistant hypertension but more studies are required to validate these preliminary findings. In the present paper, we put forward the hypothesis that reduced NO bioavailability contributes substantially to the development of resistant hypertension.
Subject(s)
Arginine/physiology , Hypertension/physiopathology , Nitric Oxide/physiology , Biological Availability , Endothelium, Vascular/physiopathology , Humans , Hypertension/etiology , Hypertension/therapy , Inflammation/complications , Nitric Oxide/deficiency , Nitric Oxide/pharmacokinetics , Renin-Angiotensin System/physiology , Signal Transduction/physiology , Sympathetic Nervous System/physiopathology , Treatment Failure , Vascular Stiffness/physiologyABSTRACT
The essential role of the Y chromosome in male sex determination has largely overshadowed the possibility that it may exert other biologic roles. Here, we show that Y-chromosome lineage is a strong determinant of perivascular and renal T-cell infiltration in the stroke-prone spontaneously hypertensive rat, which, in turn, may influence vascular function and blood pressure (BP). We also show, for the first time to our knowledge, that augmented perivascular T-cell levels can directly instigate vascular dysfunction, and that the production of reactive oxygen species that stimulate cyclo-oxygenase underlies this. We thus provide strong evidence for the consideration of Y-chromosome lineage in the diagnosis and treatment of male hypertension, and point to the modulation of cardiovascular organ T-cell infiltration as a possible mechanism that underpins Y- chromosome regulation of BP.-Khan, S. I., Andrews, K. L., Jackson, K. L., Memon, B., Jefferis, A.-M., Lee, M. K. S., Diep, H., Wei, Z., Drummond, G. R., Head, G. A., Jennings, G. L., Murphy, A. J., Vinh, A., Sampson, A. K., Chin-Dusting, J. P. F. Y-chromosome lineage determines cardiovascular organ T-cell infiltration in the stroke-prone spontaneously hypertensive rat.
Subject(s)
Blood Pressure , Hypertension/metabolism , Hypertension/physiopathology , T-Lymphocytes/metabolism , Y Chromosome/metabolism , Animals , Hypertension/genetics , Male , Rats , Rats, Inbred SHR , Rats, Transgenic , T-Lymphocytes/pathology , Y Chromosome/geneticsABSTRACT
Over the past several decades, studies of the sympathetic nervous system in humans, sheep, rabbits, rats, and mice have substantially increased mechanistic understanding of cardiovascular function and dysfunction. Recently, interest in sympathetic neural mechanisms contributing to blood pressure control has grown, in part because of the development of devices or surgical procedures that treat hypertension by manipulating sympathetic outflow. Studies in animal models have provided important insights into physiological and pathophysiological mechanisms that are not accessible in human studies. Across species and among laboratories, various approaches have been developed to record, quantify, analyze, and interpret sympathetic nerve activity (SNA). In general, SNA demonstrates "bursting" behavior, where groups of action potentials are synchronized and linked to the cardiac cycle via the arterial baroreflex. In humans, it is common to quantify SNA as bursts per minute or bursts per 100 heart beats. This type of quantification can be done in other species but is only commonly reported in sheep, which have heart rates similar to humans. In rabbits, rats, and mice, SNA is often recorded relative to a maximal level elicited in the laboratory to control for differences in electrode position among animals or on different study days. SNA in humans can also be presented as total activity, where normalization to the largest burst is a common approach. The goal of the present paper is to put together a summary of "best practices" in several of the most common experimental models and to discuss opportunities and challenges relative to the optimal measurement of SNA across species.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/guidelines-for-measuring-sympathetic-nerve-activity/.
Subject(s)
Action Potentials/physiology , Baroreflex/physiology , Diagnostic Techniques, Neurological/standards , Peripheral Nerves/physiology , Practice Guidelines as Topic , Sympathetic Nervous System/physiology , Animals , Humans , Rabbits , Rats , Sheep , Species SpecificityABSTRACT
PURPOSE OF REVIEW: The major health issue of being overweight or obese relates to the development of hypertension, insulin resistance and diabetic complications. One of the major underlying factors influencing the elevated blood pressure in obesity is increased activity of the sympathetic nerves to particular organs such as the kidney. RECENT FINDINGS: There is now convincing evidence from animal studies that major signals such as leptin and insulin have a sympathoexcitatory action in the hypothalamus to cause hypertension. Recent studies suggest that this may involve 'neural plasticity' within hypothalamic signalling driven by central actions of leptin mediated via activation of melanocortin receptor signalling and activation of brain neurotrophic factors. This review describes the evidence to support the contribution of the SNS to obesity related hypertension and the major metabolic and adipokine signals.
Subject(s)
Hypertension/etiology , Obesity/complications , Sympathetic Nervous System/physiopathology , Animals , Humans , Hypertension/drug therapy , Hypothalamus/physiopathology , Leptin/metabolism , Risk Factors , Signal TransductionABSTRACT
One of the main constraints associated with recording sympathetic nerve activity (SNA) in both humans and experimental animals is that microvolt values reflect characteristics of the recording conditions and limit comparisons between different experimental groups. The nasopharyngeal response has been validated for normalizing renal SNA (RSNA) in conscious rabbits, and in humans muscle SNA is normalized to the maximum burst in the resting period. We compared these two methods of normalization to determine whether either could detect elevated RSNA in hypertensive rabbits compared with normotensive controls. We also tested whether either method eliminated differences based only on different recording conditions by separating RSNA of control (sham) rabbits into two groups with low or high microvolts. Hypertension was induced by 5 wk of renal clipping (2K1C), 3 wk of high-fat diet (HFD), or 3 mo infusion of a low dose of angiotensin (ANG II). Normalization to the nasopharyngeal response revealed RSNA that was 88, 51, and 34% greater in 2K1C, HFD, and ANG II rabbits, respectively, than shams (P < 0.05), but normalization to the maximum burst showed no differences. The RSNA baroreflex followed a similar pattern whether RSNA was expressed in microvolts or normalized. Both methods abolished the difference between low and high microvolt RSNA. These results suggest that maximum burst amplitude is a useful technique for minimizing differences between recording conditions but is unable to detect real differences between groups. We conclude that the nasopharyngeal reflex is the superior method for normalizing sympathetic recordings in conscious rabbits.
Subject(s)
Baroreflex , Electrodiagnosis/methods , Hypertension/physiopathology , Kidney/innervation , Muscle, Skeletal/innervation , Nasopharynx/innervation , Sympathetic Nervous System/physiopathology , Action Potentials , Angiotensin II , Animals , Arterial Pressure , Blood Pressure Determination/methods , Calibration , Consciousness , Constriction , Diet, High-Fat , Disease Models, Animal , Electrodiagnosis/standards , Heart Rate , Hypertension/etiology , Male , Models, Animal , Rabbits , Renal Artery/physiopathology , Renal Artery/surgery , Reproducibility of Results , Signal Processing, Computer-Assisted , Telemetry/methods , Time FactorsABSTRACT
We examined the effect of chronic angiotensin (Ang II)-induced hypertension on activity of postganglionic renal sympathetic units to determine whether altered whole renal nerve activity is due to recruitment or changes in firing frequency. Rabbits were treated with a low (20 ng kg(-1) min(-1), 8 weeks) or high dose (50 ng kg(-1) min(-1), 4 weeks) of Ang II before the experiment under chloralose-urethane anaesthesia. Spontaneously active units were detected from multiunit recordings using an algorithm that separated units by action potential shape using templates that matched spikes within a prescribed standard deviation. Multiunit sympathetic nerve activity was 40% higher in rabbits treated with low-dose Ang II than in sham (P = 0.012) but not different in high-dose Ang II. Resting firing frequency was similar in sham rabbits (1.00 ± 0.09 spikes s(-1), n = 144) and in those treated with high-dose Ang II (1.10 ± 0.08 spikes s(-1), n = 112) but was lower with low-dose Ang II (0.65 ± 0.08 spikes s(-1), n = 149, P < 0.05). Unit firing rhythmicity was linked to the cardiac cycle and was similar in sham and low-dose Ang II groups but 29-32% lower in rabbits treated with high-dose Ang II (P < 0.001). Cardiac linkage followed a similar pattern during hypoxia. All units showed baroreceptor dependency. Baroreflex gain and range were reduced and curves shifted to the right in Ang II groups. Firing frequency during hypoxia increased by +39% in low-dose Ang II and +82% in shams, but the greatest increase was in the high-dose Ang II group (+103%, P(dose) = 0.001). Responses to hypercapnia were similar in all groups. Increases in sympathetic outflow in hypertension caused by low-dose chronic Ang II administration are due to recruitment of neurons, but high-dose Ang II increases firing frequency in response to chemoreceptor stimuli independently of the arterial baroreceptors.
Subject(s)
Angiotensin II , Hypertension/chemically induced , Hypertension/physiopathology , Kidney/innervation , Kidney/physiopathology , Sympathetic Nervous System/physiopathology , Vasoconstrictor Agents , Action Potentials , Angiotensin II/administration & dosage , Animals , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/physiopathology , Baroreflex , Dose-Response Relationship, Drug , Electrocardiography , Heart/physiopathology , Hemodynamics , Male , Rabbits , Vasoconstrictor Agents/administration & dosageABSTRACT
BACKGROUND: Home blood pressure (BP) monitoring is the self-measurement of BP in the home environment. It is complementary to 24-hour ambulatory BP, for better diagnosis and management of patients with high BP. Home BP monitoring is in widespread use, but variation in monitoring protocols could lead to inaccurate assessment of BP. OBJECTIVE: The aim of this article is to provide a practical guide (with resources) for patients and doctors on how to measure home BP according to a standardised, evidence-based protocol. DISCUSSION: Home BP should be measured using a validated, automatic BP device (preferably with memory storage), using an appropriately sized upper arm cuff. Measurements should be taken after five minutes of seated rest and before medication, food or vigorous exercise. BP should be recorded for seven days (five days minimum) in the morning and evening (two readings each). Overall, home BP is the average systolic and diastolic BP over seven days (excluding the first day); an average of ≥135/85 mmHg is indicative of hypertension.
Subject(s)
Blood Pressure Determination/standards , Blood Pressure Monitoring, Ambulatory/standards , Practice Guidelines as Topic , Algorithms , Australia , Blood Pressure , Blood Pressure Determination/methods , Blood Pressure Monitoring, Ambulatory/methods , Humans , Hypertension/diagnosis , Hypertension/physiopathology , Patient ComplianceABSTRACT
NEW FINDINGS: What is the central question of this study? Is the elevated tonic renal nerve activity induced by chronic angiotensin administration mediated by recruitment or increased firing frequency and does this occur via stress, chemoreflex or baroreflex pathways? What is the main finding and its importance? Long-term angiotensin treatment in rabbits elevates renal sympathetic nerve activity by recruitment of previously silent fibres. This was similar to the effect of chemoreflex stimulation, but not to stress or baroreceptor activation, suggesting that presympathetic pathways activated by angiotensin may be common to those activated by chemoreceptors. Modulation of sympathetic nerve activity involves control by the CNS of the amplitude of neural discharges, reflecting recruitment of neurons and their firing frequency. We tested whether elevated tonic renal sympathetic nerve activity (RSNA) induced by chronic angiotensin administration is mediated by recruitment or increased firing frequency and whether this is characteristic of the pattern observed with activation of stress, chemoreflex or baroreflex pathways. Conscious rabbits treated with angiotensin II for 12 weeks to increase blood pressure by 10-30% were subjected to stress (air jet), hypoxia (10% O2 + 3% CO2) and drug-induced changes in blood pressure to produce baroreflexes. Total RSNA and RSNA burst amplitude were scaled to 100 normalized units (n.u.) by the maximal response to smoke. After 12 weeks of treatment, blood pressure was 17% higher than baseline 68 ± 1 mmHg (P = 0.02). Compared with sham treatment, total RSNA and burst amplitude were +82% (P < 0.001) and 39% (P = 0.04) greater, but burst frequency was similar. Total RSNA increased during hypoxia (+38% from 4.9 ± 0.7 n.u.), owing to greater amplitude, but not frequency. Air-jet stress increased total RSNA (+44% from 4.3 ± 0.5 n.u.) and burst frequency (+21% from 5.4 ± 0.7 bursts s(-1) ), but not amplitude. Angiotensin enhanced total RSNA responses to both air jet (+33%) and hypoxia (+58%), but only increased the amplitude response to air jet. The RSNA baroreflexes reset to the higher blood pressure, but amplitude or frequency was not differentially altered. Chronic angiotensin treatment elevated RSNA by recruitment of neurons, which is similar to chemoreflex stimulation, but not to stress or baroreceptor activation, suggesting that presympathetic pathways activated by angiotensin may be common to those activated by chemoreceptors.
Subject(s)
Angiotensin II , Baroreflex , Hypertension/physiopathology , Hypoxia/physiopathology , Kidney/innervation , Pressoreceptors/physiopathology , Stress, Physiological , Sympathetic Nervous System/physiopathology , Action Potentials , Animals , Blood Pressure , Carbon Dioxide/blood , Chemoreceptor Cells/metabolism , Disease Models, Animal , Heart Rate , Hypertension/chemically induced , Hypoxia/blood , Male , Oxygen/blood , Rabbits , Time FactorsABSTRACT
The degradation of ANG II by angiotensin-converting enzyme 2 (ACE2), leading to the formation of ANG(1-7), is an important step in the regulation of the renin-angiotensin-aldosterone system (RAAS), and one that is significantly altered in the diabetic kidney. This study examined the role of ACE2 in the hyperfiltration associated with diabetes. Streptozotocin diabetes was induced in male C57BL6 mice and ACE2 knockout (KO) mice. C57BL6 mice were further randomized to receive the selective ACE2 inhibitor MLN-4760. After 2 wk of study, animals were subjected to micropuncture experiments. The renal reserve was further assessed in C57BL6 mice and ACE2 KO mice after exposure to a high-protein diet. The induction of diabetes in wild-type mice was associated with increased renal ACE2 activity, hyperfiltration, and renal hypertrophy. On micropuncture, diabetes was associated with increased tubular free flow and stop-flow pressure, enhanced tubuloglomerular feedback reactivity, and an increased maximal response indicative of increased glomerular hydrostatic capillary pressure. Each of these increases were prevented in diabetic ACE2 KO mice and diabetic mice treated with a selective ACE2 inhibitor for 2 wk. However, unlike chronically treated animals, ACE2 inhibition with MLN-4760 had no acute effect on stop-flow pressure or tubuloglomerular feedback reactivity. ACE2 KO mice also failed to increase their creatinine clearance in response to a high-protein diet. The results of our study suggest that ACE2 plays a key role in the recruitment of the renal reserve and hyperfiltration associated with diabetes.
Subject(s)
Diabetes Mellitus, Experimental/enzymology , Diabetic Nephropathies/enzymology , Glomerular Filtration Rate , Kidney/enzymology , Peptidyl-Dipeptidase A/metabolism , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Capillaries/physiopathology , Creatinine/blood , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/physiopathology , Diabetic Nephropathies/genetics , Diabetic Nephropathies/pathology , Diabetic Nephropathies/physiopathology , Dietary Proteins/metabolism , Glomerular Filtration Rate/drug effects , Hydrostatic Pressure , Hypertrophy , Kidney/blood supply , Kidney/drug effects , Kidney/pathology , Kidney/physiopathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Peptidyl-Dipeptidase A/deficiency , Peptidyl-Dipeptidase A/genetics , Renal Circulation , Renin-Angiotensin SystemABSTRACT
BACKGROUND: Numerous studies have shown sex differences in the onset and severity of hypertension. Despite these sex-differences the majority of animal studies are carried out in males. This study investigated expression changes in both male and female hypertensive mouse kidneys to identify common mechanisms that may be involved in the development of hypertension. METHODS: The Schlager hypertensive mouse model (BPH/2J) and its normotensive control (BPN/3J) were used in this study. Radiotelemetry was performed on 12 to 13 week old BPH/2J and BPN/3J male and female animals. Affymetrix GeneChip Mouse Gene 1.0 ST Arrays were performed in kidney tissue from 12 week old BPH/2J and BPN/3J male and female mice (n = 6/group). Genes that were differentially expressed in both male and female datasets were validated using qPCR. RESULTS: Systolic arterial pressure and heart rate was significantly higher in BPH/2J mice compared with BPN/3J mice in both males and females. Microarray analysis identified 153 differentially expressed genes that were common between males and females (70 upregulated and 83 downregulated). We validated 15 genes by qPCR. Genes involved in sympathetic activity (Hdc, Cndp2), vascular ageing (Edn3), and telomere maintenance (Mcm6) were identified as being differentially expressed between BPH/2J and BPN/3J comparisons. Many of these genes also exhibited expression differences between males and females within a strain. CONCLUSIONS: This study utilised data from both male and female animals to identify a number of genes that may be involved in the development of hypertension. We show that female data can be used to refine candidate genes and pathways, as well as highlight potential mechanisms to explain the differences in prevalence and severity of disease between men and women.
Subject(s)
Gene Expression Regulation , Gene Regulatory Networks , Hypertension/genetics , Hypertension/pathology , Animals , Blood Pressure , Disease Models, Animal , Female , Gene Expression Profiling , Kidney/metabolism , Male , Mice , Oligonucleotide Array Sequence AnalysisABSTRACT
The activation of the sympathetic nervous system is a major mechanism underlying both human and experimental models of obesity-related hypertension. While insulin and the adipokine leptin have long been thought to contribute to obesity-related neurogenic mechanisms, the evidence is now very strong that they play a major role, shown particularly in animal studies using selective receptor antagonists. There is not just maintenance of leptin's sympatho-excitatory actions as previously suggested but considerable amplification particularly in renal sympathetic nervous activity. Importantly, these changes are not dependent on short-term elevation or reduction in plasma leptin or insulin, but require some weeks to develop indicating a slow "neural adaptivity" within hypothalamic signalling. These effects can be carried across generations even when offspring are raised on a normal diet. A better understanding of the underlying mechanism should be a high research priority given the prevalence of obesity not just in the current population but also for future generations.
Subject(s)
Blood Pressure , Central Nervous System Diseases/etiology , Central Nervous System/physiopathology , Hypertension/complications , Obesity/complications , Sympathetic Nervous System/physiopathology , Animals , Central Nervous System Diseases/physiopathology , Humans , Hypertension/physiopathology , Obesity/physiopathologyABSTRACT
High blood pressure (BP) variability, which may be an important determinant of hypertensive end-organ damage, is emerging as an important predictor of cardiovascular health. Dietary antioxidants can influence BP, but their effects on variability are yet to be investigated. The aim of the present study was to assess the effects of vitamin E, vitamin C and polyphenols on the rate of daytime and night-time ambulatory BP variation. To assess these effects, two randomised, double-blind, placebo-controlled trials were performed. In the first trial (vitamin E), fifty-eight individuals with type 2 diabetes were given 500 mg/d of RRR-α-tocopherol, 500 mg/d of mixed tocopherols or placebo for 6 weeks. In the second trial (vitamin C-polyphenols), sixty-nine treated hypertensive individuals were given 500 mg/d of vitamin C, 1000 mg/d of grape-seed polyphenols, both vitamin C and polyphenols, or neither (placebo) for 6 weeks. At baseline and at the end of the 6-week intervention, 24 h ambulatory BP and rate of measurement-to-measurement BP variation were assessed. Compared with placebo, treatment with α-tocopherol, mixed tocopherols, vitamin C and polyphenols did not significantly alter the rate of daytime or night-time systolic BP, diastolic BP or pulse pressure variation (P>0·05). Treatment with the vitamin C and polyphenol combination resulted in higher BP variation: the rate of night-time systolic BP variation (P= 0·022) and pulse pressure variation (P= 0·0036) were higher and the rate of daytime systolic BP variation was higher (P= 0·056). Vitamin E, vitamin C or grape-seed polyphenols did not significantly alter the rate of BP variation. However, the increase in the rate of BP variation suggests that the combination of high doses of vitamin C and polyphenols could be detrimental to treated hypertensive individuals.
Subject(s)
Antioxidants/administration & dosage , Ascorbic Acid/administration & dosage , Blood Pressure/drug effects , Hypertension/drug therapy , Polyphenols/administration & dosage , Vitamin E/administration & dosage , Aged , Ascorbic Acid/adverse effects , Diet , Double-Blind Method , Female , Humans , Male , Middle Aged , Placebos , Polyphenols/adverse effects , Seeds/chemistry , Tocopherols/administration & dosage , Vitis/chemistry , alpha-Tocopherol/administration & dosageABSTRACT
Observational studies indicate that psychological stress may contribute to the pathogenesis of hypertension and this may be further accentuated by factors such as endothelial dysfunction. On this basis, we aimed to determine whether oxidative stress enhances pressor responses to stressful stimuli and whether augmenting endothelial function by increasing the transport of L-arginine can counter the effects of oxidative stress. Telemetry probes were used to measure mean arterial pressure (MAP) in wild-type (WT; n = 6) and endothelial cationic amino acid transporter-1 (CAT-1)-overexpressing (CAT+) mice (n = 6) before and during an aversive (restraint) and non-aversive (almond feeding) stressor. The superoxide dismutase inhibitor diethyldithiocarbamic acid (DETCA; 30 mg/kg per day; 14 days) was then administered via a minipump to induce oxidative stress. Stress responses to feeding and restraint were repeated during Days 11-12 of DETCA infusion. In WT mice, pressor responses to restraint and feeding were augmented during infusion of DETCA (35 ± 1 and 28 ± 1 mmHg, respectively) compared with respective pretreatment responses (28 ± 2 and 24 ± 1 mmHg, respectively; P ≤ 0.01). In CAT+ mice, pressor responses to feeding were blunted during DETCA (20 ± 1 mmHg) compared with the control response (23 ± 1 mmHg; P = 0.03). In these mice, pressor responses to restraint were similar before (28 ± 1 mmHg) and during (26 ± 1 mmHg) DETCA infusion (P = 0.26). We conclude that endothelial CAT-1 overexpression can counter the ability of oxidative stress to augment pressor responses to behavioural stress.
Subject(s)
Blood Pressure/genetics , Cationic Amino Acid Transporter 1/genetics , Endothelial Cells/metabolism , Oxidative Stress/genetics , Animals , Arginine/genetics , Blood Pressure/drug effects , Endothelial Cells/drug effects , Hypertension/genetics , Mice , Mice, Transgenic , Oxidative Stress/drug effects , Superoxide Dismutase/genetics , Vasoconstrictor Agents/pharmacologyABSTRACT
AIMS: Formylpeptide receptors (FPRs) play a critical role in the regulation of inflammation, an important driver of hypertension-induced end-organ damage. We have previously reported that the biased FPR small-molecule agonist, compound17b (Cmpd17b), is cardioprotective against acute, severe inflammatory insults. Here, we reveal the first compelling evidence of the therapeutic potential of this novel FPR agonist against a longer-term, sustained inflammatory insult, i.e. hypertension-induced end-organ damage. The parallels between the murine and human hypertensive proteome were also investigated. METHODS AND RESULTS: The hypertensive response to angiotensin II (Ang II, 0.7â mg/kg/day, s.c.) was attenuated by Cmpd17b (50â mg/kg/day, i.p.). Impairments in cardiac and vascular function assessed via echocardiography were improved by Cmpd17b in hypertensive mice. This functional improvement was accompanied by reduced cardiac and aortic fibrosis and vascular calcification. Cmpd17b also attenuated Ang II-induced increased cardiac mitochondrial complex 2 respiration. Proteomic profiling of cardiac and aortic tissues and cells, using label-free nano-liquid chromatography with high-sensitivity mass spectrometry, detected and quantified â¼6000 proteins. We report hypertension-impacted protein clusters associated with dysregulation of inflammatory, mitochondrial, and calcium responses, as well as modified networks associated with cardiovascular remodelling, contractility, and structural/cytoskeletal organization. Cmpd17b attenuated hypertension-induced dysregulation of multiple proteins in mice, and of these, â¼110 proteins were identified as similarly dysregulated in humans suffering from adverse aortic remodelling and cardiac hypertrophy. CONCLUSION: We have demonstrated, for the first time, that the FPR agonist Cmpd17b powerfully limits hypertension-induced end-organ damage, consistent with proteome networks, supporting development of pro-resolution FPR-based therapeutics for treatment of systemic hypertension complications.
ABSTRACT
The rise in blood pressure during an acute aversive stress has been suggested to involve activation of angiotensin type 1A receptors (AT(1A)Rs) at various sites within the brain, including the rostral ventrolateral medulla. In this study we examine the involvement of AT(1A)Rs associated with a subclass of sympathetic premotor neurons of the rostral ventrolateral medulla, the C1 neurons. The distribution of putative AT(1A)R-expressing cells was mapped throughout the brains of three transgenic mice with a bacterial artificial chromosome-expressing green fluorescent protein under the control of the AT(1A)R promoter. The overall distribution correlated with that of the AT(1A)Rs mapped by other methods and demonstrated that the majority of C1 neurons express the AT(1A)R. Cre-recombinase expression in C1 neurons of AT(1A)R-floxed mice enabled demonstration that the pressor response to microinjection of angiotensin II into the rostral ventrolateral medulla is dependent upon expression of the AT(1A)R in these neurons. Lentiviral-induced expression of wild-type AT(1A)Rs in C1 neurons of global AT(1A)R knock-out mice, implanted with radiotelemeter devices for recording blood pressure, modulated the pressor response to aversive stress. During prolonged cage-switch stress, expression of AT(1A)Rs in C1 neurons induced a greater sustained pressor response when compared to the control viral-injected group (22 ± 4 mmHg for AT(1A)R vs 10 ± 1 mmHg for GFP; p < 0.001), which was restored toward that of the wild-type group (28 ± 2 mmHg). This study demonstrates that AT(1A)R expression by C1 neurons is essential for the pressor response to angiotensin II and that this pathway plays an important role in the pressor response to aversive stress.