The adrenal medulla in cardiovascular medicine: an untold story
- Authors: Esler, Murray , Jennings, Garry , Schlaich, Markus , Lambert, Gavin , Thompson, Jane , Lambert, Elisabeth , Guo, Ling , Alvarenga, Marlies , Esler, Danielle , Eikelis, Nina , Kaye, David
- Date: 2021
- Type: Text , Journal article
- Relation: Journal of Hypertension Vol. 39, no. 5 (2021), p. 819-829
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- Description: Unlike noradrenaline, the sympathetic neurotransmitter which overflows to the circulation, adrenaline (ADR) is a secreted hormone, with a low plasma concentration, and plasma concentration for biological action a log order lower than that of noradrenaline. The venous drainage of the left adrenal medulla into the left renal vein does expose this vein to uniquely high plasma ADR concentrations and possible risk of thrombosis at high rates of ADR secretion. There is typically a different timeframe for adrenal medullary and sympathetic nervous system responsesADR release is short term in contrast with sympathetic activation persisting for years in heart failure and hypertension. The historic view of Walter Cannon, subject to recent review, that the sympathoadrenal system is a unified biological system, was deconstructed further with demonstration of frequent mismatching of adrenal medullary and sympathetic nervous responses. Under gravity stimulation with standing, there is prompt sympathetic activation without ADR release. In many diseases, notably obesity, hypertension, heart failure and depressive illness, an activated sympathetic nervous system and silent adrenal medulla coexist. The therapeutic corollary of this is that ADR blockade is much less commonly needed clinically than pharmacological antagonism of the sympathetic nervous system.
Renal nerves contribute to hypertension in Schlager BPH/2J mice
- Authors: Gueguen, Cindy , Jackson, Kristy , Marques, Francine , Eikelis, Nina , Phillips, Sarah , Stevenson, Emily , Charchar, Fadi , Lambert, Gavin , Davern, Pamela , Head, Geoffrey
- Date: 2019
- Type: Text , Journal article
- Relation: Hypertension Research Vol. 42, no. 3 (2019), p. 306-318
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- Description: Schlager mice (BPH/2J) are hypertensive due to a greater contribution of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS). The kidneys of BPH/2J are hyper-innervated suggesting renal nerves may contribute to the hypertension. We therefore determined the effect of bilateral renal denervation (RD) on hypertension in BPH/2J. Mean arterial pressure (MAP) was measured by radiotelemetry before and for 3 weeks after RD in BPH/2J and BPN/3J. The effects of pentolinium and enalaprilat were examined to determine the contribution of the SNS and RAS, respectively. After 3 weeks, MAP was −10.9 ± 2.1 mmHg lower in RD BPH/2J compared to baseline and −2.1 ± 2.2 mmHg in sham BPH/2J (P < 0.001, n = 8–10). RD had no effect in BPN/3J (P > 0.1). The depressor response to pentolinium was greater in BPH/2J than BPN/3J, but in both cases the response in RD mice was similar to sham. Enalaprilat decreased MAP more in RD BPH/2J compared to sham (−12 vs −3 mmHg, P < 0.001) but had no effect in BPN/3J. RD reduced renal noradrenaline in both strains but more so in BPH/2J. RD reduced renin mRNA and protein, but not plasma renin in BPH/2J to levels comparable with BPN/3J mice. We conclude that renal nerves contribute to hypertension in BPH mice as RD induced a sustained fall in MAP, which was associated with a reduction of intrarenal renin expression. The lack of inhibition of the depressor effects of pentolinium and enalaprilat by RD suggests that vasoconstrictor effects of the SNS or RAS are not involved.
Neural suppression of miRNA-181a in the kidney elevates renin expression and exacerbates hypertension in Schlager mice
- Authors: Jackson, Kristy , Gueguen, Cindy , Lim, Kyungjoon , Eikelis, Nina , Stevenson, Emily , Charchar, Fadi , Lambert, Gavin , Burke, Sandra , Paterson, Madeleine , Marques, Francine , Head, Geoffrey
- Date: 2020
- Type: Text , Journal article
- Relation: Hypertension Research Vol. 43, no. 11 (2020), p. 1152-1164
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- Description: BPH/2J mice are a genetic model of hypertension with overactivity of the sympathetic nervous system (SNS) and renin–angiotensin system (RAS). BPH/2J display higher renal renin mRNA and low levels of its negative regulator microRNA-181a (miR-181a). We hypothesise that high renal SNS activity may reduce miR-181a expression, which contributes to elevated RAS activity and hypertension in BPH/2J. Our aim was to determine whether in vivo administration of a renal-specific miR-181a mimic or whether renal denervation could increase renal miR-181a abundance to reduce renal renin mRNA, RAS activity and hypertension in BPH/2J mice. Blood pressure (BP) in BPH/2J and normotensive BPN/3J mice was measured via radiotelemetry probes. Mice were administered miR-181a mimic or a negative control (1–25 nmol, i.v., n = 6–10) with BP measured for 48 h after each dose or they underwent renal denervation or sham surgery (n = 7–9). Injection of 5–25 nmol miR-181a mimic reduced BP in BPH/2J mice after 36–48 h (−5.3 ± 1.8, −6.1 ± 1.9 mmHg, respectively, P < 0.016). Treatment resulted in lower renal renin and inflammatory marker (TLR4) mRNA levels in BPH/2J. The mimic abolished the hypotensive effect of blocking the RAS with enalaprilat (P < 0.01). No differences between mimic or vehicle were observed in BPN/3J mice except for a higher level of renal angiotensinogen in the mimic-treated mice. Renal miR-181a levels that were lower in sham BPH/2J mice were greater following renal denervation and were thus similar to those of BPN/3J. Our findings suggest that the reduced renal miR-181a may partially contribute to the elevated BP in BPH/2J mice, through an interaction between the renal sympathetic nerves and miR-181a regulation of the RAS. © 2020, The Japanese Society of Hypertension.
- Description: This work was supported by a grant from the National Health & Medical Research Council of Australia (NHMRC, Project grant 1065714) and in part by the Victorian Government’s OIS Program. Investigators were supported by NHMRC/National Heart Foundation (NHF) Postdoctoral Fellowships (NHMRC APP1091688 to KLJ, NHMRC APP1052659 and NHF PF12M6785 and 101185 to FZM) and NHMRC Research Fellowships (APP1042492 to GWL and APP1002186 to GAH).
Pain duration is associated with increased muscle sympathetic nerve activity in patients with Achilles tendinopathy
- Authors: Jewson, Jacob , Lambert, Elizabeth , Docking, Sean , Storr, Michael , Lambert, Gavin , Gaida, Jamie
- Date: 2017
- Type: Text , Journal article
- Relation: Scandinavian Journal of Medicine & Science in Sports Vol. 27, no. 12 (2017), p. 1942-1949
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- Description: Tendinopathy is a common condition, which has been linked to surrogate measures of sympathetic nervous system (SNS) activity and insulin resistance. This study aimed to compare in vivo measures of the SNS and insulin resistance between individuals with and without Achilles tendinopathy. This case–control study compared Achilles tendinopathy sufferers to healthy controls. SNS activity was quantified using muscle sympathetic nerve activity (MSNA), while metabolic status was assessed via a modified glucose tolerance test and fasting lipid panel. Ultrasound tissue characterization assessed tendon structure. Resting MSNA did not differ between the 15 cases and 20 controls. Tendon pain duration in tendinopathy patients was correlated with burst frequency (R2=.32, P=.02) and burst incidence (R2=.41, P=.01) of MSNA. After adjusting for multiple comparisons, there was a trend suggesting fasting glucose was greater in cases (median 4.80, IQR .70 in cases vs 4.51, .38 in controls) and correlated with pain severity (R2=.14, P=.03), but no other metabolic measures were associated with tendon pain/structure. This study indicates that SNS activity is associated with tendon pain duration, building on previous data indicating the SNS is involved in recalcitrant tendinopathy. Metabolic parameters had little relationship with Achilles tendinopathy in this metabolically homogenous sample. Prospective studies are required to uncover the precise relationship between SNS activity, insulin resistance, and tendinopathy.
- Description: Tendinopathy is a common condition, which has been linked to surrogate
Pain assessment of the adult sedated and ventilated patients in the intensive care setting : a scoping review
- Authors: Kerbage, Samira , Garvey, Loretta , Lambert, Gavin , Willetts, Georgina
- Date: 2021
- Type: Text , Journal article , Review
- Relation: International Journal of Nursing Studies Vol. 122, no. (2021), p.
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- Description: Background: Pain is frequently encountered in the intensive care setting. Given the impact of pain assessment on patient outcomes and length of hospital stay, studies have been conducted to validate tools, establish guidelines and cast light on practices relating to pain assessment. Objective: To examine the extent, range and nature of the evidence around pain assessment practices in adult patients who cannot self-report pain in the intensive care setting and summarise the findings from a heterogenous body of evidence to aid in the planning and the conduct of future research and management of patient care. The specific patient cohort studied was the sedated/ ventilated patient within the intensive care setting. Design: A scoping review protocol utilised the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping review checklist (PRISMA-ScR). Methods: The review comprised of five phases: identifying the research question, identifying relevant studies, study selection, charting the data and collating, summarizing, and reporting the results. Databases were systematically searched from January to April 2020. Databases included were Scopus, Web of Science, Medline via Ovid, CINAHL COMPLETE via EBSCO host, Health Source and PUBMED. Limits were applied on dates (2000 to current), language (English), subject (human) and age (adult). Key words used were “pain”, “assessment”, “measurement”, “tools”, “instruments”, “practices”, “sedated”, “ventilated”, “adult”. A hand search technique was used to search citations within articles. Database alerts were set to apprise the availability of research articles pertaining to pain assessment practices in the intensive care setting. Results: The review uncovered literature categorised under five general themes: behaviour pain assessment tools, pain assessment guidelines, position statements and quality improvement projects, enablers and barriers to pain assessment, and evidence appertaining to actual practices. Behaviour pain assessment tools are the benchmark for pain assessment of sedated and ventilated patients. The reliability and validity of physiologic parameters to assess pain is yet to be determined. Issues of compliance with pain assessment guidelines and tools exist and impact on practices. In some countries like Australia, there is a dearth of information regarding the prevalence and characteristics of patients receiving analgesia, type of analgesia used, pain assessment practices and the process of recording pain management. In general, pain assessment varies across different intensive care settings and lacks consistency. Conclusion: Research on pain assessment practices requires further investigation to explore the causative mechanisms that contribute to poor compliance with established pain management guidelines. The protocol of this review was registered with Open Science Framework (https://osf.io/25a6) Tweetable abstract: Pain assessment in intensive care settings lacks consistency. New information is needed to understand the causative mechanisms underpinning poor compliance with guidelines. © 2021