Pressure Regulation Research Articles

Ultrasound biomicroscopy analysis of ciliary muscle dynamics and its relation to intra-ocular pressure after phacoemulsification in dogs.

This study investigates the relationship between ciliary muscle dynamics, thickness, and the regulation of intraocular pressure (IOP), focusing on the progression of cataracts and changes post-phacoemulsification. It explores how these factors impact canine ocular health, particularly in the context of cataract development and subsequent surgical intervention. Data was collected using Ultrasound Biomicroscopy (UBM) from dogs at the Veterinary Medical Teaching Hospital of Chungbuk National University, Korea. The study involved 57 eyes from 35 dogs, categorized into five groups: 13 normal eyes, 14 with incipient cataracts, 12 with immature cataracts, 6 with mature cataracts, and 12 post-phacoemulsification. UBM measurements assessed various ciliary muscle parameters including ciliary body axial length (CBAXL), ciliary process-sclera angle (CPSA), longitudinal fibers of ciliary muscle thickness (Lf-CMT), and longitudinal and radial fibers of ciliary muscle thickness (LRf-CMT). Findings indicated a decrease in CBAXL and an increase in Lf-CMT as cataracts progressed in severity. Post-phacoemulsification, there was a notable increase in CBAXL and a decrease in CPSA, Lf-CMT, and LRf-CMT, compared to both cataractous and normal eyes. Regression analysis revealed a significant positive association between CBAXL and IOP, alongside a negative association between Lf-CMT and IOP. These findings suggest that variations in ciliary muscle dynamics and thickness, as influenced by cataract progression and phacoemulsification, have distinct impacts on intraocular pressure. The study proposes that phacoemulsification leads to ciliary muscle contraction, causing an inward and anterior movement of the ciliary muscle. This movement results in the narrowing of the ciliary cleft and constriction of the unconventional outflow pathway, potentially causing an increased risk of glaucoma post-surgery. Our research contributes to understanding the anatomical and physiological changes in the canine eye following cataract surgery and underscores the importance of monitoring IOP and ciliary muscle dynamics in these patients.

Angiotensinergic effect of β-Caryophyllene on Lipopolysaccharide- induced systemic inflammation

Renin-Angiotensin System (RAS) is a peptidergic system, canonically known for its role in blood pressure regulation. Furthermore, a non-canonical RAS regulates pathophysiological phenomena, such as inflammation since it consists of two main axes: the pro-inflammatory renin/(pro)renin receptor ((P)RR) axis, and the anti-inflammatory angiotensin-converting enzyme 2 (ACE2)/Angiotensin-(1–7) (Ang-(1–7))/Mas Receptor (MasR) axis. Few phytochemicals have shown to exert angiotensinergic and anti-inflammatory effects through some of these axes; nevertheless, anti-inflammatory drugs, such as phytocannabinoids have not been studied regarding this subject. Among phytocannabinoids, β-Caryophyllene stands out as a dietary phytocannabinoid with antiphlogistic activity that possess a unique sesquiterpenoid structure. Although its cannabinergic effect has been studied, its angiotensinergic effect reminds underexplored. This study aims to explore the angiotensinergic effect of β-Caryophyllene on inflammation and stress at a systemic level. After intranasal Lipopolysaccharide (LPS) installation and oral treatment with β-Caryophyllene, the concentration and activity of key RAS elements in the serum, such as Renin, ACE2 and Ang-(1–7), along with the stress hormone corticosterone and pro/anti-inflammatory cytokines, were measured in mice serum. The results show that β-Caryophyllene treatment modified RAS levels by increasing Renin and Ang-(1–7), alongside the reduction of pro-inflammatory cytokines and corticosterone levels. These results indicate that β-Caryophyllene exhibits angiotensinergic activity in favor of anti-inflammation.

Screening and rational identification of a novel angiotensin-converting enzyme C-domain inhibitory peptide from Fabaceae food peptide library

Angiotensin-converting enzyme (ACE), consisting of N-domain and C-domain, is a key regulator of blood pressure. The use of cACE-specific inhibitors helps minimize side effects in clinical applications. Legumes are a good source of proteins containing ACE inhibitory peptides; however, no studies have reported the identification of cACE-specific inhibitory peptides from Fabaceae. In this study, thermal hydrolysates from seeds, sprouts, pods, seedlings, and flowers of legumes were analyzed. Flowers of legumes exhibited a C-domain-preference ACE inhibition and anti-hypertensive effect in rats. Screening the legume peptide library identified a novel cACE inhibitory peptide, SJ-1. This study reported the first identification of cACE inhibitory peptide from Fabaceae foods. SJ-1, identified from the legume flowers, interacted with active site residues of cACE, leading to the inhibition of ACE activity, downregulation of bradykinin levels, and reduction of blood pressure. These findings also suggested the potential of legume proteins as a source of cACE inhibitory peptides.

Spatial-Temporal Heterogeneity and Decoupling Mechanism of Resource Curse, Environmental Regulation and Resource Industry Transformation in Post-Development Areas: Evidence from Inner Mongolia, China

Resource curse and environmental regulation are the key bottlenecks that hinder the sustainable development of the resource industry. A reasonable assessment of the decoupling relationship between resource supply, environment regulation and resource industry transformation is helpful to promote the decision-making of industrial restructuring in post-development regions. Taking Inner Mongolia Autonomous Region of China as the research object, panel data related to resources, environment and industry from 2010 to 2021 are selected to evaluate the spatial and temporal evolution of regional resource supply security, environmental regulatory pressure and resource industry transformation efficiency, measure the decoupling index among the factors, and use geographic detector technology to identify the constraints affecting factor decoupling. The results show the following: (1) the resource curse effect of Inner Mongolia is not significant, and some resource industries have prominent advantages; (2) the security of resource supply and the transformation efficiency of the resource industry show overall upward trend, the pressure of environmental regulation is basically balanced, and the development level of factors in resource-endowed regions and central cities is relatively high; (3) the spatial and temporal evolution of the decoupling relationship between resource supply, environmental regulation and resource industry transformation is uncertain, and the resilience of regional economic and social governance is poor; (4) resource endowment and resource industry advantages are the key that restricts the decoupling of factors, and the cumulative effect of ecological governance is likely to lead to the randomness of the decoupling of environmental regulation and resource industry transformation. In addition, this study suggests that the post-development areas should pay attention to the classification of resource industry relief, trans-regional economic and social collaborative governance and special resources exploitation.

Regulatory or market pressures: What promotes environmental grandstanding in Bangladesh?

Many factors affect the adoption of the mandatory technology of effluent treatment plants for pollution management in Bangladesh. Some of these factors could also affect the adoption of voluntary environmental standards. Therefore, it is important to identify and analyze the importance of these key factors, considering their role in enhancing environmental performance in crucial industries for the country's economy. In this study, a literature review preceded an analysis of factors through structural equation modelling to investigate how attributes of the regulatory agency combine with market aspects to influence environmental practices such as the adoption of mandatory ETP and voluntary certifications. Using official quarterly data, the results of this study show that access to green finance and the number of employees of the regulatory agency significantly affect the adoption of additional ETPs. On the other hand, the size of fines for pollution does not significantly affect the adoption of ETPs. It was also found that green finance and additional ETP adoption also increased the adoption of green factory buildings, which is a voluntary exercise. This study sheds light on the underlying relationships that can guide ongoing multilateral interventions to enhance capacity of regulatory agencies to implement environmental regulations. It also provides new evidence to formulate relevant strategies for enhancing environmental performance by scaling up green finance.

PHARMACEUTICAL INDUSTRY ANALYSIS: A COMPREHENSIVE REVIEW OF MARKET TRENDS, COMPETITIVE LANDSCAPE, AND FUTURE OUTLOOK

The pharmaceutical industry, a cornerstone of modern healthcare, undergoes constant evolution to meet the dynamic demands of the healthcare landscape. This comprehensive review delves into the multifaceted dimensions of the industry, encompassing market trends, competitive dynamics, and future projections. Market trends reveal a shift towards personalized medicine, leveraging advancements in genomics and biotechnology, alongside a growing focus on specialty drugs catering to niche patient populations. The prevalence of chronic diseases and an aging populace accentuate the necessity for innovative therapies, while the digital revolution introduces new paradigms in patient care and drug development, propelled by telemedicine, digital therapeutics, and artificial intelligence. Simultaneously, regulatory pressures and pricing constraints exert significant influence, necessitating adaptability among industry players. In the competitive landscape, established pharmaceutical giants vie for market dominance amidst patent expirations and generic competition, while biotech startups and niche players disrupt traditional models. Mergers and acquisitions serve as strategic imperatives for pipeline fortification and market expansion. Looking forward, the industry must navigate a terrain characterized by rapid technological advancements, evolving patient needs, and regulatory complexities, all while striving for innovation, accessibility, and sustainability in the delivery of healthcare solutions. Keywords: Pharmaceutical industry, healthcare landscape, market trends, personalized medicine, specialty drugs, chronic diseases.

Mechanisms of norepinephrine induced calcium responses in perivascular adipocytes

Perivascular adipose tissue (PVAT) has emerged as a key regulator of vascular tone and blood pressure making it an intriguing avenue for research related to pervasive aliments such as high blood pressure. PVAT surrounds the majority of blood vessels where it releases anticontractile factors such as nitric oxide, hydrogen sulfide, adiponectin, and leptin. The production of these anticontractile factors is driven by the sympathetic neurotransmitter norepinephrine (NE), but there is little known about mechanisms which mediate the NE response in PVAT. Based on the known role of beta adrenergic receptors in other fat depots, we hypothesized that NE primarily acts on beta II and III adrenergic receptors. Adiponectin cre positive transgenic mice genetically encoded with calcium indicators were used for live calcium imaging. The peaks of the NE response before and after the receptor antagonists were applied by comparing the change in fluorescence. The beta receptor antagonist, SR 59230A, was used at 6.5μM to block both beta II and III receptors. In addition, the A1a antagonist RS 100329 at 1μM was used to block alpha receptors present. Both antagonists were chosen because they have previously used in the literature successfully at these concentrations. The beta II and beta III antagonist significantly decreased the calcium response in the mesenteric PVAT (p=<0.0001) by 33% and a 27% significant decrease in the subcutaneous fat pad (p=). The alpha 1a antagonist significantly decreased the calcium response in the mesenteric PVAT (p=<0.0001) by 59%, as well as an 86% significant decrease in the subcutaneous fat pad (p=<0.0001), and a 60% significant decrease in the aortic PVAT (p=<0.0001). The combination of both antagonists significantly decreased the calcium response in the mesenteric PVAT (p=<0.0001) by 33%, as well as 46% in the subcutaneous fat pad (p=<0.0001), and 37% decrease in the aortic PVAT (p=0.0354). Both beta and alpha adrenergic receptors are present in mesenteric PVAT and subcutaneous fat, while primarily alpha adrenergic receptors are present in aortic PVAT. These observations suggest the mechanisms responsible for NE induced calcium responses are tissue dependent. HL152951. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Role of Renal Medullary Bilirubin and Biliverdin Reductase in Ang II Induced Hypertension

Previous studies have demonstrated the importance of renal medullary heme oxygenase-1 (HO-1) in blood pressure response to angiotensin II. However, the role of the HO metabolite, bilirubin, in this response remains unknown. The goal of the present study was to test the hypothesis that generation of bilirubin in the renal medulla plays an important role in the regulation of blood pressure in response to angiotensin II. Twenty-week-old male C57Bl/6J mice were implanted with intrarenal medullary interstitial (IRMI) catheters following unilateral nephrectomy. After this time, biliverdin IXα was specifically infused into the kidney (3.6 mg/day) for 3 days prior to implantation with an osmotic minipump delivering angiotensin II (1000 ng/kg/min). Blood pressure was recorded for 3 days, 1 week after minipump infusion, in conscious mice. IRMI infusion of biliverdin significantly decreased blood pressure as compared to mice infused with vehicle (118 ± 4 vs. 158 ± 2 mmHg, p<0.05). To further explore the antihypertensive role of renal medullary bilirubin generation, mice with specific deletion of biliverdin reductase-A (BVRA) in the thick ascending loop of Henle (TALH) were generated by crossing BVRAflox/flox mice with Tamm-Horsfall Cre (THP-Cre) mice. THP-Cre/BVRAflox/flox mice exhibited specific deletion of BVRA in the TALH by co-immunostaining with endogenous THP protein. THP-Cre/BVRAflox/flox mice did not exhibit any differences in baseline blood pressure as compared to BVRAflox/flox mice (108 ± 2 vs. 108 ± 2 mmHg). However, angiotensin-II infusion resulted in significantly higher blood pressure measured in conscious mice 7 days after implantation in THP-Cre/BVRAflox/flox as compared to BVRAflox/flox mice (152 ± 2 vs. 140 ± 3 mmHg, p<0.05). These results demonstrate an important role for renal medullary bilirubin and biliverdin reductase in the blood pressure response to angiotensin II. Strategies which increase renal medullary bilirubin/biliverdin reductase levels could be novel antihypertensive therapies. Future studies will examine the mechanistic link between bilirubin and electrolyte transporters in the kidney, specifically, the Na+-K+-2Cl2 cotransporter (NKCC2), which is a major transporter of electrolyte in the thick ascending limb and is known to play a role in Ang II-induced hypertension. This work was supported by National Institutes of Health grants (RO1-HL088421 to DS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Role of Endothelial Nrf2 in the Regulation of Vasomotor Capacity and Arterial Blood Pressure

Introduction: Hypertension is a serious global public health issue. It is a complex disease with multiple factors contributing to its pathophysiology. One of these factors is oxidative stress, which results from an imbalance between the production and elimination of reactive oxygen species (ROS). Studies have shown that an increased ROS in endothelial cells (EC) impairs the vasodilatory capacity of blood vessels that contributes to blood pressure elevation. However, the modulation of endothelial ROS in the setting of hypertension is still not completely understood. To maintain cellular homeostasis, antioxidant enzymes continually adjust ROS levels under the orchestrating of transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of endogenous antioxidant responses. Modulation of endothelial Nrf2 expression may be a potential therapeutic option in hypertension. Therefore, the major objective of this study was to evaluate the role of Nrf2 in the modulation of endothelium associated vascular function and how it regulates vascular tone and blood pressure (BP). Methods: BP was measured in the conscious state using radiotelemetry transducers implanted into EC-specific Nrf2-knockout mice (Tie2-Cre-Nrf2 Floxed), EC specific Keap1 knockout mice (Tie2-Cre-Keap1 Floxed) and Wildtype (WT), all on the C57B6J background. After baseline BP recordings, mice were implanted with subcutaneous osmotic minipumps (7 days) for Angiotensin II (Ang II) (600ng/Kg/min) infusion or in a separate group L-nitroarginine methyl ester (L-NAME) (100 mg/kg/d in drinking water) for 2 weeks. For each intervention, recordings were done daily for 2 hours and one 24-hour measurement was done once per week. Endothelial specific downregulation or upregulation of Nrf2 was confirmed by immunohistochemistry on mouse aortic tissue and protein expression from mouse EC. For in-vitro studies: femoral-to-popliteal artery segments were harvested from mice of each genotype. Vasodilation was assessed in response to flow (30 uL·min−1) and acetylcholine (ACh, 10−7-10−3 M) with and without L-NAME, using video microscopy. Results: Ang II infusion significantly increased the mean arterial pressure (MAP) in each group when compared to their baseline values (Baseline: Nrf2KO = 92.6 ± 3.1, Keap1KO = 93.8 ± 4.1 and WT = 92.8 ± 1.7 mmHg; after Ang II Nrf2KO = 141.7 ± 3.8, Keap1KO = 121.9±5.4 and WT = 120.4±5.4 mmHg). The response to ANG II was significantly (p<0.05) augmented in Nrf2KO mice and stayed elevated for a longer period after emptying of the pump. The response to L-NAME was similar in both Nrf2KO and WT mice. Protein expression of Nrf2 was decreased in Nrf2KO mice in comparison to WT mice. Nrf2KO mice exhibited reduced endothelium-dependent vasodilation induced by flow (WT: 35.8± 1.3%, Nrf2KO: 24.1 ±1.7%; p<0.0001) and ACh (10−3M) (WT: 60.4±4.1%, Nrf2KO: 44.7± 2.1%; p<0.0001) compared to WT. In contrast, endothelial dependent vasodilatory responses to flow and Ach were markedly elevated in Keap1KO mice (51.3± 6.8%, p<0.0001; 71.6±11.6%, p<0.0087, respectively) compared to both WT and Nrf2KO mice. Conclusion: These results suggest that antioxidant defense mediated by Nrf2 in the endothelium plays a significant role in the modulation of blood pressure and vascular tone. Based on the L-NAME data, these effects are most likely due to an increase in the nitric oxide bioavailability and reduced ROS. University of Nebraska Theodore Hubbard foundation. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

On the Regulation of Arterial Blood Pressure by an Intracranial Baroreceptor

Introduction: There is significant evidence for the existence of an intracranial baroreceptor mechanism(s) capable of sensing physiological changes in cerebral blood flow (Marina et al., 2020). However, little is known about the sensitivity of this mechanism to changes in brain perfusion and its interaction with inputs from the peripheral (arterial) baroreceptors. The aim of this study was to characterise the cardiovascular responses to physiological changes in cerebral perfusion induced by experimental manipulations of intracranial pressure (ICP). Methods: The experiments were performed in adult Sprague-Dawley rats (250–300 g), anesthetized with urethane (induction: 1.3 g kg−1, i.p.; maintenance: 10–25 mg kg−1 h−1, i.v.). The femoral artery and vein were cannulated for measurement of arterial blood pressure (ABP) and administration of anaesthetic. The trachea was cannulated, and the animal was mechanically ventilated. The lateral cerebral ventricles were cannulated and connected via saline-filled catheters to a pressure transducer to record ICP and to a “water column” to allow controlled manipulation of ICP. The experiments included the denervation of the arterial baroceptors, stimulation of the aortic depressor nerve and recording of renal sympathetic nerve activity. Results: The resting ICP in rats anesthetized with urethane was 6.2 ± 0.7 mmHg (n=8). Following a small craniotomy that reduced ICP to 0 mmHg, ABP decreased by 11.2 mmHg (n=6) within 30 min. Restoring the integrity of the intracranial space increased ABP to the baseline level. Progressive increases in ABP were observed in response to experimentally-induced increases in ICP by 5, 10, 15 and 20 mmHg, revealing a linear relationship between ICP and systemic arterial pressure within the physiological range of ICP changes. In the absence of inputs from the arterial baroceptors (bilateral sino-aortic denervation and vagotomy) the ABP responses to ICP increases were preserved. Analysis of the ABP and heart rate responses to the electrical stimulation of the aortic depressor nerve suggested baroreflex re-setting at raised ICP. Renal nerve recordings demonstrated increased sympathetic activity at raised ICP (172 ± 34.91 % at 20 mmHg ICP (p=0.003; n=7) with markedly enhanced bursts of activity during the inspiratory phase of the respiratory cycle. Conclusion: These data demonstrate that the intracranial baroceptor mechanism is highly sensitive to changes in cerebral perfusion within the physiological range and suggest that cerebral blood flow is an important determinant of systemic ABP. The data suggest that at raised ICP the baroreflex control of sympathetic vasomotor activity is reset and provides effective control of arterial blood pressure at a higher level required to compensate for reduced brain perfusion. Marina, N., Christie, I.N., Korsak, A., Doronin, M., Brazhe, A., Hosford, P.S., Wells, J.A., Sheikhbahaei, S., Humoud, I., Paton, J.F. and Lythgoe, M.F., 2020. Astrocytes monitor cerebral perfusion and control systemic circulation to maintain brain blood flow. Nature Communications, 11(1), 131. This PhD Studentship is funded by the British Heart Foundation. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Mitochondrial AKAP1 Is Necessary for Obesity- and Angiotensin II-induced Hypertension

Best known as the powerhouse of the cell, mitochondria play a crucial role in obesity and associated cardiovascular diseases. A-kinase anchoring protein 1 (AKAP1) is a mitochondrial scaffold protein that regulates mitochondria function by promoting protein kinase A (PKA)-mediated phosphorylation of Dynamin-related protein 1 at Ser637 through recruitment of PKA to the outer mitochondrial membrane. However, the role of mitochondrial AKAP1 in the regulation of blood pressure and the development of hypertension is not known. Here, we used mice harboring the Akap1 gene deletion to investigate the importance of AKAP1 in obesity- and angiotensin II (Ang II)-induced hypertension. AKAP1−/− mice and wild type (WT) littermates were maintained on a high fat high sucrose diet (HFHSD) for 12 weeks starting from 4 weeks of age. Interestingly, AKAP1−/− mice fed HFHSD displayed significantly attenuated weight gain compared to control mice fed HFHSD (male: 39.5 ± 1.7 vs 47.3 ± 2.3 g, and female: 29.7 ± 1.3 vs 32.5 ± 1.5 g, p<0.05 for both). This was associated with decreased fat mass in AKAP1−/− mice-fed HFHSD (male:16.2 ± 0.9 g and female: 8.7 ± 1.1 g) compared to controls (male: 21.2 ± 1.7 g and female: 13.9 ± 1.6 g, p<0.05 for both). Transmission electron microscope analysis of neuronal mitochondrial in the accurate nucleus of the hypothalamus showed that AKAP1−/− mice fed HFHSD have remarkably reduced mitochondria size (0.14 ± 0.05 vs 0.20 ± 0.07 μm2, p<0.05) and mitochondria length (0.57 ± 0.10 vs 0.50 ± 0.10 μm, p<0.05) relative to controls. Next, using the radio-telemetry system, we found that blood pressure was lower in AKAP1−/− male mice fed HFHSD compared to WT mice fed HFHSD (systolic: 118.2 ± 3.2 mmHg vs 126.7 ± 4.3 mmHg, p = 0.05, n= 5WT and 6 AKAP1−/−). Furthermore, infusion of Ang II (600ng/kg/min for 14 days) via osmotic minipumps in normal chow-fed male mice tended to evoke less increase in mean blood pressure in AKAP1−/− mice compared to WT controls (35.2 ± 3.5 vs 45.7 ± 10.1 mmHg, n=3). Taken together, our findings point to the importance of mitochondrial AKAP1 for the development of hypertension induced by obesity and Ang II. Veterans Affairs NIH. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Deletion of AT1a Receptors Selectively in Renomedullary Interstitial Cells Attenuates Basal, Angiotensin II-, or Vasopressin-induced Vasoactive Factors' mRNA Expression in The Mouse Kidney Medulla

We recently shown that deletion of the vasoactive peptide angiotensin II (Ang II) AT1a receptors selectively in renomedullary interstitial cells (RMICs) of the kidney medulla significantly lowered basal blood pressure and impaired urine concentration in mice. However, the underlying signaling mechanisms involved remains poorly understood. In the present study, AT1a receptors were selectively deleted in the RMICs of the mouse kidney medulla using tamoxifen-inducible Tenascin-C-CreER2/Agtr1af/f approach. Three groups of adult male wild-type (WT) and RMIC- Agtr1a−/− mice (n=6-10) were pretreated with or without tamoxifen (150 mg/kg, i.p., for 5 days) before Ang II was infused to induce Ang II-dependent hypertension (~0.75 mg/kg/day, i.p., for 2 weeks). Systolic, diastolic, and mean arterial blood pressure and urine osmolality were determined before and after Ang II treatment. At the end of the experiment, the kidneys were harvested, and the inner and outer medulla were dissected out for the measurement of the mRNA expression of key vasoactive factors that are associated with the regulation of blood pressure and urine concentration using digital droplet PCR. Deletion of AT1a receptors in RMICs significantly decreased AT1a receptor mRNA expression by 41% (WT: 554 ± 49 vs. RMIC- Agtr1a−/−: 327 ± 10 copies/ng RNA; P<0.01) and bradykinin B2 receptor mRNA expression by 52% (WT: 10.10 ± 0.75 vs. RMIC- Agtr1a−/−: 4.90 ± 0.56 copies/ng RNA; P<0.01), without altering the expression of endothelin ETB (WT: 466 ± 21 vs. RMIC- Agtr1a−/−: 393 ± 24 copies/ng RNA; n.s.) and vasopressin V2 receptor mRNAs in the kidney medulla (WT: 580 ± 60 vs. RMIC- Agtr1a−/−: 586 ± 61 copies/ng RNA; n.s.). Deletion of AT1a receptors in RMICs also significantly decreased the expression of eNOS (WT: 87.0 ± 3.0 vs. RMIC- Agtr1a−/−: 61.2 ± 2.8 copies/ng RNA; P<0.01) and aquaporin 2 (AQP2) mRNAs (WT: 12463 ± 2015 vs. RMIC- Agtr1a−/−: 6613 ± 692 copies/ng RNA; P<0.01). Interestingly, deletion of AT1a receptors in RMICs did not alter the mRNA expression of cyclooxygenase-2 (COX-2, n.s.), prostaglandin E2 (PGE2, n.s.), epithelial sodium channel (ENaC, n.s.) or prorenin receptors (PRR, n.s.) in the kidney medulla. In response to Ang II infusion, deletion of AT1a receptors in RMICs significantly attenuated Ang II-induced expression of bradykinin B2 receptors, COX-2, eNOS, and AQP2 mRNAs ( P<0.01), respectively. Furthermore, deletion of AT1a receptors in RMICs also significantly attenuated vasopressin-induced bradykinin B2 receptor, eNOS, and AQP2 mRNA expression in the kidney medulla ( P<0.01). We concluded that AT1a receptors in RMICs in the kidney medulla play an important role in maintaining physiological blood pressure homeostasis and urine concentration process likely via AT1a receptor/bradykinin B2 receptor/eNOS/AQP2-mediated signaling pathways. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Exploring the relationship between gut microbiome modulation and blood pressure in type 2 diabetes: An umbrella review

AimsGiven the epidemic proportions of type 2 diabetes mellitus (T2DM) globally, it's crucial to comprehensively understand the factors influencing its management. The gut microbiome, known for its influence on various aspects of health, has emerged as a potential regulator of blood pressure in individuals with T2DM. This umbrella review aimed to consolidate the findings of existing meta-analyses investigating the impact of gut microbiome modulation on systolic and diastolic blood pressure in T2DM patients. Data synthesisAdhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, we systematically searched PubMed, Scopus, and Web of Science databases from inception to July 2023. Quality assessment was performed using the AMSTAR2 and GRADE checklists. Statistical analyses were conducted using Comprehensive Meta-Analysis (CMA) version 3. A total of 6 meta-analyses meeting the inclusion criteria were included. The results revealed a significant association between microbial modulation and diastolic blood pressure (SMD: −0.133; 95% CI: −0.219 to −0.048; P = 0.002). However, the effect of gut microbial modulation on systolic blood pressure did not reach statistical significance (SMD: −0.077; 95% CI: −0.162 to 0.009; P = 0.078). ConclusionThis study found that modulating the gut microbiome had a statistically significant impact on diastolic blood pressure in individuals with type 2 diabetes mellitus (T2DM). However, no significant effect was observed on systolic blood pressure. While high-quality meta-analyses reported favorable outcomes, caution is warranted due to the low clinical importance, diversity in study populations, and variations in interventions.

Deletion of Kcnj16 altered transcriptomic and metabolomic profiles of Dahl salt-sensitive rats

The essential role of inwardly rectifying K+ Channel Kir5.1 (encoded by the Kcnj16 gene) in renal salt handling and blood pressure control has been demonstrated in both human and animal models. However, the underlying mechanisms are still not fully understood. Here, we aimed to integrate transcriptomics and metabolomics to profile the comprehensive changes of genes and metabolites under the deletion of Kcnj16 in the Dahl salt-sensitive (SS) rat background to identify novel mechanisms. For the transcriptomics profiling, we performed RNA-sequencing on kidney cortex tissue of Kcnj16 knockout (KO) and wild-type (WT) SS rats (N=5 per group). For the metabolomics profiling, we performed untargeted metabolomics of kidney cortex tissue, plasma, and urine of KO (N=6) and WT (N=5) rats. Transcriptomics analysis revealed over 6,000 differentially expressed genes in KO rats compared to WT rats, with renin Ren (the gene encoding renin) being the most upregulated gene. Consistent with the phenotype observed in the KO rats, ingenuity pathway analysis (IPA) based on the transcriptomic profile predicted reduced blood pressure and kidney damage and increased ion transport. Canonical pathway analysis suggested activation of metabolic-related pathways [e.g., xenobiotic metabolism, tricarboxylic acid (TCA) cycle, phenylalanine degradation, etc.] and suppression of immune responses-related pathways [e.g., pathogen-induced cytokine storm signaling pathway, macrophage classical activation signaling pathway, nuclear factor of activated T cells (NFAT) pathway, etc.] in KO rats. Untargeted metabolomic analysis suggested distinct metabolic profiles of plasma, urine, and kidneys between WT and KO rats, with 219, 790, and 31 differentially expressed metabolites identified in plasma, urine, and kidney in KO rats compared to WT rats. Canonical pathway analysis identified spermine and spermidine degradation pathways in both plasma and urine and taurine biosynthesis pathways in both urine and kidney. Integration analysis based on transcriptomic and metabolomic profiles suggested an altered TCA cycle, amino acid, and reactive oxygen species metabolism. In conclusion, besides significantly altered ion transport, our transcriptomics and metabolomics data suggest significant suppressed immune responses-related and altered metabolic-related pathways in SS rats lacking Kir5.1, which provides new insights into the underlying mechanisms of the regulation of blood pressure and renal function by Kir5.1. This work is supported by National Institutes of Health Grants R35 HL135749 and R01 DK135644 (to A.S.), Department of Veteran Affairs grant I01 BX004024 (to A.S.), the American Physiological Society Postdoctoral Fellowship (to B.X.) and the American Society of Nephrology Dimitrios G. Oreopoulos Research Fellowship Award (to L.V.D.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Signaling switches maintain intercellular communication in the vascular endothelium

The endothelium is a sophisticated coordination center that controls a wide range of vascular functions, which include the regulation of blood pressure and blood flow via changes in vascular contractility. To coordinate vascular function, cell communication and interactions are required for tissue level responses to emerge. A significant form of cell-cell communication occurs by the propagation of Ca2+ signals between cells (‘Ca2+ waves’). The objective of our study was to tease apart the mechanisms driving these intercellular Ca2+ waves in the vascular endothelium. We hypothesised that diffusion of free Ca2+ would drive endothelial Ca2+ wave propagation and effect vessel diameter changes. To investigate the mechanisms, intact mesenteric arteries from male Sprague Dawley rats were mounted in an en face preparation, stained with the Ca2+ indicator Cal-520/AM and were imaged on specialised epifluorescence microscopes. Intercellular endothelial signaling was manipulated using caged compounds in concert with precise spatial and temporal control of UV illumination, as well as global or localized drug application. We show that multiple mechanisms maintain communication so that Ca2+ wave propagation occurs irrespective of the status of cell connectivity. Contrary to our hypothesis, regenerative IP3-induced IP3 production transmits Ca2+ signals between adjoining cells and explains the propagated vasodilation that underlies the increased blood flow accompanying tissue activity. By controlling the production of IP3, the inositide is itself suffcient to evoke a regenerative phospholipase C-dependent Ca2+ wave across coupled cells. None of gap junctions, Ca2+ diffusion nor the release of extracellular messengers are required to support this type of intercellular Ca2+ signaling. Surprisingly, when a discontinuity between cells was created using a fire-polished pipette tip, signal was propagated to the other side of the discontinuity and was able to drive propagated vasodilation. Experiments using counter flow and localised perfusion in the absence and presence of P2Y inhibitors revealed that it is ATP released as a diffusible extracellular messenger that transmits Ca2+ signals across endothelial discontinuities. These results show that signaling switches underlie endothelial cell-cell signal transmission, and reveal how communication is maintained in the face of endothelial damage. The findings provide a new framework for understanding Ca2+ wave propagation and cell-cell signaling in the endothelium. This work was funded by the British Heart Foundation (RG/F/20/110007; PG/20/9/34859 ). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Gut bacteria contribute to rodent hypertension via modulation of colonic serotonin and gut vagal 5ht3aRs

Hypertension is associated with gut dysbiosis and autonomic dysfunction in humans and rodent models. While hypertension-associated gut dysbiosis elevates blood pressure in rodents, the precise mechanisms are unknown. In our model gut dysbiosis-induced hypertension, fecal matter transplant from hypertensive SHR reduced colonic serotonin and relative expression of serotonergic 5ht3a receptors (5ht3aRs) on vagal afferents in the control WKY rats. To investigate the role of serotonergic gut vagal axis in regulation of blood pressure, in a cre-dependent manner we first overexpressed channelrhodopsin 2 in the 5ht3aR-expressing gut-projecting vagal afferents (NG5ht3Ar) in 5ht3aR Cre rats. Acute bilateral optic stimulation of NG5ht3Ar produced an immediate decrease in blood pressure and heart rate. Conversely, chronic ablation of NG5ht3Ar by cre-dependent expression of caspase elevated blood pressure in 5ht3aR Cre rats. This effect was potentiated both by the infusion of low dose of angiotensin II and exposure to acute restraint stress separately. On the other hand, overexpression of 5ht3aRs in NG5ht3Ar reduced blood pressure in the SHR, the effect that was further potentiated by dietary tryptophan supplementation. Altogether, these data propose that hypertension-associated microbiota contribute to rodent hypertension via modulation of colonic serotonin and gut vagal 5ht3aRs. NIHR01HL152162. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Older versus Younger Females Matched for Body Composition Have Lower Sympathetic Transduction at Rest

BACKGROUND: Older female (OF) adults have the highest risk for hypertension and cardiovascular disease among any demographic in America. Therefore, there is a need to better understand the contributors to impaired blood pressure (BP) regulation in female aging. Bursts of spontaneously occurring muscle sympathetic nerve activity (MSNA) contribute to BP regulation on a beat-to-beat basis (i.e., sympathetic transduction). Previous work suggests that OF have attenuated resting sympathetic transduction but there is a need for additional work considering covariates that affect sympathetic transduction (e.g., body mass index (BMI) & sodium intake). We tested the hypothesis that aging attenuates sympathetic transduction in OF (>55 years) compared with young female (YF; 18-35 years) participants matched for body composition and pre-trial sodium intake. METHODS: We studied seven post-menopausal OF (65±6 years) and nine YF (24±4 years; tested in early follicular phase) participants with seated brachial BP <140/90 mmHg after three days of specified sodium intake (target 2300mg/day). We measured mean BP (photoplethysmography) and MSNA (microneurography) during a 10-min rest period in the supine position. We also assessed BMI, body fat % (BF%; bioelectrical impedance), and habitual moderate-to-vigorous physical activity (MVPA) during ≥7 consecutive days using waist-worn accelerometers (ActiGraph). We compared the average change in BP for 10 cardiac cycles after an MSNA burst (i.e., signal-averaged sympathetic transduction) using mixed-effects models (group*time[repeated measure]). We compared other variables using unpaired, two-tailed t-tests for normally distributed data and Mann-Whitney U tests for non-normally distributed data (i.e., failed Shapiro-Wilk test). We compared sodium intake, BMI, BF% and MVPA using equivalence testing. Significance was set to α<0.05. RESULTS: Sodium intake, BMI, BF% and MVPA were equivalent between groups (p>0.06). The following data are presented as OF vs. YF with mean ± SD or median[IQR]. Mean BP (97[22] vs. 77[5] mmHg, p=0.008) and MSNA burst frequency (35±6 vs. 13±4 bursts/min, p<0.0001) were higher in OF. OF had lower mean BP changes following MSNA bursts (time: p<0.0001, group: p=0.013, interaction: p=0.026) with pairwise differences among cardiac cycles 4-10 (post hoc p-values: p≤0.012). Moreover, peak increases in mean BP following MSNA bursts were lower in OF (Δ1.9±0.4 vs. 4.9±2.2 mmHg, p=0.003). CONCLUSION: We found that OF have attenuated sympathetic transduction to BP when compared to YF matched for body composition and sodium intake. This extends past work suggesting that female aging is associated with attenuated sympathetic transduction to BP. National Institutes of Health K01HL160772 (JCW), American Heart Association 23CDA1037938 (JCW), & Florida State University Graduate School Legacy Fellowship, 2023 (CD). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Incorporating sustainability into product lifecycle management: a systematic literature review

AbstractAmidst environmental, regulatory, and societal pressures, integrating sustainability into Product Lifecycle Management (PLM) is key, evolving into Sustainable PLM (sPLM). This paper uses a systematic literature review and text-mining (C-value method) to categorise sPLM research into clusters, assess their integration at organisational levels, and evaluate the level's maturity. Findings highlight a gap in operational sPLM research. Future studies should bridge the gap between theory and industrial application, enhance sPLM operationalisation, and explore emerging technologies’ impact on sPLM.

Overexpression of Regulator of G-Protein Signaling 2 in the Paraventricular Nucleus Reduces Blood Pressure in Spontaneously Hypertensive Rats

The hypothalamic paraventricular nucleus (PVN) is important in mediating sympathetic activity to regulate blood pressure. The regulator of G protein signaling 2 (RGS2) is a negative G protein regulator. RGS2 selectively regulates Gαq signaling, an important cause of hypertension and cardiac hypertrophy. However, little-to-no studies are being done related to G-protein-RGS2 signaling on the central mechanisms of blood pressure control and sympathetic activation. In this study, we use spontaneously hypertensive rats (SHR) to aim for the pressor effects of central viral transfection over-expressing RGS2 in the PVN compared to a Wistar-Kyoto (WKY) control. These rats were outfitted with telemetry and measurements of blood pressure and heart rate over the next 14 days, with or without RGS2 adenovirus (AV) injection into the PVN. Metabolic experiments were conducted at the 7-day mark to examine kidney function, sodium excretion, urine output, and water and food intake. We saw significant ( p<0.05) decreases in blood pressure for the SHR with AV-RGS2 throughout our telemetry experiment. In our metabolic experiments, sodium excretion significantly ( p<0.05) increased in the SHR group with AV-RGS2 compared to the SHR with AV-GFP. Water intake, food intake, and urine output remained unchanged. Following this experiment, we gave capsaicin injections into the renal pelvis at 5, 10, and 20 μM to measure blood pressure and heart rate responses. Also, blood pressure responses to renal pelvis capsaicin injection appear to be attenuated in SHR and WKY rats with AV-RGS2 injection but was not significant ( p>0.05). In addition, we conducted real-time qPCR on collected PVN tissue to evaluate gene expression changes over time. We saw expression peak at 3-days in G⍺q, G⍺s, G⍺i, and RGS2, and progressively decrease as time progressed. This study provides a value insight of central mechanisms related to G-protein-RGS2 signaling on blood pressure regulation. This study was funded by NIH R01-DK-129311 and USD G-RISE, NIH T32GM-136503. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Knockout of the V-ATPase Interacting Protein Tldc2 Inhibits Renal B-Intercalated Cell Function and Urine Alkalinization

The V-ATPase, or proton pump, generates electrochemical gradients across membranes driving cell biological processes. The kidney-specific V-ATPase is expressed in intercalated cells (ICs), which regulate acid-base homeostasis by adjusting plasma membrane V-ATPase via regulated traffcking. In the kidney, A-ICs transport protons into the tubule lumen while B-ICs move protons into the peritubular space and, ultimately, the blood. The V-ATPase is distributed between intracellular vesicles and the apical plasma membrane in A-ICs, whereas B-ICs express V-ATPase not only in intracellular vesicles, but also basolaterally. In general, V-ATPase dysfunction in ICs leads to distal renal tubular acidosis (dRTA) implying a functional dominance of A-IC in acid/base physiology. B-ICs have, however, been implicated in blood pressure regulation due to their role in chloride reabsorption and, indirectly, Na transport. We recently identified a new class of V-ATPase interacting proteins defined by their TLDc domain (Ncoa7, Oxr1, Tbc1d24, Tldc1, Tldc2), all of which interact with the IC-specific B1 subunit of the V-ATPase. Of importance, Ncoa7 knockout mice had decreased V-ATPase expression in ICs and developed dRTA, which led us to hypothesize that TLDc proteins regulate the kidney V-ATPase. While Ncoa7 is specifically expressed in A-ICs, Tldc2 is one of the most differentially expressed proteins in B-ICs, prompting us to ask whether Tldc2 deletion affected V-ATPase function in these cells. Using global Tldc2 knockout mice (KO), we found that urine pH is significantly more acidic in KO mice than in WT mice in both males and females (pH 5.8 in male KOs versus pH 6.4 in male WTs and pH 5.8 in female KOs versus pH 6.2 in female WTs). After an acid challenge with NH4Cl, the urine pH of WT mice was significantly decreased, but urine pH was unchanged in KO mice, since it was already low under baseline conditions (pH 5.8 for male and female WT and KO mice). After base challenging mice with NaHCO3−, urine pH was greatly increased in WT mice (pH 7.8 in male WTs and pH 7.5 in female WTs), while urine pH increased to a lesser, but still significant amount, in KO mice (pH 6.3 in male KOs and 7.2 in female KOs). Interestingly, after the bicarbonate challenge urine pH was significantly lower in KO males versus WT males (pH 6.3 in male KOs versus pH 7.8 in male WTs). In females, urine pH was also lower in KO mice versus WT mice after the base challenge but did not reach statistical significance due to high variability between mice (pH 7.2 in female KOs versus pH 7.5 in female WTs). There was no significant difference in blood pH between Tldc2 KO and Tldc2 WT mice of either sex, with or without treatment, suggesting possible respiratory compensation. The inability of KO mice to alkalinize their urine points to a defect in bicarbonate-secreting B-ICs, in which Tldc2 is specifically expressed. To examine this, localization of the B1 subunit was visualized in B-ICs by immunofluorescence, and membrane accumulation was quantified by line intensity scanning using FIJI. Our preliminary results show that basolateral membrane accumulation of B1 was reduced in KO mice relative to WT mice. In summary, our data suggest that loss of Tldc2 negatively affects B-IC function most likely by impairing basolateral accumulation of the V-ATPase. We conclude that Tldc2 is part of a regulatory mechanism that participates in the accumulation of the V-ATPase holoenzyme at the basolateral surface of B-ICs. Whether this is due to changes in assembly or traffcking of the holoenzyme remains to be determined. NIH/NIDDK R01DK121848. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.