Physiology最新文献

{"title":"Mosaic Loss of Y Chromosome in White Blood Cells: Its Impact on Men's Health.","authors":"Soichi Sano, Mark C Thel, Kenneth Walsh","doi":"10.1152/physiol.00008.2023","DOIUrl":"10.1152/physiol.00008.2023","url":null,"abstract":"<p><p>We present a brief introduction of loss of Y chromosome (LOY) in blood and describe the known risk factors for this condition. We then overview the associations between LOY and age-related disease traits. Finally, we discuss murine models and the potential mechanisms by which LOY contributes to disease.</p>","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"38 4","pages":"0"},"PeriodicalIF":5.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10281780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9705887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic Reprogramming of Endothelial Cell Signaling in Metastasis and Cachexia.","authors":"Stephanie F Preuss,&nbsp;Denise Grieshober,&nbsp;Hellmut G Augustin","doi":"10.1152/physiol.00001.2023","DOIUrl":"https://doi.org/10.1152/physiol.00001.2023","url":null,"abstract":"<p><p>Proliferating cancer cells secrete a multitude of factors impacting metabolism, interorgan communication, and tumor progression. The distribution of tumor-derived factors to distant organs occurs via the circulation, which provides an extensive reactive surface lined by endothelial cells. Primary tumor-derived proteins impact cancer progression by modulating endothelial cell activation at the (pre-)metastatic niche, which affects tumor cell dissemination as well as the outgrowth of seeded metastatic cells into overt tumors. In addition, new insight indicates that endothelial cell signaling contributes to metabolic symptoms of cancer, including cancer-associated cachexia, opening a new field of vascular metabolism research. This review addresses how tumor-derived factors systemically affect endothelial cell signaling and activation and impact distant organs as well as tumor progression.</p>","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"38 4","pages":"0"},"PeriodicalIF":8.4,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10281790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9710402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteinuria observed post-uninephrectomy stems from partial suppression of protein endocytosis along the proximal tubule","authors":"A. Edwards, D. Ralph, Hillmin Lei, Taylor S. Priver, A. McDonough","doi":"10.1152/physiol.2023.38.s1.5728886","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5728886","url":null,"abstract":"Living kidney donors are at higher risk of developing proteinuria, yet few studies have addressed the etiology. To investigate whether post-uninephrectomy (UNX) proteinuria was due to increased filtration and/or reduced endocytosis/reabsorption along the proximal tubule (PT), we compared renal function, morphology, and PT endocytic machinery in male Sprague Dawley rats before and after UNX.At 12 wk post-UNX, the weight of the remnant kidney rose by 50%, PT diameters by 30%, and single nephron GFR by 50% (based on 26% fall in creatinine clearance and 50% decrease in the number of nephrons). Urinary albumin excretion increased 10-fold post-UNX. Since the filtered load of proteins decreases in parallel with GFR post-UNX, increased albumin excretion likely reflects decreased endocytosis along the PT, a notion supported by a 50% reduction in abundance of albumin and plasminogen in renal cortex homogenates from remnant versus explant kidneys. We tested the hypothesis that the protein endocytic machinery was reduced following UNX. Immunoblot assays of renal cortex revealed decreased abundance of megalin and Dab2, two key mediators of protein endocytosis along the PT, and no change in cubilin abundance. Immunohistochemistry confirmed a 50% fall in megalin along the PT apical membrane.Mathematical modeling predicted that albumin uptake per nephron increases post-UNX, owing to higher single nephron GFR and PT hypertrophy, but is attenuated by the decrease in megalin abundance; moreover, modeling predicts that if the endocytic machinery were not partly suppressed, overall albumin excretion would remain at pre-UNX levels.In addition to albumin, urinary plasminogen and angiotensinogen were similarly increased post-UNX, while uromodulin (synthesized and secreted distally) was decreased post-UNX. Urinary biomarkers of renal injury, RBP4 and KIM-1, were increased post-UNX likely reflecting the impact of the increased endocytosis of albumin which can carry bound toxic lipids into the PT.Taken together, our findings suggest that the blunting of albumin endocytosis post-UNX, apparent as increased albuminuria, may serve to protect PT cells from albumin-induced cytotoxicity. DK083785; Keck School of Medicine Dean’s Pilot Funding This is the full abstract presented at the American Physiology Summit 2023 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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"45 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73258203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpha-glucosidase inhibitor mitigates bone loss in type-1 diabetes","authors":"S. Juin, S. Pushpakumar, U. Sen","doi":"10.1152/physiol.2023.38.s1.5734415","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5734415","url":null,"abstract":"Diabetic nephropathy is a hallmark of diabetes mellitus (DM) and is characterized by kidney dysfunction. The kidney plays an important role in bone health by preserving the equilibrium of minerals viz., calcium and phosphate in the blood and 1,25-Dihydoxyvitamin D3 (Calcitriol) production. Previous studies have suggested that renal dysfunction is associated with dysregulated mineral reabsorption due to mineral-hormone imbalance, leading to bone loss and increased fracture risk in DM. Alpha-glucosidase inhibitor (AGI) is known to decelerate carbohydrate catabolism and delay glucose production to improve overall diabetic health. Nimbidiol is an AGI derived from the medicinal plant, Azadirachta indica and is considered a potential anti-diabetic natural compound. The purpose of our present study was to investigate whether AGI mitigates the imbalance of mineral homeostasis and eventual bone loss in type-1 diabetes. Twelve - fourteen weeks old wild-type, C57BL/6J (WT) and type-1 diabetic, C57BL6/‐ Ins2Akita /J (Akita) mice were either treated with saline or AGI (0.40 mg kg-1 d-1) by subcutaneous implantation of micro-osmotic pump for eight weeks. Diabetic Akita mice showed a distinct downregulation of sodium-phosphate co-transporter, Npt2a expression in the renal tubules compared to the WT mice. In addition, Akita mice exhibited a significant increase in alkaline phosphatase activity and decrease in Calcitriol and bone minerals such as calcium and phosphate levels in the blood. The changes were associated with a significant bone loss as evidenced by the increased thinning and porosity of cortical and trabecular bone and reduction of osteoblasts and osteocytes in diabetic femur. AGI treatment mitigated the pathological changes in Akita mice. Taken together, our results suggest that AGI preserves mineral homeostasis and thereby protects from bone loss in type-1 diabetes. DK116591 This is the full abstract presented at the American Physiology Summit 2023 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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"8 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73303902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of scleraxis in angiotensin II-induced cardiac fibrosis","authors":"Sikta Chattopadhyaya, R. Nagalingam, D. Ledingham, M. Czubryt","doi":"10.1152/physiol.2023.38.s1.5725178","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5725178","url":null,"abstract":"Cardiac fibrosis involves the activation and conversion of fibroblasts to myofibroblasts in response to pathophysiological stresses, resulting in structural and functional remodeling of the heart leading to heart failure and death. Although it affects millions of people worldwide, currently no medications are available against cardiac fibrosis. Similar to the pro-fibrotic growth factor TGF-β, angiotensin II (AngII) contributes to cardiac fibrosis, however AngII inhibitors are not used against fibrosis despite growing evidence of efficacy. AngII induces the nuclear translocation of Myocardin Related Transcription Factor-A (MRTF-A) which acts with Serum Response Factor (SRF) to play a major role in the conversion of fibroblasts to myofibroblasts, similar to the transcription factor scleraxis. Scleraxis has been shown by our lab to induce fibrosis by transactivating various pro-fibrotic gene promoters. Here we investigated whether AngII works through an MRTF-A/SRF/scleraxis pathway to induce cardiac fibrosis. AngII delivery (1mg/kg/day for 28 days) through osmotic mini-pumps in C57Bl/6 mice significantly increased blood pressure (systolic, diastolic, and mean) and cardiac hypertrophy compared to saline control group. In the AngII group, cardiac fibrosis was observed with enhanced mRNA expression of pro-fibrotic genes, Col1a1, Col3a1, periostin, and EDA-fibronectin. Interestingly there was a significant increase in scleraxis as well, suggesting its involvement in AngII-mediated fibrosis. Our in vitro studies of rat cardiac fibroblasts treated with AngII showed a significant increase in scleraxis mRNA and protein expression, and scleraxis knockdown significantly attenuated AngII-induced collagen expression, confirming a requirement for scleraxis in the AngII-mediated fibrosis pathway. NIH3T3 cells transfected with MRTF-A and SRF together showed a high level of induction of scleraxis expression. Luciferase assays in both COS7 and NIH3T3 cells showed that MRTF-A and SRF act together to regulate scleraxis expression by binding to and transactivating the scleraxis promoter, indicating that AngII activates a MRTF-A/SRF/scleraxis pathway for inducing cardiac fibrosis, therefore targeting scleraxis may be an effective anti-fibrotic strategy. Canadian Institutes of Health Research Project Grant This is the full abstract presented at the American Physiology Summit 2023 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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"100 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73313088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maximal aerobic capacity is not correlated with microvascular nitric oxide contribution to endothelium- or beta-2-adrenergic receptor-dependent vasodilation in female adults","authors":"Gabrielle A. Dillon, J. Barnes, J. Limberg, S. Ranadive, Sarah Baker, T. Curry, M. Joyner, R. Harvey","doi":"10.1152/physiol.2023.38.s1.5732410","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5732410","url":null,"abstract":"Background: The menopausal transition is characterized by impairments in microvascular endothelium- and β2-adrenergic receptor (β2AR)-dependent vasodilation, both mediated in part by nitric oxide. Greater aerobic capacity is associated with preserved endothelium-dependent vasodilation in middle-aged and older males, but not estrogen-deficient postmenopausal females. However, the association between aerobic capacity and the nitric oxide contribution to endothelium-dependent vasodilation has not been described in pre- or postmenopausal females. Further, the association between aerobic capacity and β2AR-dependent vasodilation in pre- and postmenopausal females remains elusive. Thus, this study tested the hypothesis that maximal aerobic capacity (V̇O2max) and endothelium- and β2AR-dependent vasodilation (and their respective nitric oxide contributions) would be positively correlated in premenopausal, but not estrogen-deficient postmenopausal females. Methods: Ten premenopausal (PRE, 27±3 yrs) and ten postmenopausal (PM, 59±4 yrs) females participated. V̇O2max was determined by a graded exercise test on a cycle ergometer. Brachial arterial catheters were placed for continuous blood pressure measurement and pharmacologic infusions. Forearm blood flow (FBF) was measured (venous occlusion plethysmography) at baseline (saline infusion) and during infusion of an endothelium-dependent vasodilator (acetylcholine: 1, 2, 4, 8 μg/100mL tissue/min) and β2AR agonist (terbutaline: 0.1, 0.5, 1, 2 μg/100mL tissue/min), both with and without a nitric oxide synthase inhibitor co-infusion (L-NG-monomethylarginine [L-NMMA]: 1 mg/min). Forearm vascular conductance (FVC) was calculated as FBF/mean blood pressure×100. Vasodilation was calculated as the area under the FVC dose response curve (AUC). The nitric oxide contributions were calculated as the difference between the AUC of acetylcholine or terbutaline alone and the AUC of the co-infusion with L-NMMA. Statistical analyses included independent t-tests and linear regression analysis. Results: V̇O2max was not different between groups (PRE: 35.4±8.3 vs. PM: 29.1±7.9 ml/kg/min, p=0.15). Endothelial and β2AR vasodilation were greater in pre- compared to postmenopausal females (endothelial: PRE 45±15 vs. PM 17±13 FVC AUC, p&lt;0.01; β2AR: PRE 35±12 vs. PM 18±11 FVC AUC, p&lt;0.01). V̇O2max was not correlated with endothelium-dependent vasodilation or the nitric oxide contribution of endothelium-dependent vasodilation in pre- or postmenopausal females (r=-0.48-0.06, p&gt;0.05 for all). V̇O2max was not correlated with β2AR-dependent vasodilation or the nitric oxide contribution of β2AR-mediated vasodilation in pre- or postmenopausal females (r=-0.27-0.26, p&gt;0.05 for all). Conclusion: In contrast to what has been previously observed in males, maximal aerobic capacity was not correlated with endothelium- or β2AR-dependent microvascular vasodilation ortheir respective nitric oxide contributions in pre- or postmenopausal females. AHA 14PR","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"118 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73512669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRPV4 and mechanosensitive regulation of hemichannel function in ocular nonpigmented ciliary epithelium","authors":"M. Shahidullah, N. Delamere","doi":"10.1152/physiol.2023.38.s1.5730232","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5730232","url":null,"abstract":"Purpose: Previously we reported a mechanosensitive ion channel, TRPV4, along with functional connexin hemichannels on the NPE basolateral surface. In the lens, we have evidence of TRPV4-mediated hemichannel opening as part of a feedback mechanism that enables the lens to sense and respond to swelling. The present study was undertaken to test the hypothesis that TRPV4 and hemichannels might function as a mechanosensor in ocular nonpigmented ciliary epithelium (NPE). Methods: Porcine NPE cells were cultured on either plastic culture plates to study effects of osmotic swelling stretch, or on flexible membranes (Flexcell) to study effects of axial cyclic stretch. ATP release and the uptake of the large molecule propidium iodide (PI) from the bathing medium were taken as indicators of hemichannel opening and determined by luminescence and fluorescence. Results: NPE cells subjected to cyclic stretch for 1-10 min (10%, 0.5 Hz) significantly increased ATP release (CTRL 0.3±0.002 vs Stretch 0.7±0.004, nmoles/mg protein, n=6, p<.0001) into the bathing medium. The same stretch stimulus also increased uptake of large molecule propidium iodide (PI) from the bathing medium (CTRL 1.5±0.09 vs stretch 2.49±0.09, Fl unit/mg protein, n=6, p<0.001). The ATP release and PI uptake responses both were prevented by a TRPV4 antagonist, HC067047 (10 μM) and a connexin blocking peptide, GAP27 (200μm). Cells subjected to a hypoosmotic stimulus (200 mOsm) also displayed a significant increase in PI uptake (CTRL 4.65±0.24 vs Hypo 8.26±0.43 nmoles/mg protein, n=5, p<0.001) and the response was abolished by HC067047. The TRPV4 agonist GSK1016790A (10 nM) markedly increased ATP release (CTRL 0.56±0.03 vs GSK 1.24±0.06 nmoles/mg protein, n=12, p<0.001) and PI uptake (CTRL 1.83±0.05 vs GSK 3.69±0.09 Fl unit/mg protein) in the absence of any swelling or stretch stimulus and both responses were abolished by GAP27. Conclusion: The findings are consistent with TRPV4-dependent connexin hemichannel opening in response to mechanical stretch. The TRPV4-hemichannel mechanism may act as mechanosensor that facilitates release of ATP and other autocrine or paracrine signaling molecules that influence fluid (aqueous humor) secretion by the NPE. This research was funded by an NIH (NEI) grant, R01EY029171. This is the full abstract presented at the American Physiology Summit 2023 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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"47 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73565742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alterations of Mitochondrial Respiratory Function in Isolated Nephron Segments of Dahl Salt-Sensitive Rats in Salt-Induced Hypertension","authors":"R. Dash, Chun Yang, S. Shimada, N. Zheleznova, A. Cowley","doi":"10.1152/physiol.2023.38.s1.5732709","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5732709","url":null,"abstract":"Rationale: Mammalian kidneys actively reabsorb nearly 99% of the glomerular filtrate to maintain body fluid and solute homeostasis which requires a great amount of ATP generation and O2 consumption to meet these demands. A high salt diet increases glomerular filtration of Na+ and places a high metabolic demand on the renal tubules to reabsorb more Na+in order for the organism to maintain Na+ balance. Dahl salt-sensitive (SS) rats which mimic the human condition become hypertensive when fed a high salt diet. They are also known to reabsorb greater amounts of Na+ in the proximal tubules (PT) and medullary thick ascending limbs (mTAL) thereby requiring greater ATP production and O2consumption. We hypothesized that the mitochondrial respiratory function of the PT and mTAL would be altered when SS rats are fed a high salt diet in ways that reduce the ability of the kidney to function efficiency thereby leading to salt-induced hypertension. Method: Agilent Seahorse XF96 Extracellular Flux Analyzer was used to assess mitochondrial respiratory function in freshly bulk isolated PT and mTAL from age-matched SS rats during the development of salt-induced hypertension fed with 0.4% NaCl diet (low salt; LS) or 4.0% NaCl diet (high salt; HS) for 7, 14, and 21 days. The Seahorse “Cell Mito Stress Test Protocol” was slightly modified with a substrate addition step to assess the segment-specific and substrate-dependent tubular O2 consumption rate (OCR) under different perturbations, which was used to determine alterations in different mitochondrial respiratory parameters, including H+ leak and ATP production dependent OCR, in the PT and mTAL during the development of salt-induced hypertension. Results: Renal tubular OCR data show that PT of SS rats preferred to use lactate, glutamine, and palmitate, while mTAL preferred to use glucose, pyruvate, and lactate for ATP production under LS diet condition. HS diet resulted in significantly reduced substrate-induced OCR in PT but increased OCR in mTAL. In addition, HS induced a higher level of OCR in the baseline as well as when oligomycin (an inhibitor of F1F0-ATP synthase) was added to both PT and mTAL suspensions indicating that an increased proton leakage/uncoupling of mitochondria occurs in SS rats during the development of salt-induced hypertension. Conclusion: Our emergent data demonstrated that the mitochondrial respiratory function is differentially altered in the PT and mTAL of SS rats in response to different circulatory substrates during the development of salt-induced hypertension. These changes in metabolism appear to be necessary to meet the increased tubular workloads and need for greater ATP production and O2 utilization in both the PT and mTAL of SS rats. NIH R01-HL151587. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved ","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"96 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73585954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective alpha 1-adrenergic blockade attenuates resting beat-to-beat blood pressure variability in healthy young men","authors":"L. Vianna, Gustavo Rodrigues, M. Daher, A. Teixeira, Igor Fernandes","doi":"10.1152/physiol.2023.38.s1.5732317","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5732317","url":null,"abstract":"Resting beat-to-beat blood pressure variability is a powerful predictor of cardiovascular events and end-organ damage. However, its underlying mechanisms remain incompletely understood. For instance, alterations in beat-to-beat blood pressure variability are thought to be driven by changes in both the reflex control of the autonomic nervous system and peripheral vascular function. To determine the role of peripheral sympathetic vasoconstriction on the beat-to-beat blood pressure variability, beat-to-beat heart rate (HR, by electrocardiography) and blood pressure (finger photoplethysmography) were continuously measured in seven healthy men (22 ± 5 yr) at rest (supine position), with and without (Control) a systemic and selective blockade of alpha 1-adrenergic receptors through the oral administration of Prazosin (1 mg/20 kg of body weight). Stroke volume was estimated from the blood pressure waveform (ModelFlow), permitting the calculation of cardiac output and total peripheral resistance. Two hours post-Prazosin ingestion, blood pressure responses to intravenous bolus infusion of phenylephrine were robustly reduced (-80 ± 15%, P = 0.001), indicating a significant functional blockade of alpha 1-adrenergic receptors. However, all resting hemodynamic variables were unchanged after the oral ingestion of Prazosin. Compared with control, Prazosin significantly reduced the standard deviation of systolic (5.5 ± 0.9 vs. 3.7 ± 0.7 mmHg, P = 0.004), diastolic (3.3 ± 1.0 vs. 2.4 ± 0.6 mmHg, P = 0.05), and mean blood pressure (3.7 ± 0.8 vs. 2.5 ± 0.5 mmHg, P = 0.02), as well as cardiac output (652 ± 251 vs. 428 ± 78 mL/min, P = 0.02) and total peripheral resistance (1.1 ± 0.6 vs. 0.5 ± 0.4 mmHg/L/min, P = 0.03). Similar results were found using different indices of blood pressure variability. Altogether, these findings suggest that peripheral sympathetic vasoconstriction plays a pivotal role in modulating resting beat-to-beat blood pressure variability in healthy young men. National Council for Scientific and Technological Development (CNPq; grant: 307293/2019-0 and 431740/2018-6). This is the full abstract presented at the American Physiology Summit 2023 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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"41 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72700476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optogenetic therapy on cardiac vagal dysfunction-related ventricular arrhythmia in type 2 diabetes","authors":"Wenfeng Hu, H. Tu, M. Wadman, Yulong Li, Dongze Zhang","doi":"10.1152/physiol.2023.38.s1.5727980","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5727980","url":null,"abstract":"Withdrawal of cardiac vagal activity is associated with ventricular arrhythmias-related sudden cardiac death and high mortality in T2DM patients. Although vagal nerve stimulation (VNS) has emerged as a promising therapy for ventricular arrhythmias, VNS-induced off-target side effects due to a lack of organ specificity severely limit its prescription in the clinic. To avoid the limitations of the VNS, we employed an optogenetic technique that combines with a miniaturized bio-optoelectronic implant with genetic targeting strategies to achieve cardiac-specific vagal activation in T2DM rats. We hypothesize that optogenetic activation in cardiac vagal postganglionic (CVP) neurons can restore vagal control of cardiac function, and further reduce susceptibility to ventricular arrhythmias in T2DM. Rat T2DM was induced by a high-fat diet plus streptozotocin injection. AAV-channelrhodopsin-2 (ChR2, 2 μl, 5x1012 vg/ml), an excitatory light-sensitive opsin gene, was in vivo transfected into CVP neurons located in the atrioventricular ganglion (AVG). At three weeks after opsin gene (i.e., AAV-ChR2) transfection, continual optogenetic stimulation in CVP neurons was applied twice daily (10 Hz, 50% duty cycle, 5 mW for 1 hour) by illuminating a LED probe that is controlled and powered wirelessly in conscious rats. Our data from immunofluorescence staining showed that microinjection of AAV-ChR2 into the AVG induced expression of ChR2-mcherry in almost all CVP neurons. Optogenetic activation of CVP neurons resulted in a negative inotropic reaction on the left ventricular systolic pressure in a frequency-dependent manner in anesthetized rats. Data from spectral analysis of heart rate variability demonstrated that optogenetic stimulation gradually restored T2DM-reduced high-frequency power (an index of cardiac vagal activation) from one to three days after optogenetic therapy in vivo, whereas it has no effect on low-frequency power (an index of cardiac sympathetic activation). Additionally, data from 24-hour continuous ECG recording in conscious rats demonstrated that optogenetic stimulation in CVP neurons improved the T2DM-impaired heterogeneity of ventricular electrical activity, which was measured by evaluating ventricular arrhythmia-related ECG parameters at three days after optogenetic therapy in vivo. These data suggested that optogenetic activation in CVP neurons might be an effective intervention against cardiac vagal dysfunction-related ventricular arrhythmias in the T2DM state. This study was supported by the Great Plains IDeA-CTR Pilot Grant (to DZ), NIH-NHLBI (R01HL144146 to YLL), and AHA Career Development Award (851929 to DZ). This is the full abstract presented at the American Physiology Summit 2023 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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"97 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72770361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}