Pflügers Archiv - European Journal of Physiology最新文献_第3页

Renal and cardiac effects of the PDE9 inhibitor BAY 73–6691 in 5/6 nephrectomized rats PDE9 抑制剂 BAY 73-6691 对 5/6 肾切除大鼠肾脏和心脏的影响

Pflügers Archiv - European Journal of Physiology Pub Date : 2024-02-02 DOI: 10.1007/s00424-024-02915-2

Xin Chen, Denis Delić, Yaochen Cao, Zeyu Zhang, Hongwei Wu, Ahmed A. Hasan, Mohamed M. S. Gaballa, Lianghong Yin, Bernhard K. Krämer, Thomas Klein, Xin Shi, Ben He, Linghong Shen, Berthold Hocher

{"title":"Renal and cardiac effects of the PDE9 inhibitor BAY 73–6691 in 5/6 nephrectomized rats","authors":"Xin Chen, Denis Delić, Yaochen Cao, Zeyu Zhang, Hongwei Wu, Ahmed A. Hasan, Mohamed M. S. Gaballa, Lianghong Yin, Bernhard K. Krämer, Thomas Klein, Xin Shi, Ben He, Linghong Shen, Berthold Hocher","doi":"10.1007/s00424-024-02915-2","DOIUrl":"https://doi.org/10.1007/s00424-024-02915-2","url":null,"abstract":"It has been suggested that the novel selective phosphodiesterase 9 (PDE9) inhibitor may improve cardiac and renal function by blocking 3′,5′-cyclic guanosine monophosphate (cGMP) degradation. 5/6 nephrectomized (5/6Nx) rats were used to investigate the effects of the PDE9 inhibitor (BAY 73–6691) on the heart and kidney. Two doses of BAY 73–6691 (1 mg/kg/day and 5 mg/kg/day) were given for 95 days. The 5/6Nx rats developed albuminuria, a decrease in serum creatinine clearance (Ccr), and elevated serum troponin T levels. Echocardiographic data showed that 5/6 nephrectomy resulted in increased fractional shortening (FS), stroke volume (SV), and left ventricular ejection fraction (EF). However, 95 days of PDE9 inhibitor treatment did not improve any cardiac and renal functional parameter. Histopathologically, 5/6 nephrectomy resulted in severe kidney and heart damage, such as renal interstitial fibrosis, glomerulosclerosis, and enlarged cardiomyocytes. Telmisartan attenuated renal interstitial fibrosis and glomerulosclerosis as well as improved cardiomyocyte size. However, except for cardiomyocyte size and renal perivascular fibrosis, BAY 73–6691 had no effect on other cardiac and renal histologic parameters. Pathway enrichment analysis using RNA sequencing data of kidney and heart tissue identified chronic kidney disease pathways, such as phosphatidylinositol 3-kinase (PI3K)—protein kinase B (Akt) signaling pathway, complement and coagulation cascades, and nuclear factor kappa B (NF-κB) signaling pathway. PDE9i did not affect any of these disease-related pathways. Two dosages of the PDE9 inhibitor BAY 73–6691 known to be effective in other rat models have only limited cardio-renal protective effects in 5/6 nephrectomized rats.","PeriodicalId":19762,"journal":{"name":"Pflügers Archiv - European Journal of Physiology","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139662135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The mechanism of 25-hydroxycholesterol-mediated suppression of atrial β1-adrenergic responses 25- 羟基胆固醇介导的心房 β1-肾上腺素能反应抑制机制

Pflügers Archiv - European Journal of Physiology Pub Date : 2024-01-22 DOI: 10.1007/s00424-024-02913-4

{"title":"The mechanism of 25-hydroxycholesterol-mediated suppression of atrial β1-adrenergic responses","authors":"","doi":"10.1007/s00424-024-02913-4","DOIUrl":"https://doi.org/10.1007/s00424-024-02913-4","url":null,"abstract":"<h3>Abstract</h3> 25-Hydroxycholesterol (25HC) is a biologically active oxysterol, whose production greatly increases during inflammation by macrophages and dendritic cells. The inflammatory reactions are frequently accompanied by changes in heart regulation, such as blunting of the cardiac β-adrenergic receptor (AR) signaling. Here, the mechanism of 25HC-dependent modulation of responses to β-AR activation was studied in the atria of mice. 25HC at the submicromolar levels decreased the β-AR-mediated positive inotropic effect and enhancement of the Ca2+ transient amplitude, without changing NO production. Positive inotropic responses to β1-AR (but not β2-AR) activation were markedly attenuated by 25HC. The depressant action of 25HC on the β1-AR-mediated responses was prevented by selective β3-AR antagonists as well as inhibitors of Gi protein, Gβγ, G protein-coupled receptor kinase 2/3, or β-arrestin. Simultaneously, blockers of protein kinase D and C as well as a phosphodiesterase inhibitor did not preclude the negative action of 25HC on the inotropic response to β-AR activation. Thus, 25HC can suppress the β1-AR-dependent effects via engaging β3-AR, Gi protein, Gβγ, G protein-coupled receptor kinase, and β-arrestin. This 25HC-dependent mechanism can contribute to the inflammatory-related alterations in the atrial β-adrenergic signaling.","PeriodicalId":19762,"journal":{"name":"Pflügers Archiv - European Journal of Physiology","volume":"157 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139518695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The role of HCN channels on the effects of T-type calcium channels and GABAA receptors in the absence epilepsy model of WAG/Rij rats 在 WAG/Rij 大鼠失神性癫痫模型中，HCN 通道对 T 型钙通道和 GABAA 受体影响的作用

Pflügers Archiv - European Journal of Physiology Pub Date : 2023-12-30 DOI: 10.1007/s00424-023-02900-1

Emre Soner Tiryaki, Gökhan Arslan, Caner Günaydın, Mustafa Ayyıldız, Erdal Ağar

{"title":"The role of HCN channels on the effects of T-type calcium channels and GABAA receptors in the absence epilepsy model of WAG/Rij rats","authors":"Emre Soner Tiryaki, Gökhan Arslan, Caner Günaydın, Mustafa Ayyıldız, Erdal Ağar","doi":"10.1007/s00424-023-02900-1","DOIUrl":"https://doi.org/10.1007/s00424-023-02900-1","url":null,"abstract":"In this study we used ivabradine (IVA), a hyperpolarization-activated cyclic nucleotide–gated (HCN) channel blocker, to identify its effect on spike-wave discharges (SWDs); and aimed to determine the role of IVA on the effects of T-type calcium channel blocker NNC 55-0396, GABAA receptor agonist muscimol and antagonist bicuculline in male WAG/Rij rats. After tripolar electrodes for electrocorticogram (ECoG) recordings were placed on the WAG/Rij rats' skulls, 5, 10, and 20 mg/kg IVA were intraperitoneally administered for 7 consecutive days and ECoG recordings were obtained on days 0th, 3rd, 6th, and 7th for three hours before and after injections. While acute injection of 5, 10, and 20 mg/kg IVA did not affect the total number and the mean duration of SWDs, subacute administration (7 days) of IVA decreased the SWDs parameters 24 hours after the 7th injection. Interestingly, when IVA was administered again 24 hours after the 6th IVA injection, it increased the SWDs parameters. Western-blot analyses showed that HCN1 and HCN2 expressions decreased and HCN4 increased in the 5-month-old WAG/Rij rats compared to the 1-month-old WAG/Rij and 5-month-old native Wistar rats, while subacute IVA administration increased the levels of HCN1 and HCN2 channels, except HCN4. Subacute administration of IVA reduced the antiepileptic activity of NNC, while the proepileptic activity of muscimol and the antiepileptic activity of bicuculline were abolished. It might be suggested that subacute IVA administration reduces absence seizures by changing the HCN channel expressions in WAG/Rij rats, and this affects the T-type calcium channels and GABAA receptors.","PeriodicalId":19762,"journal":{"name":"Pflügers Archiv - European Journal of Physiology","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139067624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pendrin: linking acid base to blood pressure Pendrin: 将酸碱与血压联系起来

Pflügers Archiv - European Journal of Physiology Pub Date : 2023-12-19 DOI: 10.1007/s00424-023-02897-7

引用次数: 0

Pain quality patterns in delayed onset muscle soreness of the lower back suggest sensitization of fascia rather than muscle afferents: a secondary analysis study 下背部迟发性肌肉酸痛的疼痛质量模式表明筋膜而非肌肉传入敏化：二次分析研究

Pflügers Archiv - European Journal of Physiology Pub Date : 2023-12-16 DOI: 10.1007/s00424-023-02896-8

Andreas Brandl, Jan Wilke, Christoph Egner, Tobias Schmidt, Andreas Schilder, Robert Schleip

{"title":"Pain quality patterns in delayed onset muscle soreness of the lower back suggest sensitization of fascia rather than muscle afferents: a secondary analysis study","authors":"Andreas Brandl, Jan Wilke, Christoph Egner, Tobias Schmidt, Andreas Schilder, Robert Schleip","doi":"10.1007/s00424-023-02896-8","DOIUrl":"https://doi.org/10.1007/s00424-023-02896-8","url":null,"abstract":"Delayed onset muscle soreness (DOMS) of the lower back is considered a surrogate for acute low back pain (aLBP) in experimental studies. Of note, it is often unquestioningly assumed to be muscle pain. To date, there has not been a study analyzing lumbar DOMS in terms of its pain origin, which was the aim of this study. Sixteen healthy individuals (L-DOMS) were enrolled for the present study and matched to participants from a previous study (n = 16, L-PAIN) who had undergone selective electrical stimulation of the thoracolumbar fascia and the multifidus muscle. DOMS was induced in the lower back of the L-DOMS group using eccentric trunk extensions performed until exhaustion. On subsequent days, pain on palpation (100-mm analogue scale), pressure pain threshold (PPT), and the Pain Sensation Scale (SES) were used to examine the sensory characteristics of DOMS. Pain on palpation showed a significant increase 24 and 48 h after eccentric training, whereas PPT was not affected (p > 0.05). Factor analysis of L-DOMS and L-PAIN sensory descriptors (SES) yielded a stable three-factor solution distinguishing superficial thermal (“heat pain “) from superficial mechanical pain (“sharp pain”) and “deep pain.” “Heat pain “ and “deep pain” in L-DOMS were almost identical to sensory descriptors from electrical stimulation of fascial tissue (L-PAIN, all p > 0.679) but significantly different from muscle pain (all p < 0.029). The differences in sensory description patterns as well as in PPT and self-reported DOMS for palpation pain scores suggest that DOMS has a fascial rather than a muscular origin.","PeriodicalId":19762,"journal":{"name":"Pflügers Archiv - European Journal of Physiology","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138682758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cardiac optogenetics: shining light on signaling pathways 心脏光遗传学：照亮信号通路

Pflügers Archiv - European Journal of Physiology Pub Date : 2023-12-14 DOI: 10.1007/s00424-023-02892-y

Siri Leemann, Franziska Schneider-Warme, Sonja Kleinlogel

{"title":"Cardiac optogenetics: shining light on signaling pathways","authors":"Siri Leemann, Franziska Schneider-Warme, Sonja Kleinlogel","doi":"10.1007/s00424-023-02892-y","DOIUrl":"https://doi.org/10.1007/s00424-023-02892-y","url":null,"abstract":"In the early 2000s, the field of neuroscience experienced a groundbreaking transformation with the advent of optogenetics. This innovative technique harnesses the properties of naturally occurring and genetically engineered rhodopsins to confer light sensitivity upon target cells. The remarkable spatiotemporal precision offered by optogenetics has provided researchers with unprecedented opportunities to dissect cellular physiology, leading to an entirely new level of investigation. Initially revolutionizing neuroscience, optogenetics quickly piqued the interest of the wider scientific community, and optogenetic applications were expanded to cardiovascular research. Over the past decade, researchers have employed various optical tools to observe, regulate, and steer the membrane potential of excitable cells in the heart. Despite these advancements, achieving control over specific signaling pathways within the heart has remained an elusive goal. Here, we review the optogenetic tools suitable to control cardiac signaling pathways with a focus on GPCR signaling, and delineate potential applications for studying these pathways, both in healthy and diseased hearts. By shedding light on these exciting developments, we hope to contribute to the ongoing progress in basic cardiac research to facilitate the discovery of novel therapeutic possibilities for treating cardiovascular pathologies.","PeriodicalId":19762,"journal":{"name":"Pflügers Archiv - European Journal of Physiology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138682644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In silico optical modulation of spiral wave trajectories in cardiac tissue 心脏组织螺旋波轨迹的硅学光学调制

Pflügers Archiv - European Journal of Physiology Pub Date : 2023-12-14 DOI: 10.1007/s00424-023-02889-7

Sayedeh Hussaini, Rupamanjari Majumder, Valentin Krinski, Stefan Luther

{"title":"In silico optical modulation of spiral wave trajectories in cardiac tissue","authors":"Sayedeh Hussaini, Rupamanjari Majumder, Valentin Krinski, Stefan Luther","doi":"10.1007/s00424-023-02889-7","DOIUrl":"https://doi.org/10.1007/s00424-023-02889-7","url":null,"abstract":"Life-threatening cardiac arrhythmias such as ventricular tachycardia and fibrillation are common precursors to sudden cardiac death. They are associated with the occurrence of abnormal electrical spiral waves in the heart that rotate at a high frequency. In severe cases, arrhythmias are combated with a clinical method called defibrillation, which involves administering a single global high-voltage shock to the heart to reset all its activity and restore sinus rhythm. Despite its high efficiency in controlling arrhythmias, defibrillation is associated with several negative side effects that render the method suboptimal. The best approach to optimize this therapeutic technique is to deepen our understanding of the dynamics of spiral waves. Here, we use computational cardiac optogenetics to study and control the dynamics of a single spiral wave in a two-dimensional, electrophysiologically detailed, light-sensitive model of a mouse ventricle. First, we illuminate the domain globally by applying a sequence of periodic optical pulses with different frequencies in the sub-threshold regime where no excitation wave is induced. In doing so, we obtain epicycloidal, hypocycloidal, and resonant drift trajectories of the spiral wave core. Then, to effectively control the wave dynamics, we use a method called resonant feedback pacing. In this approach, each global optical pulse is applied when the measuring electrode positioned on the domain registers a predefined value of the membrane voltage. This enables us to steer the spiral wave in a desired direction determined by the position of the electrode. Our study thus provides valuable mechanistic insights into the success or failure of global optical stimulation in executing efficient arrhythmia control.","PeriodicalId":19762,"journal":{"name":"Pflügers Archiv - European Journal of Physiology","volume":"104 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138632190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lectin-mediated, time-efficient, and high-yield sorting of different morphologically intact nephron segments 以凝集素为媒介，对不同形态的完整肾小管片段进行省时高效的分拣

Pflügers Archiv - European Journal of Physiology Pub Date : 2023-12-13 DOI: 10.1007/s00424-023-02894-w

Jessica Roskosch, Uyen Huynh-Do, Stefan Rudloff

{"title":"Lectin-mediated, time-efficient, and high-yield sorting of different morphologically intact nephron segments","authors":"Jessica Roskosch, Uyen Huynh-Do, Stefan Rudloff","doi":"10.1007/s00424-023-02894-w","DOIUrl":"https://doi.org/10.1007/s00424-023-02894-w","url":null,"abstract":"The kidney is a highly complex organ equipped with a multitude of miniscule filter-tubule units called nephrons. Each nephron can be subdivided into multiple segments, each with its own morphology and physiological function. To date, conventional manual approaches to isolate specific nephron segments are very laborious, time-consuming, often limited to only a specific segment, and typically have low yield. Here, we describe a novel, unconventional method that is superior in many aspects to previous protocols by combining low-cost fluorophore-conjugated lectins or agglutinins (Flaggs) with flow sorting. This allows the simultaneous separation of different nephron segments with preserved 3D morphology from mouse or human samples in under 3 h. Using a 200-µm nozzle and 5 psi, glomeruli, proximal, or distal convoluted tubules are sorted with Cy3-labeled Sambucus Nigra agglutinin (SNA-Cy3), Fluorescein-labeled Lotus Tetragonolobus lectin (LTL-FITC), or Pacific Blue-labeled soybean agglutinin (SBA-PB), respectively. Connecting tubules and collecting ducts are sorted by double-positive SBA-PB and SNA-Cy3 signals, while thick ascending limb segments are characterized by the absence of any Flaggs labeling. From two mouse kidneys, this yields 37–521 ng protein/s or 0.71–16.71 ng RNA/s, depending on the specific nephron segment. The purity of sorted segments, as assessed by mRNA expression level profiling of 15 genes, is very high with a 96.1-fold median enrichment across all genes and sorted segments. In summary, our method represents a simple, straightforward, cost-effective, and widely applicable tool yielding high amounts of pure and morphologically largely intact renal tubule materials with the potential to propel nephron segment-specific research.","PeriodicalId":19762,"journal":{"name":"Pflügers Archiv - European Journal of Physiology","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138632188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

State-independent inhibition of the oncogenic Kv10.1 channel by desethylamiodarone, a comparison with amiodarone 去乙基胺碘酮对致癌 Kv10.1 通道的状态依赖性抑制作用，与胺碘酮的比较

Pflügers Archiv - European Journal of Physiology Pub Date : 2023-12-08 DOI: 10.1007/s00424-023-02893-x

F. Gomez-Lagunas, C. Barriga-Montoya, J. P. Pardo

{"title":"State-independent inhibition of the oncogenic Kv10.1 channel by desethylamiodarone, a comparison with amiodarone","authors":"F. Gomez-Lagunas, C. Barriga-Montoya, J. P. Pardo","doi":"10.1007/s00424-023-02893-x","DOIUrl":"https://doi.org/10.1007/s00424-023-02893-x","url":null,"abstract":"Kv10.1 is a voltage-dependent K channel whose ectopic expression is associated with several human cancers. Additionally, Kv10.1 has structure–function properties which are not yet well understood. We are using drugs of clinical importance in an attempt to gain insight on the relationship between pharmacology and characteristic functional properties of this channel. Herein, we report the interaction of desethylamiodarone (desAd), the active metabolic product of the antiarrhythmic amiodarone with Kv10.1: desAd binds to both closed and open channels, with most inhibition taking place from the open state, with affinity ~ 5 times smaller than that of amiodarone. Current inhibition by desAd and amiodarone is not synergistic. Upon repolarization desAd becomes trapped in Kv10.1 and thereafter dissociates slowly from closed-and-blocked channels. The addition of the Cole-Moore shift plus desAd open-pore-block time courses yields an increasing phase on the steady-state inhibition curve (H∞) at hyperpolarized holding potentials. In contrast to amiodarone, desAd does not inhibit the Kv10.1 Cole-Moore shift, suggesting that a relevant hydrophobic interaction between amiodarone and Kv10.1 participates in the inhibition of the Cole-Moore shift, which is lost with desAd.","PeriodicalId":19762,"journal":{"name":"Pflügers Archiv - European Journal of Physiology","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138563824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ischemic limb preconditioning-induced anti-arrhythmic effect in reperfusion-induced myocardial injury: is it mediated by the RISK or SAFE pathway? 缺血肢体预适应诱导的再灌注心肌损伤的抗心律失常作用:是通过RISK还是SAFE途径介导的?

Pflügers Archiv - European Journal of Physiology Pub Date : 2022-06-13 DOI: 10.1007/s00424-022-02716-5

Xu Cheng, Huan Li, Zhi-Zhong Yan, Jin Liu, Zhaoyang Hu

引用次数: 0