Browsing by Subject "Sympathetic nervous system"
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Item Carvedilol Analogue Modulates both Basal and Stimulated Sinoatrial Node Automaticity(Springer, 2014-05) Shinohara, Tetsuji; Kim, Daehyeok; Joung, Boyoung; Maruyama, Mitsunori; Vembaiyan, Kannan; Back, Thomas G.; Chen, Wayne; Chen, Peng-Sheng; Lin, Shien-Fong; Department of Medicine, IU School of MedicineThe membrane voltage clock and calcium (Ca(2+)) clock jointly regulate sinoatrial node (SAN) automaticity. VK-II-36 is a novel carvedilol analog that suppresses sarcoplasmic reticulum (SR) Ca(2+) release but does not block the β-receptor. The effect of VK-II-36 on SAN function remains unclear. The purpose of this study was to evaluate whether VK-II-36 can influence SAN automaticity by inhibiting the Ca(2+) clock. We simultaneously mapped intracellular Ca(2+) and membrane potential in 24 isolated canine right atriums using previously described criteria of the timing of late diastolic intracellular Ca elevation (LDCAE) relative to the action potential upstroke to detect the Ca(2+) clock. Pharmacological interventions with isoproterenol (ISO), ryanodine, caffeine, and VK-II-36 were performed after baseline recordings. VK-II-36 caused sinus rate downregulation and reduced LDCAE in the pacemaking site under basal conditions (P < 0.01). ISO induced an upward shift of the pacemaking site in SAN and augmented LDCAE in the pacemaking site. ISO also significantly and dose-dependently increased the sinus rate. The treatment of VK-II-36 (30 μmol/l) abolished both the ISO-induced shift of the pacemaking site and augmentation of LDCAE (P < 0.01), and it suppressed the ISO-induced increase in sinus rate (P = 0.02). Our results suggest that the sinus rate may be partly controlled by the Ca(2+) clock via SR Ca(2+) release during β-adrenergic stimulation.Item Cracking the Code: The Role of Peripheral Nervous System Signaling in Fracture Repair(Springer, 2024) Morris, Ashlyn J.; Parker, Reginald S.; Nazzal, Murad K.; Natoli, Roman M.; Fehrenbacher, Jill C.; Kacena, Melissa A.; White, Fletcher A.; Orthopaedic Surgery, School of MedicinePurpose of review: The traditionally understated role of neural regulation in fracture healing is gaining prominence, as recent findings underscore the peripheral nervous system's critical contribution to bone repair. Indeed, it is becoming more evident that the nervous system modulates every stage of fracture healing, from the onset of inflammation to repair and eventual remodeling. Recent findings: Essential to this process are neurotrophins and neuropeptides, such as substance P, calcitonin gene-related peptide, and neuropeptide Y. These molecules fulfill key roles in promoting osteogenesis, influencing inflammation, and mediating pain. The sympathetic nervous system also plays an important role in the healing process: while local sympathectomies may improve fracture healing, systemic sympathetic denervation impairs fracture healing. Furthermore, chronic activation of the sympathetic nervous system, often triggered by stress, is a potential impediment to effective fracture healing, marking an important area for further investigation. The potential to manipulate aspects of the nervous system offers promising therapeutic possibilities for improving outcomes in fracture healing. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.Item Neurohormonal Regulation of IKs in Heart Failure: Implications for Ventricular Arrhythmogenesis and Sudden Cardiac Death(American Heart Association, 2020-09-15) Shugg, Tyler; Hudmon, Andy; Overholser, Brian R.; Medicine, School of MedicineHeart failure (HF) results in sustained alterations in neurohormonal signaling, including enhanced signaling through the sympathetic nervous system and renin-angiotensin-aldosterone system pathways. While enhanced sympathetic nervous system and renin-angiotensin-aldosterone system activity initially help compensate for the failing myocardium, sustained signaling through these pathways ultimately contributes to HF pathophysiology. HF remains a leading cause of mortality, with arrhythmogenic sudden cardiac death comprising a common mechanism of HF-related death. The propensity for arrhythmia development in HF occurs secondary to cardiac electrical remodeling that involves pathological regulation of ventricular ion channels, including the slow component of the delayed rectifier potassium current, that contribute to action potential duration prolongation. To elucidate a mechanistic explanation for how HF-mediated electrical remodeling predisposes to arrhythmia development, a multitude of investigations have investigated the specific regulatory effects of HF-associated stimuli, including enhanced sympathetic nervous system and renin-angiotensin-aldosterone system signaling, on the slow component of the delayed rectifier potassium current. The objective of this review is to summarize the current knowledge related to the regulation of the slow component of the delayed rectifier potassium current in response to HF-associated stimuli, including the intracellular pathways involved and the specific regulatory mechanisms.Item Renal Denervation Update From the International Sympathetic Nervous System Summit: JACC State-of-the-Art Review(Elsevier, 2019-06-18) Kiuchi, Márcio G.; Esler, Murray D.; Fink, Gregory D.; Osborn, John W.; Banek, Christopher T.; Böhm, Michael; Denton, Kate M.; DiBona, Gerald F.; Everett, Thomas H., IV.; Grassi, Guido; Katholi, Richard E.; Knuepfer, Mark M.; Kopp, Ulla C.; Lefer, David J.; Lohmeier, Thomas E.; May, Clive N.; Mahfoud, Felix; Paton, Julian F.R.; Schmieder, Roland E.; Pellegrino, Peter R.; Sharabi, Yehonatan; Schlaich, Markus P.; Medicine, School of MedicineThree recent renal denervation studies in both drug-naïve and drug-treated hypertensive patients demonstrated a significant reduction of ambulatory blood pressure compared with respective sham control groups. Improved trial design, selection of relevant patient cohorts, and optimized interventional procedures have likely contributed to these positive findings. However, substantial variability in the blood pressure response to renal denervation can still be observed and remains a challenging and important problem. The International Sympathetic Nervous System Summit was convened to bring together experts in both experimental and clinical medicine to discuss the current evidence base, novel developments in our understanding of neural interplay, procedural aspects, monitoring of technical success, and others. Identification of relevant trends in the field and initiation of tailored and combined experimental and clinical research efforts will help to address remaining questions and provide much-needed evidence to guide clinical use of renal denervation for hypertension treatment and other potential indications.Item Shp2 deletion in post-migratory neural crest cells results in impaired cardiac sympathetic innervation(2014-05) Lajiness, Jacquelyn D.; Ingram, David A., Jr.; Harrington, Maureen A.; Mirmira, Raghavendra G.; Payne, Mark; Rubart, MichaelAutonomic innervation of the heart begins in utero and continues during the neonatal phase of life. A balance between the sympathetic and parasympathetic arms of the autonomic nervous system is required to regulate heart rate as well as the force of each contraction. Our lab studies the development of sympathetic innervation of the early postnatal heart in a conditional knockout (cKO) of Src homology protein tyrosine phosphatase 2 (Shp2). Shp2 is a ubiquitously expressed non-receptor phosphatase involved in a variety of cellular functions including survival, proliferation, and differentiation. We targeted Shp2 in post-migratory neural crest (NC) lineages using our novel Periostin-Cre. This resulted in a fully penetrant mouse model of diminished cardiac sympathetic innervation and concomitant bradycardia that progressively worsen. Shp2 is thought to mediate its basic cellular functions through a plethora of signaling cascades including extracellular signal-regulated kinases (ERK) 1 and 2. We hypothesize that abrogation of downstream ERK1/2 signaling in NC lineages is primarily responsible for the failed sympathetic innervation phenotype observed in our mouse model. Shp2 cKOs are indistinguishable from control littermates at birth and exhibit no gross structural cardiac anomalies; however, in vivo electrocardiogram (ECG) characterization revealed sinus bradycardia that develops as the Shp2 cKO ages. Significantly, 100% of Shp2 cKOs die within 3 weeks after birth. Characterization of the expression pattern of the sympathetic nerve marker tyrosine hydroxylase (TH) revealed a loss of functional sympathetic ganglionic neurons and reduction of cardiac sympathetic axon density in Shp2 cKOs. Shp2 cKOs exhibit lineage-specific suppression of activated pERK1/2 signaling, but not of other downstream targets of Shp2 such as pAKT (phosphorylated-Protein kinase B). Interestingly, restoration of pERK signaling via lineage-specific expression of constitutively active MEK1 (Mitogen-activated protein kinase kinase1) rescued TH-positive cardiac innervation as well as heart rate. These data suggest that the diminished sympathetic cardiac innervation and the resulting ECG abnormalities are a result of decreased pERK signaling in post-migratory NC lineages.Item Urinary excretion of norepinephrine:role of tubular secretion and renal sympathetic nerves(1980) Lappe, Rodney W.