scholarly journals Regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling

2019 ◽  
Vol 151 (8) ◽  
pp. 1051-1058 ◽  
Author(s):  
Richard Z. Lin ◽  
Zhongju Lu ◽  
Evgeny P. Anyukhovsky ◽  
Ya-Ping Jiang ◽  
Hong Zhan Wang ◽  
...  
Keyword(s):  
Heart Rate ◽  
Sinoatrial Node ◽  
Cardiac Pacing ◽  
Pacemaker Current ◽  
Physiological Conditions ◽  
Diastolic Depolarization ◽  
Important Regulator ◽  
Phosphoinositide 3 Kinase

Heart rate in physiological conditions is set by the sinoatrial node (SN), the primary cardiac pacing tissue. Phosphoinositide 3-kinase (PI3K) signaling is a major regulatory pathway in all normal cells, and its dysregulation is prominent in diabetes, cancer, and heart failure. Here, we show that inhibition of PI3K slows the pacing rate of the SN in situ and in vitro and reduces the early slope of diastolic depolarization. Furthermore, inhibition of PI3K causes a negative shift in the voltage dependence of activation of the pacemaker current, IF, while addition of its second messenger, phosphatidylinositol 3,4,5-trisphosphate, induces a positive shift. These shifts in the activation of IF are independent of, and larger than, those induced by the autonomic nervous system. These results suggest that PI3K is an important regulator of heart rate, and perturbations in this signaling pathway may contribute to the development of arrhythmias.

Absorption of beta-casomorphins from autoperfused lamb and piglet small intestine

1990 ◽  
Vol 259 (3) ◽  
pp. G443-G452 ◽  
Author(s):  
L. C. Read ◽  
A. P. Lord ◽  
V. Brantl ◽  
G. Koch
Keyword(s):  
Small Intestine ◽  
Intestinal Lumen ◽  
Physiological Conditions ◽  
Naturally Occurring ◽  
Gut Epithelium ◽  
Measured Absorption ◽  
Beta Casein ◽  
Kinetics Of

beta-Casomorphins (beta-CMs) derived from milk beta-casein may exert various opiate activities in milk-fed infants. To assess the physiological significance of beta-CMs as a source of circulating opioids in infants, we measured absorption rates of several beta-CMs under near-physiological conditions using in situ autoperfused lamb intestine. The naturally occurring beta-CMs, beta-CM-7 and beta-CM-4-amide, were absorbed readily into blood with no transfer into lymph. Uptake peaked within several minutes of the luminal infusion of peptide but then declined sharply and stopped within a further 10-15 min. The recovery in blood, intestinal contents, and tissue at the end of the 30-min experiment was less than 1% of the infused dose. The low recovery was due to rapid proteolysis based on in vitro studies that demonstrated half-lives of less than 5 min in lamb blood, luminal contents, and lymph. The synthetic dipeptidyl peptidase IV-resistant analogue beta-[D-Ala2]CM- 4-amide was stable during incubation in blood, lymph, or luminal contents and was absorbed into blood at rates that were maximal within several minutes and remained steady for the 30-min period. We conclude that although natural beta-CMs are transferred across the lamb small intestine, rapid degradation within the intestinal lumen, gut epithelium, and blood would prevent entry into the circulation under normal conditions. Val-beta-CM-7, a putative stable precursor, had similar stability and kinetics of absorption to beta-CM-7, results that exclude Val-beta-CM-7 as a stable precursor for delivery of beta-CMs to the circulation. Essentially identical results to those in lambs were obtained in 7-day-old piglets.

scholarly journals Shenxian-Shengmai Oral Liquid Improves Sinoatrial Node Dysfunction through the PKC/NOX-2 Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Heng Zhang ◽  
Miao Hao ◽  
Lingkang Li ◽  
Keyan Chen ◽  
Jing Qi ◽  
...  
Keyword(s):  
Heart Rate ◽  
Signaling Pathway ◽  
Sinoatrial Node ◽  
Cardiac Conduction ◽  
Potential Mechanism ◽  
Cardiac Syncope ◽  
Common Causes ◽  
Oral Liquid ◽  
Masson Staining

Sick sinus syndrome (SSS) is one of the common causes of cardiac syncope and sudden death; the occurrence of SSS is associated with the accumulation of ROS in the sinoatrial node (SAN). Shenxian-shengmai (SXSM) is a traditional Chinese medicine available as oral liquid that causes a significant increase in heart rate. The objective of this study is to observe the improvement of SXSM on SAN function in SSS mice and explore its potential mechanism. In the current study, SSS was simulated in mice by inducing SAN dysfunction using a micro-osmotic pump to inject angiotensin II (Ang II). The mouse model with SSS was used to determine the effect of SXSM on SAN function and to explore its potential mechanism. Furthermore, the HL-1 cell line, derived from mouse atrial myocytes, was used to simulate SAN pacemaker cells. Our results indicated that SXSM significantly increased the heart rate of SSS mice by reducing the AngII-induced accumulation of ROS in the SAN and by inhibiting the expression of HDAC4, thereby reducing the loss of HCN4, a critical component of the cardiac conduction system. MASSON staining revealed a reduction of SAN damage in SSS mice that were treated with SXSM compared with controls. In vitro experiments showed that AngII treatment caused an upregulation of the PKC/NOX-2 signaling pathway in HL-1 cells which could be prevented by pretreatment with SXSM. The protective effect of SXSM was attenuated upon treatment with the PCK agonist PMA. In conclusion, SXSM reduced the AngII-induced accumulation of ROS in the SAN through the PKC/NOX2 signaling pathway, improving the functioning of the SAN and preventing the decrease of heart rate in SSS mice.

scholarly journals Phosphorylation and modulation of hyperpolarization-activated HCN4 channels by protein kinase A in the mouse sinoatrial node

2010 ◽  
Vol 136 (3) ◽  
pp. 247-258 ◽  
Author(s):  
Zhandi Liao ◽  
Dean Lockhead ◽  
Eric D. Larson ◽  
Catherine Proenza
Keyword(s):  
Heart Rate ◽  
Protein Kinase ◽  
Cyclic Nucleotide ◽  
Sinoatrial Node ◽  
Voltage Dependence ◽  
C Terminus ◽  
Sympathetic Regulation ◽  
Direct Binding ◽  
End Effectors

The sympathetic nervous system increases heart rate by activating β adrenergic receptors and increasing cAMP levels in myocytes in the sinoatrial node. The molecular basis for this response is not well understood; however, the cardiac funny current (If) is thought to be among the end effectors for cAMP signaling in sinoatrial myocytes. If is produced by hyperpolarization-activated cyclic nucleotide–sensitive (HCN4) channels, which can be potentiated by direct binding of cAMP to a conserved cyclic nucleotide binding domain in the C terminus of the channels. β adrenergic regulation of If in the sinoatrial node is thought to occur via this direct binding mechanism, independent of phosphorylation. Here, we have investigated whether the cAMP-activated protein kinase (PKA) can also regulate sinoatrial HCN4 channels. We found that inhibition of PKA significantly reduced the ability of β adrenergic agonists to shift the voltage dependence of If in isolated sinoatrial myocytes from mice. PKA also shifted the voltage dependence of activation to more positive potentials for heterologously expressed HCN4 channels. In vitro phosphorylation assays and mass spectrometry revealed that PKA can directly phosphorylate at least 13 sites on HCN4, including at least three residues in the N terminus and at least 10 in the C terminus. Functional analysis of truncated and alanine-substituted HCN4 channels identified a PKA regulatory site in the distal C terminus of HCN4, which is required for PKA modulation of If. Collectively, these data show that native and expressed HCN4 channels can be regulated by PKA, and raise the possibility that this mechanism could contribute to sympathetic regulation of heart rate.

Frequency-force relationships of mammalian ventricular muscle in vivo and in vitro

1976 ◽  
Vol 230 (3) ◽  
pp. 631-636 ◽  
Author(s):  
ML Kahn ◽  
F Kavaler ◽  
VJ Fisher
Keyword(s):  
Heart Rate ◽  
Left Ventricle ◽  
Room Temperature ◽  
Physiological Role ◽  
Ventricular Muscle ◽  
Contractile State ◽  
Force Relationship

The change in contractility with increasing heart rate was studied in the left ventricle of dogs and in isolated trabeculae carneae of cats. For some of the studies in situ a transient isovolumic state was created by aortic occlusion. At physiological temperatures the frequency-force relationship is flatter than at room temperature and at the same temperature it is flatter in vivo than in vitro. The frequency-(dF/dt)max relationship is steeper than the frequency-force relationship at both temperatures in vivo and in vitro. The frequency-(dF/dt)max relationship is steeper in vitro than it is in situ, although the discrepancy is less marked than in the case of the frequency-force relationship. It is concluded that "staircase" plays less of a physiological role in adjustment of contractile state in situ than might be inferred from studies of isolated tissue.

scholarly journals RE-EVALUATION OF THE STRETCH SENSITIVITY HYPOTHESIS OF CRUSTACEAN HEARTS: HYPOXIA, NOT LACK OF STRETCH, CAUSES REDUCTION IN HEART RATE OF ISOLATED HEARTS

1993 ◽  
Vol 176 (1) ◽  
pp. 223-232
Author(s):  
J. L. Wilkens
Keyword(s):  
Heart Rate ◽  
Isolated Heart ◽  
Carcinus Maenas ◽  
Three Dimensional ◽  
Decapod Crustacean ◽  
Diastolic Filling ◽  
Elastic Recoil ◽  
Isolated Hearts

Decapod crustacean hearts are suspended by a three-dimensional array of alary ligaments. These ligaments are stretched during systole; diastolic filling via the ostia occurs as the ventricle is stretched by ligamental elastic recoil. There is no direct venous return to the hearts in these animals. In the present study, an isolated heart preparation with intact ligaments, hereafter called in situ, was used to evaluate the effects of artificially induced stretch on heart rate. Strongly beating in situ neurogenic hearts of the crab Carcinus maenas responded to direct perfusion of the ventricle with oxygenated saline and the attendant augmentation of natural stretch with a small increase in heart rate (fh); however, fh was well maintained for up to 15 min after eliminating stretch by cutting the alary ligaments. In contrast to crabs, high rates of artificial perfusion usually depressed fh in crayfish hearts. Crab heart rate falls during hypoxia and this is readily reversed by even low rates of perfusion with oxygenated saline. It is concluded that the gradual decline in fh of totally isolated in vitro hearts arises from the deepening intraventricular hypoxia experienced by the cardiac ganglion.

scholarly journals Beating Rate Variability of Isolated Mammal Sinoatrial Node Tissue: Insight Into Its Contribution to Heart Rate Variability

2021 ◽  
Vol 14 ◽  
Author(s):  
Ori Shemla ◽  
Kenta Tsutsui ◽  
Joachim A. Behar ◽  
Yael Yaniv
Keyword(s):  
Heart Rate ◽  
Heart Rate Variability ◽  
Frequency Band ◽  
Sinoatrial Node ◽  
Low Frequency ◽  
Relative Increase ◽  
Test Mouse ◽  
Beating Rate

BackgroundBecause of the complexity of the interaction between the internal pacemaker mechanisms, cell interconnected signals, and interaction with other body systems, study of the role of individual systems must be performed under in vivo and in situ conditions. The in situ approach is valuable when exploring the mechanisms that govern the beating rate and rhythm of the sinoatrial node (SAN), the heart’s primary pacemaker. SAN beating rate changes on a beat-to-beat basis. However, to date, there are no standard methods and tools for beating rate variability (BRV) analysis from electrograms (EGMs) collected from different mammals, and there is no centralized public database with such recordings.MethodsWe used EGM recordings obtained from control SAN tissues of rabbits (n = 9) and mice (n = 30) and from mouse SAN tissues (n = 6) that were exposed to drug intervention. The data were harnessed to develop a beat detector to derive the beat-to-beat interval time series from EGM recordings. We adapted BRV measures from heart rate variability and reported their range for rabbit and mouse.ResultsThe beat detector algorithm performed with 99% accuracy, sensitivity, and positive predictive value on the test (mouse) and validation (rabbit and mouse) sets. Differences in the frequency band cutoff were found between BRV of SAN tissue vs. heart rate variability (HRV) of in vivo recordings. A significant reduction in power spectrum density existed in the high frequency band, and a relative increase was seen in the low and very low frequency bands. In isolated SAN, the larger animal had a slower beating rate but with lower BRV, which contrasted the phenomena reported for in vivo analysis. Thus, the non-linear inverse relationship between the average HR and HRV is not maintained under in situ conditions. The beat detector, BRV measures, and databases were contributed to the open-source PhysioZoo software (available at: https://physiozoo.com/).ConclusionOur approach will enable standardization and reproducibility of BRV analysis in mammals. Different trends were found between beating rate and BRV or HRV in isolated SAN tissue vs. recordings collected under in vivo conditions, respectively, implying a complex interaction between the SAN and the autonomic nervous system in determining HRV in vivo.

T3 treatment does not prevent myocardial dysfunction in chronically diabetic rats

1988 ◽  
Vol 254 (2) ◽  
pp. H265-H273
Author(s):  
R. W. Barbee ◽  
R. E. Shepherd ◽  
A. H. Burns
Keyword(s):  
Heart Rate ◽  
Cardiac Function ◽  
Myocardial Dysfunction ◽  
Systolic Pressure ◽  
Cardiac Pacing ◽  
Diabetic Rats ◽  
Heart Weight ◽  
Citrate Buffer ◽  
Heart Preparation

The isolated working heart preparation was used to investigate the effect of continuous triiodothyronine (T3) administration on cardiac function and metabolism of rats rendered diabetic for a period of 4 wk with streptozocin (STZ). T3 controlled-release pellets were implanted 1 wk after STZ (70 mg/kg) injection. Rats injected with citrate buffer without STZ received T3 pellets 1 and/or 2 wk later. A comparable number of rats received placebo pellets. Untreated diabetic rats exhibited a decrease in spontaneous heart rate and myocardial cytochrome c concentrations concurrent with depressed plasma T3 values compared with untreated controls. T3 treatment did not improve in vitro cardiac performance (assessed as cardiac output times peak systolic pressure per gram dry heart weight) in hearts from diabetic rats perfused with glucose alone. Addition of octanoate reversed this depression and improved cardiac function to a greater extent in treated than in untreated diabetic animals. However, these differences between treated and untreated diabetic animals disappeared when heart rate was controlled by cardiac pacing. Furthermore, T3 treatment of controls and diabetics did not alter the oxidation of octanoate or the cardiac responsiveness to isoproterenol. These results suggest that experimental diabetic cardiomyopathy is partly attributable to a substrate deficiency and is not due entirely to hypothyroidism.

Specific receptor for hydrazine: mapping the in situ release of hydrazine in live cells and in an in vitro enzymatic assay

2016 ◽  
Vol 52 (36) ◽  
pp. 6166-6169 ◽  
Author(s):  
Firoj Ali ◽  
Anila H. A. ◽  
Nandaraj Taye ◽  
Devraj G. Mogare ◽  
Samit Chattopadhyay ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Enzymatic Assay ◽  
Live Cells ◽  
Specific Receptor ◽  
Specific Detection ◽  
Physiological Conditions

New chemodosimetric reagent for the specific detection of hydrazine in physiological conditions as well as for the mapping of its in situ generation in live Hct116 and HepG2 cells by enzymatic transformations.

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