PKC catalytic subunit and phenylephrine induce a comparable decrease in myofilament calcium sensitivity

2007 ◽  
Vol 42 (6) ◽  
pp. S46
Author(s):  
Judit Barta ◽  
Jolanda van der Velden ◽  
Nicky M. Boontje ◽  
Ruud Zaremba ◽  
Ger J.M. Stienen
Keyword(s):  
Calcium Sensitivity ◽  
Catalytic Subunit ◽  
Myofilament Calcium Sensitivity

Abstract 219: Histidine Substituted Cardiac Troponin I (a164h) Improves Survival And Protects Cardiac Contractility During Acute Hypoxia In The Aged Murine Heart.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Nathan Palpant ◽  
Sharlene Day ◽  
Kimber Converso ◽  
Joseph Metzger
Keyword(s):  
Cardiac Troponin ◽  
Troponin I ◽  
Acute Hypoxia ◽  
Cardiac Contractility ◽  
Systolic Pressure ◽  
Calcium Sensitivity ◽  
The Elderly ◽  
Cardiac Troponin I ◽  
Pump Failure ◽  
Myofilament Calcium Sensitivity

Contractile dysfunction associated with ischemia is a significant cause of morbidity and mortality particularly in the elderly. Strategies designed to protect the aged heart from ischemia-mediated pump failure are needed. We have generated transgenic (Tg) mice expressing a modified form of adult cardiac troponin I, the Ca ++ -activated molecular switch of the myofilament. Consonant with the fetal isoform, this transgene encodes a histidine substitution (A164H) in the critical switch domain of TnI thus increasing myofilament calcium sensitivity in a pH-dependent manner. We hypothesized that aged mice (24 months), intrinsically susceptible to myocardial dysfunction, would retain improved cardiac contractility at baseline and during an acute hypoxic challenge by means of myofilament-mediated calcium sensitization. Methods/Results: At baseline, by echocardiography, Tg hearts had increased systolic function, with a 26% higher mean ejection fraction compared to nontransgenic (Ntg) mice: 75 ± 3% [Tg: n = 13] vs. 63 ± 4% [Ntg: n = 12], P < 0.05, with no differences in diastolic function between the groups. To study the effects of acute hypoxia on cardiac hemodynamics mice underwent microconductance Millar catheterization while ventilated with 12% oxygen. Aged Tg mice had improved survival compared to Ntg mice: time to pump failure (65% of baseline peak systolic pressure) 11.59 ± 1.25 min. [Tg: n = 3] vs. 4.11 ± 1.90 min. [Ntg: n = 3], P < 0.05. After four minutes of hypoxia, Tg mice had markedly improved cardiac contractility compared to Ntg mice with increased stroke volume (30.05 ± 4.49 uL [Tg] vs. 13.23 ± 3.21 uL [Ntg], P < 0.05), end systolic pressure (106.09 ± 11.81 mmHg [Tg] vs. 64.49 ± 4.05 mmHg [Ntg], P < 0.05) and rate of positive left ventricular pressure development (12958.66 ± 2544.68 mmHg/sec [Tg] vs. 5717.00 ± 745.67 mmHg/sec [Ntg], P = 0.05). Conclusion: An alteration in myofilament calcium sensitivity via a pH-responsive histidine button in cardiac troponin I augments baseline heart function in Tg mice over their lifetime. During acute hypoxia, cTnI A164H improves survival in aged mice by maintaining cardiac contractility, and thus holds promise for the design of gene therapeutics to treat pump failure associated with acute ischemic events in the elderly.

High-throughput assessment of calcium sensitivity in skinned cardiac myocytes

2001 ◽  
Vol 281 (2) ◽  
pp. H969-H974 ◽  
Author(s):  
Chee Chew Lim ◽  
Michiel H. B. Helmes ◽  
Douglas B. Sawyer ◽  
Mohit Jain ◽  
Ronglih Liao
Keyword(s):  
Cardiac Myocytes ◽  
High Throughput ◽  
High Throughput Screening ◽  
Rapid Determination ◽  
Isometric Force ◽  
Calcium Sensitivity ◽  
Pharmacological Agents ◽  
Length Changes ◽  
Myofilament Calcium Sensitivity ◽  
High Degree

Isolated permeabilized cardiac myocytes have been used in the study of myofilament calcium sensitivity through measurement of the isometric force-pCa curve. Determining this force-pCa relationship in skinned myocytes is relatively expensive and carries a high degree of variability. We therefore attempted to establish an alternative high-throughput method to measure calcium sensitivity in cardiac myocytes. With the use of commercially available software that allows for precise measurement of sarcomere spacing, we measured sarcomere length changes in unloaded skinned cardiac myocytes over a range of calcium concentrations. With the use of this technique, we were able to accurately detect acute increases or decreases in myofilament calcium sensitivity after exposure to 10 mM caffeine or 5 mM 2,3-butanedione monoxime, respectively. This technique allows for the simple and rapid determination of myofilament calcium sensitivity in cardiac myocytes in a reproducible and inexpensive manner and could be used for high-throughput screening of pharmacological agents and/or transgenic mouse models for changes in myofilament calcium sensitivity.

scholarly journals Myogenic contractility is more dependent on myofilament calcium sensitization in term fetal than adult ovine cerebral arteries

2007 ◽  
Vol 293 (1) ◽  
pp. H548-H556 ◽  
Author(s):  
Renan J. Sandoval ◽  
Elisha R. Injeti ◽  
James M. Williams ◽  
William T. Georthoffer ◽  
William J. Pearce
Keyword(s):  
Calcium Influx ◽  
Cerebral Arteries ◽  
Calcium Sensitivity ◽  
Cytosolic Calcium ◽  
Stretch Ratio ◽  
Myogenic Tone ◽  
Postnatal Maturation ◽  
Calcium Sensitization ◽  
Myofilament Calcium Sensitivity ◽  
Krebs Buffer

Regulation of cytosolic calcium and myofilament calcium sensitivity varies considerably with postnatal age in cerebral arteries. Because these mechanisms also govern myogenic tone, the present study used graded stretch to examine the hypothesis that myogenic tone is less dependent on calcium influx and more dependent on myofilament calcium sensitization in term fetal compared with adult cerebral arteries. Term fetal and adult posterior communicating cerebral arteries exhibited similar myogenic responses, with peak tensions averaging 24 and 26% of maximum contractile force produced in any given tissue in response to an isotonic Krebs buffer containing 122 mM K+ (Kmax) at optimum stretch ratios (working diameter/unstressed diameter) of 2.19 and 2.23, respectively. Graded stretch increased cytosolic Ca2+ concentration at stretch ratios >2.0 in adult arteries, but increased Ca2+ concentration only at stretch ratios >2.3 in fetal arteries. In permeabilized arteries, myogenic tone peaked at a stretch ratio of 2.1 in both fetal and adult arteries. The fetal %Kmax values at peak myogenic tone were not significantly different at either pCa 7.0 (23%) or pCa 5.5 (25%) but were significantly less at pCa 8.0 (8.4 ± 2.3%). Conversely, adult %Kmax values at peak myogenic tone were significantly less at both pCa 8.0 (10.4 ± 1.8%) and pCa 7.0 (16%) than at pCa 5.5 (27%). The maximal extents of stretch-induced increases in myosin light chain phosphorylation in intact fetal (20%) and adult (17%) arteries were similar. The data demonstrate that the cerebrovascular myogenic response is highly conserved during postnatal maturation but is mediated differently in fetal and adult cerebral arteries.

scholarly journals Striated muscle tropomyosin isoforms differentially regulate cardiac performance and myofilament calcium sensitivity

2010 ◽  
Vol 31 (3) ◽  
pp. 227-239 ◽  
Author(s):  
Ganapathy Jagatheesan ◽  
Sudarsan Rajan ◽  
Rafeeq P. H. Ahmed ◽  
Natalia Petrashevskaya ◽  
Greg Boivin ◽  
...  
Keyword(s):  
Striated Muscle ◽  
Calcium Sensitivity ◽  
Cardiac Performance ◽  
Tropomyosin Isoforms ◽  
Muscle Tropomyosin ◽  
Myofilament Calcium Sensitivity

Increased myocardial calcium cycling and reduced myofilament calcium sensitivity in early endotoxemia

Surgery ◽  
1999 ◽  
Vol 126 (2) ◽  
pp. 231-238 ◽  
Author(s):  
Koh Takeuchi ◽  
Pedro J. del Nido ◽  
Andra E. Ibrahim ◽  
Dimitrios N. Poutias ◽  
Paul Glynn ◽  
...  
Keyword(s):  
Calcium Sensitivity ◽  
Calcium Cycling ◽  
Myofilament Calcium Sensitivity

The Anrep effect: 100 years later

2013 ◽  
Vol 304 (2) ◽  
pp. H175-H182 ◽  
Author(s):  
Horacio E. Cingolani ◽  
Néstor G. Pérez ◽  
Oscar H. Cingolani ◽  
Irene L. Ennis
Keyword(s):  
Gradual Increase ◽  
Growth Factor Receptor ◽  
Calcium Transient ◽  
Calcium Sensitivity ◽  
Myocardial Stretch ◽  
Epidermal Growth ◽  
Endothelin 3 ◽  
Myofilament Calcium Sensitivity ◽  
Intact Heart

Myocardial stretch elicits a rapid increase in developed force, which is mainly caused by an increase in myofilament calcium sensitivity (Frank-Starling mechanism). Over the ensuing 10–15 min, a second gradual increase in force takes place. This slow force response to stretch is known to be the result of an increase in the calcium transient amplitude and constitutes the in vitro equivalent of the Anrep effect described 100 years ago in the intact heart. In the present review, we will update and discuss what is known about the Anrep effect as the mechanical counterpart of autocrine/paracrine mechanisms involved in its genesis. The chain of events triggered by myocardial stretch comprises 1) release of angiotensin II, 2) release of endothelin, 3) activation of the mineralocorticoid receptor, 4) transactivation of the epidermal growth factor receptor, 5) increased formation of mitochondria reactive oxygen species, 6) activation of redox-sensitive kinases upstream myocardial Na+/H+ exchanger (NHE1), 7) NHE1 activation, 8) increase in intracellular Na+ concentration, and 9) increase in Ca2+ transient amplitude through the Na+/Ca2+ exchanger. We will present the experimental evidence supporting each of the signaling steps leading to the Anrep effect and its blunting by silencing NHE1 expression with a specific small hairpin interference RNA injected into the ventricular wall.

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