Positive and negative effects of nitric oxide on Ca2+ sparks: influence of β-adrenergic stimulation

2001 ◽  
Vol 281 (6) ◽  
pp. H2295-H2303 ◽  
Author(s):  
Mark T. Ziolo ◽  
Hideki Katoh ◽  
Donald M. Bers
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Ventricular Myocytes ◽  
Cardiac Contractility ◽  
Adrenergic Stimulation ◽  
High Concentration ◽  
Negative Effects ◽  
Dual Effect ◽  
Kinase A

Nitric oxide (NO) can have a positive or negative effect on cardiac contractility and the ryanodine receptor (RyR). This dual effect has been explained as being dependent on the concentration of NO. We find that cellular RyR response to NO is also dependent on the degree of β-adrenergic stimulation, and thus the state of protein kinase A activation. Ca2+ spark frequency (CaSpF) in rat ventricular myocytes was used as an index of resting RyR activity. CaSpF response to β-adrenergic stimulation was used as an index of protein kinase A activation. High concentration of isoproterenol, a β-adrenergic agonist, caused a large increase in CaSpF; addition of NO (spermine NONOate, 300 μM) then caused a decrease in CaSpF. Low concentration of isoproterenol produced only a slight increase in CaSpF, but the same NO concentration now caused a large increase in CaSpF. A dual effect was also observed in twitch. Thus the net direction of the effects of NO on RyR activity and Ca2+transients (directly or by alteration of sarcoplasmic reticulum Ca2+ load) can be reversed, depending on the ambient level of β-adrenergic activation.

scholarly journals Pyruvate restores β-adrenergic sensitivity of L-type Ca2+ channels in failing rat heart: role of protein phosphatase

2013 ◽  
Vol 304 (10) ◽  
pp. H1352-H1360 ◽  
Author(s):  
Ming-Qi Zheng ◽  
Xun Li ◽  
Kang Tang ◽  
Neeru M. Sharma ◽  
Todd A. Wyatt ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Okadaic Acid ◽  
Protein Phosphatase ◽  
Ventricular Myocytes ◽  
Intracellular Camp ◽  
Adrenergic Stimulation ◽  
Thioredoxin System ◽  
Kinase A

Oxidative stress plays a major role in the pathogenesis of heart failure, where the contractile response to β-adrenergic stimulation is profoundly depressed. This condition involves L-type Ca2+ channels, but the mechanisms underlying their impaired adrenergic regulation are unclear. Thus the present study explored the basis for impaired adrenergic control of Ca2+ channels in a rat infarction model of heart failure. Patch-clamp recordings of L-type Ca2+ current ( ICa,L) from ventricular myocytes isolated from infarcted hearts showed a blunted response to intracellular cAMP that was reversed by treatment with exogenous pyruvate. Biochemical studies showed that basal and cAMP-stimulated protein kinase A activities were similar in infarcted and sham-operated hearts, whereas molecular analysis also found that binding of protein kinase A to the α1C subunit of voltage-gated Ca2+ channel isoform 1.2 was not different between groups. By contrast, protein phosphatase 2A (PP2A) activity and binding to α1C were significantly less in infarcted hearts. The PP2A inhibitor okadaic acid markedly increased ICa,L in sham-operated myocytes, but this response was significantly less in myocytes from infarcted hearts. However, pyruvate normalized ICa,L stimulation by okadaic acid, and this effect was blocked by inhibitors of thioredoxin reductase, implicating a functional role for the redox-active thioredoxin system. Our data suggest that blunted β-adrenergic stimulation of ICaL in failing hearts results from hyperphosphorylation of Ca2+ channels secondary to oxidation-induced impairment of PP2A function. We propose that the redox state of Ca2+ channels or PP2A is controlled by the thioredoxin system which plays a key role in Ca2+ channel remodeling of the failing heart.

Nitric oxide and cGMP protein kinase activity in aged ventricular myocytes

2001 ◽  
Vol 281 (6) ◽  
pp. H2304-H2309 ◽  
Author(s):  
Qihang Zhang ◽  
Bruno Molino ◽  
Lin Yan ◽  
Todd Haim ◽  
Yakir Vaks ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Ventricular Myocytes ◽  
Nitric Oxide Donor ◽  
Protein Kinase Activity ◽  
Edge Detector ◽  
Negative Effects ◽  
Dependent Protein

We tested the hypothesis that nitric oxide-induced negative functional effects through cGMP would be reduced in aged cardiac myocytes. Maximum rate of shortening ( R max) and percent shortening of ventricular myocytes from young (6 mo) and old (3 y) rabbits were studied using a video edge detector. cGMP-dependent phosphorylation was examined by electrophoresis and autoradiography. Myocytes received a nitric oxide donor S-nitroso- N-acetyl-penicillamine (SNAP, 10−7, 10−6, and 10−5 M) followed by KT-5823 (10−6 M), a cGMP protein kinase inhibitor. Baseline function was similar in young and old myocytes (89.1 ± 4.5 young vs. 86.4 ± 8.3 μm/s old R max, 5.6 ± 0.3 vs. 5.2 ± 0.7%shortening). SNAP (10−5 M) decreased R max in both young (25%, n = 6) and old myocytes (24%, n = 7). SNAP also reduced percent shortening by 28% in young and 23% in old myocytes. The negative effects of SNAP were partially reversed by KT-5823 only in young myocytes. Multiple proteins were phosphorylated by cGMP, and KT-5823 could reduce this effect. The degree of phosphorylation was significantly less in old myocytes. These results suggest that the functional response of ventricular myocytes to nitric oxide was preserved during aging. However, the importance of cGMP-dependent protein phosphorylation was decreased, indicating a shift to other pathways.

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