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Angiotensin II Type 1 Receptor-Mediated Electrical Remodeling in Mouse Cardiac Myocytes.

Kim J, Gao J, Cohen IS, Mathias RT - PLoS ONE (2015)

Bottom Line: Pre-application of the microtubule destabilizing agent colchicine eliminated A2 effects on Ito and AP duration, suggesting these effects depend on intracellular trafficking.Application of the biased agonist SII ([Sar1-Ile4-Ile8]A2), which stimulates receptor internalization without G protein activation, caused Ito reduction and AP prolongation similar to A2-induced changes.Moreover, all measured properties parallel those measured in dog heart, suggesting an autocrine RAS may be a fundamental feedback system that is present across species.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology & Biophysics, State University of New York at Stony Brook, Stony Brook, New York, United States of America.

ABSTRACT
We recently characterized an autocrine renin angiotensin system (RAS) in canine heart. Activation of Angiotensin II Type 1 Receptors (AT1Rs) induced electrical remodeling, including inhibition of the transient outward potassium current Ito, prolongation of the action potential (AP), increased calcium entry and increased contractility. Electrical properties of the mouse heart are very different from those of dog heart, but if a similar system existed in mouse, it could be uniquely studied through genetic manipulations. To investigate the presence of a RAS in mouse, we measured APs and Ito in isolated myocytes. Application of angiotensin II (A2) for 2 or more hours reduced Ito magnitude, without affecting voltage dependence, and prolonged APs in a dose-dependent manner. Based on dose-inhibition curves, the fast and slow components of Ito (Ito,fast and IK,slow) appeared to be coherently regulated by [A2], with 50% inhibition at an A2 concentration of about 400 nM. This very high K0.5 is inconsistent with systemic A2 effects, but is consistent with an autocrine RAS in mouse heart. Pre-application of the microtubule destabilizing agent colchicine eliminated A2 effects on Ito and AP duration, suggesting these effects depend on intracellular trafficking. Application of the biased agonist SII ([Sar1-Ile4-Ile8]A2), which stimulates receptor internalization without G protein activation, caused Ito reduction and AP prolongation similar to A2-induced changes. These data demonstrate AT1R mediated regulation of Ito in mouse heart. Moreover, all measured properties parallel those measured in dog heart, suggesting an autocrine RAS may be a fundamental feedback system that is present across species.

No MeSH data available.


Related in: MedlinePlus

The voltage dependence of A2-induced reductions in peak Ito,fast and IK,slow.Inhibitions were determined from the voltage dependence of peak Ito,fast and IK,slow in control cells (n = 8) and in cells exposed to 5 μM A2 (n = 8). Percent inhibition was calculated from the reduction in current divided by the control current. The percent reductions in Ito,fast(A) and IK,slow(B) exhibit minimal voltage dependence, suggesting A2 reduces the number of open K+-channels per unit area of plasma membrane.
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pone.0138711.g003: The voltage dependence of A2-induced reductions in peak Ito,fast and IK,slow.Inhibitions were determined from the voltage dependence of peak Ito,fast and IK,slow in control cells (n = 8) and in cells exposed to 5 μM A2 (n = 8). Percent inhibition was calculated from the reduction in current divided by the control current. The percent reductions in Ito,fast(A) and IK,slow(B) exhibit minimal voltage dependence, suggesting A2 reduces the number of open K+-channels per unit area of plasma membrane.

Mentions: A2 effects on the voltage dependences of Ito,fast and IK,slow were determined from peak current amplitudes at each test potential measured in CON cells and cells treated with 5 μM A2. A2 induced percent inhibitions of Ito,fast and IK,slow were calculated by taking the difference in the mean current amplitude at every test potential between CON and A2 groups and dividing the difference by the mean of the CON group. A2 induced percent inhibitions at test potentials between +10 and +50 mV are shown in Fig 3A (Ito,fast) and 3B (IK,slow). On average, peak currents in A2 stimulated cells were inhibited by 35 ± 11% and 43 ± 10% for Ito,fast and IK,slow, respectively, with minimal deviations at each test potential. These results suggest that A2 induces reductions in the number of open K+ channels per unit area of cell membrane.


Angiotensin II Type 1 Receptor-Mediated Electrical Remodeling in Mouse Cardiac Myocytes.

Kim J, Gao J, Cohen IS, Mathias RT - PLoS ONE (2015)

The voltage dependence of A2-induced reductions in peak Ito,fast and IK,slow.Inhibitions were determined from the voltage dependence of peak Ito,fast and IK,slow in control cells (n = 8) and in cells exposed to 5 μM A2 (n = 8). Percent inhibition was calculated from the reduction in current divided by the control current. The percent reductions in Ito,fast(A) and IK,slow(B) exhibit minimal voltage dependence, suggesting A2 reduces the number of open K+-channels per unit area of plasma membrane.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591968&req=5

pone.0138711.g003: The voltage dependence of A2-induced reductions in peak Ito,fast and IK,slow.Inhibitions were determined from the voltage dependence of peak Ito,fast and IK,slow in control cells (n = 8) and in cells exposed to 5 μM A2 (n = 8). Percent inhibition was calculated from the reduction in current divided by the control current. The percent reductions in Ito,fast(A) and IK,slow(B) exhibit minimal voltage dependence, suggesting A2 reduces the number of open K+-channels per unit area of plasma membrane.
Mentions: A2 effects on the voltage dependences of Ito,fast and IK,slow were determined from peak current amplitudes at each test potential measured in CON cells and cells treated with 5 μM A2. A2 induced percent inhibitions of Ito,fast and IK,slow were calculated by taking the difference in the mean current amplitude at every test potential between CON and A2 groups and dividing the difference by the mean of the CON group. A2 induced percent inhibitions at test potentials between +10 and +50 mV are shown in Fig 3A (Ito,fast) and 3B (IK,slow). On average, peak currents in A2 stimulated cells were inhibited by 35 ± 11% and 43 ± 10% for Ito,fast and IK,slow, respectively, with minimal deviations at each test potential. These results suggest that A2 induces reductions in the number of open K+ channels per unit area of cell membrane.

Bottom Line: Pre-application of the microtubule destabilizing agent colchicine eliminated A2 effects on Ito and AP duration, suggesting these effects depend on intracellular trafficking.Application of the biased agonist SII ([Sar1-Ile4-Ile8]A2), which stimulates receptor internalization without G protein activation, caused Ito reduction and AP prolongation similar to A2-induced changes.Moreover, all measured properties parallel those measured in dog heart, suggesting an autocrine RAS may be a fundamental feedback system that is present across species.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology & Biophysics, State University of New York at Stony Brook, Stony Brook, New York, United States of America.

ABSTRACT
We recently characterized an autocrine renin angiotensin system (RAS) in canine heart. Activation of Angiotensin II Type 1 Receptors (AT1Rs) induced electrical remodeling, including inhibition of the transient outward potassium current Ito, prolongation of the action potential (AP), increased calcium entry and increased contractility. Electrical properties of the mouse heart are very different from those of dog heart, but if a similar system existed in mouse, it could be uniquely studied through genetic manipulations. To investigate the presence of a RAS in mouse, we measured APs and Ito in isolated myocytes. Application of angiotensin II (A2) for 2 or more hours reduced Ito magnitude, without affecting voltage dependence, and prolonged APs in a dose-dependent manner. Based on dose-inhibition curves, the fast and slow components of Ito (Ito,fast and IK,slow) appeared to be coherently regulated by [A2], with 50% inhibition at an A2 concentration of about 400 nM. This very high K0.5 is inconsistent with systemic A2 effects, but is consistent with an autocrine RAS in mouse heart. Pre-application of the microtubule destabilizing agent colchicine eliminated A2 effects on Ito and AP duration, suggesting these effects depend on intracellular trafficking. Application of the biased agonist SII ([Sar1-Ile4-Ile8]A2), which stimulates receptor internalization without G protein activation, caused Ito reduction and AP prolongation similar to A2-induced changes. These data demonstrate AT1R mediated regulation of Ito in mouse heart. Moreover, all measured properties parallel those measured in dog heart, suggesting an autocrine RAS may be a fundamental feedback system that is present across species.

No MeSH data available.


Related in: MedlinePlus