Journal
PLOS ONE
Volume 10, Issue 10, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0138711
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Funding
- National Institutes of Health [HL85221, HL094910, HL111401]
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We recently characterized an autocrine renin angiotensin system (RAS) in canine heart. Activation of Angiotensin II Type 1 Receptors (AT(1)Rs) induced electrical remodeling, including inhibition of the transient outward potassium current I-to, 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 I-to in isolated myocytes. Application of angiotensin II (A2) for 2 or more hours reduced I-to magnitude, without affecting voltage dependence, and prolonged APs in a dose-dependent manner. Based on dose-inhibition curves, the fast and slow components of I-to (I-to,I- fast and I-K,I- slow) appeared to be coherently regulated by [A2], with 50% inhibition at an A2 concentration of about 400 nM. This very high K-0.5 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 I-to and AP duration, suggesting these effects depend on intracellular trafficking. Application of the biased agonist SII ([Sar(1)-Ile(4)-Ile(8)]A2), which stimulates receptor internalization without G protein activation, caused Ito reduction and AP prolongation similar to A2-induced changes. These data demonstrate AT(1)R mediated regulation of I-to 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.
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