A low dose of angiotensin II increases inotropism through activation of reverse Na+/Ca2+ exchange by endothelin release
Objective: This work was aimed to prove that release/formation of endogenous endothelin acting in an autocrine/paracrine fashion contributes to the increase in contractility promoted by a low dose of angiotensin II. Methods: Isolated cat papillary muscles were used for force, pHi, [Na<SUP>+<...
Guardado en:
| Autores principales: | , , , , , |
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| Formato: | Articulo |
| Lenguaje: | Inglés |
| Publicado: |
2003
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| Materias: | |
| Acceso en línea: | http://sedici.unlp.edu.ar/handle/10915/84453 |
| Aporte de: |
| Sumario: | Objective: This work was aimed to prove that release/formation of endogenous endothelin acting in an autocrine/paracrine fashion contributes to the increase in contractility promoted by a low dose of angiotensin II. Methods: Isolated cat papillary muscles were used for force, pHi, [Na<SUP>+</SUP>]<SUB>i</SUB> and [Ca<SUP>2+</SUP>]<SUB>i</SUB> measurements and isolated cat myocytes for patch-clamp experiments. Results: In papillary muscles, 1.0 nmol/l angiotensin II increased force by 23±2% (n=4, P<0.05), [Na<SUP>+</SUP>]<SUB>i</SUB> by 2.2±0.2 mmol/l (n=4, P<0.05), and peak (but not diastolic) Ca<SUP>2+</SUP> from 0.674±0.11 to 0.768±0.13 μmol/l (n=4, P<0.05), without affecting pH i. Force and [Na<SUP>+</SUP>]<SUB>i</SUB> increase were abolished by inhibition of the Na<SUP>+</SUP>/H<SUP>+</SUP> exchanger (NHE) with the inhibitor HOE642, blockade of endothelin receptors with the nonselective antagonist TAK044 and by inhibition of the endothelin-converting enzyme with phosphoramidon. Force but not [Na<SUP>+</SUP>]<SUB>i</SUB> increase was abolished by inhibition of reverse Na<SUP>+</SUP>/Ca<SUP>2+</SUP> exchange (NCX) with the inhibitor KB-R7943. Similar increase in force (21±2%, n=4, P<0.05) and in [Na<SUP>+</SUP>]<SUB>i</SUB> (2.4±0.4 mmol/l, n=4, P<0.05) that were also suppressed by TAK044 and HOE642 were induced by exogenous 5.0 nmol/l endothelin-1. KB-R7943 reverted the endothelin-1 effect on force but not on [Na<SUP>+</SUP>]<SUB>i</SUB>. In isolated myocytes, exogenous endothelin-1 dose-dependently increased the NCX current and shifted the NCX reversal potential (E<SUB>NCX</SUB>) to a more negative value (ΔE<SUB>NCX</SUB>: -10±3 and -17±5 mV, with 1 and 10 nmol/l endothelin-1, respectively, n=12). The latter effect was prevented by HOE642. Conclusion: Taken together, the results indicate that a low dose of angiotensin II induces release of endothelin, which, in autocrine/paracrine fashion activates the Na<SUP>+</SUP>/H<SUP>+</SUP> exchanger, increases [Na<SUP>+</SUP>]<SUB>i</SUB> and changes E<SUB>NCX</SUB>, promoting the influx of Ca<SUP>2+</SUP> that leads to a positive inotropic effect (PIE). |
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