Angiotensin II acutely decreases myocardial stiffness: a novel AT1, PKC and Na+/H+ exchanger-mediated effect
| Autor: | Adelino F, Leite-Moreira, Paulo, Castro-Chaves, Pedro, Pimentel-Nunes, Alexandre, Lima-Carneiro, Miguel S, Guerra, João Bruno, Soares, João, Ferreira-Martins |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Benzophenanthridines
Male Sodium-Hydrogen Exchangers Dose-Response Relationship Drug Angiotensin II Myocardium Heart Myocardial Contraction Elasticity Losartan Receptor Angiotensin Type 1 Ventricular Function Left Phenanthridines Amiloride Alkaloids Diastole Papers cardiovascular system Animals Rabbits Naphthyridines Angiotensin II Type 1 Receptor Blockers Protein Kinase Inhibitors hormones hormone substitutes and hormone antagonists Protein Kinase C |
| Zdroj: | British journal of pharmacology. 147(6) |
| ISSN: | 0007-1188 |
| Popis: | Acute effects of angiotensin II (AngII) on diastolic properties of the myocardium were investigated. Increasing concentrations of AngII (10(-9) to 10(-5) M) were added to rabbit papillary muscles in the absence (n=11) or presence of: (i) AT1 receptor antagonists, losartan (10(-6) M; n=7) or ZD-7155 (10(-7) M; n=8); (ii) ZD-7155 (10(-7) M) plus AT2 receptor antagonist PD-123,319 (2 x 10(-6) M; n=6); (iii) PKC inhibitor, chelerythrine (10(-5) M; n=8); or (iv) Na(+)/H(+) exchanger (NHE) inhibitor, 5-(N-methyl-N-isobutyl)-amiloride (10(-6) M; n=10). Passive length-tension relations were constructed before and after a single concentration of AngII (10(-5) M, n=6). Effects of AngII infusion (10 microg kg(-1) min(-1)) were evaluated in in situ rabbit hearts. AngII concentration dependently increased inotropy and resting muscle length (RL). At 10(-5) M, active tension increased 43.3+/-6.25% and RL 1.96+/-0.4%. Correcting RL to its initial value resulted in a 46+/-4% decrease of resting tension, indicating decreased muscle stiffness, as confirmed by the right and downward shift of the passive length-tension relation promoted by AngII. In the intact heart, at matched systolic pressures of 112 mmHg, AngII decreased end-diastolic pressures from 10.3+/-0.3 to 5.9+/-0.5 mmHg, and minimal diastolic pressures from 8.4+/-0.5 to 4.6+/-0.6 mmHg. AT1 blockade inhibited AngII effects on myocardial inotropy and stiffness, while PKC or NHE inhibition only significantly attenuated its effects on resting length and tension. In conclusion, AngII decreases myocardial stiffness, an effect that requires AT1 receptor activation and is mediated by PKC and NHE. This represents a novel mechanism of acute neurohumoral modulation of diastolic function, suggesting that AngII is a powerful regulator of cardiac filling. |
| Databáze: | OpenAIRE |
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