title: Angiotensin II acutely decreases myocardial stiffness: a novel AT1, PKC and Na+/H+ exchanger-mediated effect.
abstract: 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.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Porto, Porto 4200-319, Portugal. amoreira@med.up.pt
authors.forename: Adelino F
authors.initials: AF
authors.lastname: Leite-Moreira
authors.forename: Paulo
authors.initials: P
authors.lastname: Castro-Chaves
authors.forename: Pedro
authors.initials: P
authors.lastname: Pimentel-Nunes
authors.forename: Alexandre
authors.initials: A
authors.lastname: Lima-Carneiro
authors.forename: Miguel S
authors.initials: MS
authors.lastname: Guerra
authors.forename: João Bruno
authors.initials: JB
authors.lastname: Soares
authors.forename: João
authors.initials: J
authors.lastname: Ferreira-Martins
mesh_terms: D000470:Alkaloids; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D053119:Benzophenanthridines; D003971:Diastole; D004305:Dose-Response Relationship, Drug; D004548:Elasticity; D006321:Heart / Q000187:drug effects*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology*; D009287:Naphthyridines / Q000494:pharmacology; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016277:Ventricular Function, Left
chemical_list: D000470:Alkaloids; D047228:Angiotensin II Type 1 Receptor Blockers; D053119:Benzophenanthridines; D009287:Naphthyridines; D010617:Phenanthridines; D047428:Protein Kinase Inhibitors; D044140:Receptor, Angiotensin, Type 1; D017923:Sodium-Hydrogen Exchangers; C095905:ZD 7155; D000804:Angiotensin II; D000584:Amiloride; C056369:5-(N-methyl-N-isobutyl)amiloride; C016299:chelerythrine; D011493:Protein Kinase C; D019808:Losartan