1 Acute effects of angiotensin II (AngII) on diastolic properties of the myocardium were investigated. 2 Increasing concentrations of AngII (10 À9 to 10 À5 M) were added to rabbit papillary muscles in the absence (n ¼ 11) or presence of: (i) AT1 receptor antagonists, losartan (10 À6 M; n ¼ 7) or ZD-7155 (10 À7 M; n ¼ 8); (ii) ZD-7155 (10 À7 M) plus AT2 receptor antagonist PD-123,319 (2 Â 10 À6 M; n ¼ 6); (iii) PKC inhibitor, chelerythrine (10 À5 M; n ¼ 8); or (iv) Na þ /H þ exchanger (NHE) inhibitor, 5-(Nmethyl-N-isobutyl)-amiloride (10 À6 M; n ¼ 10). Passive length-tension relations were constructed before and after a single concentration of AngII (10 À5 M, n ¼ 6). Effects of AngII infusion (10 mg kg À1 min À1 ) were evaluated in in situ rabbit hearts. 3 AngII concentration dependently increased inotropy and resting muscle length (RL). At 10 À5 M, active tension increased 43.376.25% and RL 1.9670.4%. Correcting RL to its initial value resulted in a 4674% 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 10.370.3 to 5.970.5 mmHg, and minimal diastolic pressures from 8.470.5 to 4.670.6 mmHg. 4 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. 5 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.

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Dependence of pyruvate's positive inotropic effect on energetic substrate availability and potential role of its mitochondrial uptake were investigated. Pyruvate (3, 10 and 15 mM) was added to rabbit right ventricular papillary muscles (protocol I; n = 10) and human right auricular trabeculae (protocol II; n = 6), using glucose as energetic substrate. In protocols III & IV (rabbit papillary muscles; n = 8 and n = 10, respectively) pyruvate's mitochondrial uptake was inhibited by alpha-cyano-4-hydroxycinnamate (0.5 mM) with octanoate as energetic substrate at 5 and 0.2 mM, respectively. In 8 additional rabbit papillary muscles, effects of L-alanine (10, 20 and 50 mM) were tested. In protocols I&II, pyruvate had a dose-dependent positive inotropic effect that was maximal at 10 mM, increasing in rabbit myocardium: 45.0+/-9.4% active tension, 20.5+/-7.4% peak rate of tension rise, 32.5+/-8.6% peak isotonic shortening, 31.2+/-11.7% peak rate of lengthening, 27.8+/-3.2% twitch duration. In protocol III (5 mM octanoate), pyruvate's positive inotropic effect was still present and even enhanced, while in protocol IV (0.2 mM octanoate) it was decreased and not observed with 3 mM of pyruvate. We conclude that, in rabbit papillary muscles, the positive inotropic effect of pyruvate is modulated by the availability of metabolic substrates and presumably does not depend on its mitochondrial uptake.

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