Reversal of angiotensin-(1-12)-caused positive modulation on left ventricular contractile performance in heart failure: Assessment by pressure-volume analysis.

BACKGROUND

Angiotensin-(1-12) [Ang-(1-12)] is a renin-independent precursor for direct angiotensin-II production by chymase. Substantial evidence suggests that heart failure (HF) may alter cardiac Ang-(1-12) expression and activity; this novel Ang-(1-12)/chymase axis may be the main source for angiotensin-II deleterious actions in HF. We hypothesized that HF alters cardiac response to Ang-(1-12). Its stimulation may produce cardiac negative modulation and exacerbate left ventricle (LV) systolic and diastolic dysfunction.

METHODS AND RESULTS

We assessed the effects of Ang-(1-12) (2 nmol/kg/min, iv, 10 min) on LV contractility, LV diastolic filling, and LV-arterial coupling (AVC) in 16 SD male rats with HF-induced by isoproterenol (3 mo after 170 mg/kg sq. for 2 consecutive days) and 10 age-matched male controls. In normal controls, versus baseline, Ang-(1-12) increased LV end-systolic pressure, without altering heart rate, arterial elastance (E), LV end-diastolic pressure (P), the time constant of LV relaxation (τ) and ejection fraction (EF). Ang-(1-12) significantly increased the slopes (E) of LV end-systolic pressure (P)-volume (V) relations and the slopes (M) of LV stroke wok-end-diastolic V relations, indicating increased LV contractility. AVC (quantified as E/E) improved. In contrast, in HF, versus HF baseline, Ang-(1-12) produced a similar increase in P, but significantly increased τ, E, and P The early diastolic portion of LV PV loop was shifted upward with reduced in EF. Moreover, Ang-(1-12) significantly decreased E and M, demonstrating decreased LV contractility. AVC was decreased by 43%.

CONCLUSIONS

In both normal and HF rats, Ang-(1-12) causes similar vasoconstriction. In normal, Ang-(1-12) increases LV contractile function. In HF, Ang-(1-12) has adverse effects and depresses LV systolic and diastolic functional performance.