The Positive Inotropic Effects of Milrinone But Not of Digoxin are Attenuated at Short Cycle Lengths

Abstract

The effects of inotropically active agents on the left ventricular force-interval relation are a potential determinant of their clinical utility and safety. However, little information is available concerning the effects of noncatecholamine positive inotropic agents on this relation. Therefore this study compared the short-term effects of digoxin and milrinone on resting hemodynamics, frequency potentiation (FP), and mechanical restitution (MR) in patients undergoing nonemergency cardiac catheterization. Both digoxin and milrinone produced similar increases in LV + dP/dt at rest (12.2 +/- 1.3%, p < 0.000001 and 11.4 +/- 3.2%, p < 0.01, respectively). The positive inotropic effects of digoxin were marginally attenuated during FP (by 8.5 +/- 4.2% and 4.6 +/- 2.9% at 10 and 60 s, respectively, both p = NS compared with baseline). Similarly, on MRC analysis, the parameter c (a measure of sensitivity of contractile performance to reductions in cycle length) increased by 3.6 +/- 3.7% (p = NS). Whereas the positive inotropic effects of milrinone were not significantly attenuated during FP, they were abolished and possibly reversed at short cycle lengths on MR curve construction (6.8 +/- 5.9% negative inotropic effect at 60% of resting cycle length; p = NS; p < 0.05 vs. resting cycle length). In conclusion, in patients with well-preserved left ventricular systolic function, the positive inotropic effects of milrinone but not of digoxin are markedly dependent on heart rate. These properties may influence both relative safety and efficacy of both agents.

Attenuation of the Negative Inotropic Effects of Metoprolol at Short Cycle Lengths in Humans

“…Construction of MRCs was the primary methodology used in the current study for the quantitative examination of drug effects on the force-interval relationship. We have previously shown that this is highly reproducible, with significant determinants of the parameter c including R-R interval (held constant in the present investigation) and left ventricular ejection fraction (14,15). Sodium nitroprusside, used in part because of the known insensitivity of the force-frequency relationship to nitric oxide (17), exerted no significant effects on mechanical restitution, suggesting that the parameter c is relatively independent of small changes in preload and afterload.…”

“…Mechanical restitution. The MRCs were constructed as previously described (14,15). Briefly, premature stimuli of twice the threshold strength were inserted every 8 beats during baseline pacing, at progressively shorter R-R intervals, until refractoriness prevented impulse conduction.…”

“…Mechanical restitution is the recovery of myocardial contractility after a non-steady-state beat (7). We have recently described a mathematical model of the MRC that has proven highly reproducible in patients under investigation for ischemic heart disease (14,15). In the current investigation, we studied the acute effects of 3 pharmacologically different antiarrhythmic agents on the forceinterval relationship, metoprolol (a selective ␤ 1 -adrenoceptor antagonist), d,l-sotalol (a nonselective ␤-adrenoceptor antagonist with additional outward delayed rectifier potassium current blocking properties) and verapamil (an L-type calcium-channel antagonist).…”