The positive inotropic response to milrinone in isolated human and guinea pig myocardium

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Abstract
The bipyridine derivative, milrinone, produced positive inotropic effects in isolated, contracting right ventricular papillary muscles and left atria from guinea pigs as well as in human papillary muscle strips. The inotropic effect was biphasic in guinea pig papillary muscles (EC50, high affinity, 1.5×10−6 mol/l, about 35% of maximal effect; apparent EC50, 3×10−5 mol/l with a maximal effect at 2×10−4 mol/l) but monophasic in guinea pig left atria (EC50, 6×10−5 mol/l) and in human papillary muscle strips (EC50, 5.8×10−5 mol/l). In guinea pig papillary muscles, reserpine pretreatment or l-practolol preincubation reduced the low concentration effect only. In the presence of l-practolol, carbachol reduced the low concentration effect only. In the presence of l-practolol, carbachol reduced but not abolished the inotropic effects of milrinone (3×10−6 mol/l, 1×10−4 mol/l) in both guinea pig and human myocardium. This antagonism was prevented by atropine preincubation. The maximum inotropic effect of milrinone was similar to that of ouabain and calcium in guinea pig myocardium but markedly less than either calcium or ouabain in human myocardium. Milrinone inhibited crude guinea pig and human cardiac phosphodiesterase activity in vitro but did not inhibit 3H-ouabain binding to partially purified human cardiac (Na++K+)-ATPase-containing membranes. We conclude that the primary mode of action of milrinone in both guinea pig and human myocardium is through inhibition of phosphodiesterase. The reduced maximal inotropic effect of milrinone compared with calcium in human but not in guinea pig myocardium indicates basic differences between healthy animal and diseased human cardiac muscle.

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