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The electrophysiological properties of embryonic chick hearts (ventricles) change during development; the largest changes occur between days 2 and 8. Resting potential (E,) and peak overshoot potential (+Emx) increase, respectively, from -35 mv and +11 my at day 2 to -70 mv and +28 mv at days 12-21. Action potential duration does not change significantly. Maximum rate of rise of the action potential (+ Im,) increases from about 20 v/sec at days 2-3 to 150 v/sec at days 18-21; + ,2x of young cells is not greatly increased by applied hyperpolarizing current pulses. In resting Em vs. log [K+]o,, curves, the slope at high K+ is lower in young hearts (e.g. 30 mv/decade) than the 50-60 mv/decade obtained in old hearts, but the extrapolated [K+]i values (125-140 mM) are almost as high. Input resistance is much higher in young hearts (13 MS2 at day 2 vs. 4.5 Mi at days 8-21), suggesting that the membrane resistivity (R,) is higher. The ratio of permeabilities, PNJPK, is high (about 0.2) in young hearts, due to a low PE:, and decreases during ontogeny (to about 0.05). The low K + conductance (gKc) in young hearts accounts for the greater incidence of hyperpolarizing afterpotentials and pacemaker potentials, the lower sensitivity (with respect to loss of excitability) to elevation of [K+] 0 , and the higher chronaxie. Acetylcholine does not increase go of young or old ventricular cells. The increase in (Na+, K+)-adenosine triphosphatase (ATPase) activity during development tends to compensate for the increase in gK. +Emx,. and + ima,,. are dependent on [Na+]o in both young and old hearts. However, the Na+ channels in young hearts (2-4 days) are slow, tetrodotoxin (TTX)-insensitive, and activated-inactivated at lower E,,. In contrast, the Na+ channels of cells in older hearts ( > 8 days) are fast and TTX-sensitive, but they revert back to slow channels when placed in culture.

We compared the effects of the newer inotropic drugs, pimobendan (UD-CG 115 BS) and milrinone (Win 47203), on the electrical, mechanical and biochemical activity of intact and detergent-skinned preparations of cardiac muscle. Both of these agents increased contractile force of guinea pig papillary muscle preparations bathed under physiological conditions or depolarized with 25 mM K + o . The positive inotropic action was associated with potentiation of the Ca 3+ -dependent slow action potentials (APs). Contractile force developed in the presence of 25 mM [K]o and 1 fiM isoproterenol was increased further by addition of 50 /xM pimobendan with no effect on the slow action potential. Milrinone (50 fiM) did not produce a further increase in the force or potentiate the slow APs. Pimobendan, in a dose-dependent manner, increased active tension developed by chemically-skinned dog heart muscle fibers at submaximally activating concentrations of Ca 2+ , whereas milrinone did not. At pCa 6.25, the half-maximal concentration of pimobendan for stimulation of force development was about 40 fiM. At maximally activating levels of Ca 2+ (pCa 4.5), pimobendan had little or no effect on force development. The effect of pimobendan on force was paralleled by changes in the Ca 2+ -activated Mg-ATPase activity of the isometric skinned fiber preparations. Moreover, the tension-cost (unit increase in ATPase rate/unit increase in force) was unchanged in the presence of pimobendan. Milrinone did not affect ATP hydrolysis by the skinned fiber preparations. Force-pCa and ATPase-pCa relations of skinned fiber preparations contracting isometrically were shifted to the left by 0.15-0.20 pCa units in the presence of 50 (iM pimobendan. In contrast, there was no effect of pimobendan on the ATPase activity of unloaded myofibrillar preparations. The stimulation of force and ATPase activity of the skinned heart muscle fibers could be accounted for by an effect of pimobendan on the affinity of the regulatory (low affinity, Ca 2+ -specific) binding sites of cardiac troponin C. Ca 2+ binding to the "structural" high affinity sites of troponin C was slightly inhibited. The results indicate that the positive inotropic actions of pimobendan, but not milrinone, may involve activation of the cardiac myofilaments by a direct effect involving an increased affinity of the regulatory site on troponin C for Ca 2 + . (Circulation Research 1988;63;911-922) P imobendan (UD-CG 115 BS; 4,5-dihydro-6-2-(4-methoxyphenyl)-lH-benzimidazole-5-yl-5-methyl-3(2H)-pyridazinone) and milrinone (Win 47023; l,6-dehydro-2-methyl-6-oxo (3,4'-bipyridine)-5-carbonitrile) are two drugs belonging to a new class of nondigitalis inotropic agents.

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