The use of inotropic agents is an important form of therapy for many patients with CHF. Currently used inotropic agents generally fall into one of two classes: b-agonists or phosphodiesterase inhibitors. Although they are efficacious in many settings, their use is sometimes limited by afterload-reducing effects, by decreased effectiveness in heart failure, by the development of tolerance and by potential proarrhythmic effects such as sinus tachycardia and ventricular ectopy.
BAY y 5959 is a dihydropyridine derivative that binds to L-type calcium channels in a voltage-dependent manner and promotes calcium entry into the cell during the plateau of the
action potential by influencing mean open time (Bechem et al., 1997). In contrast to previous calcium promoters, BAY y 5959 has been shown to be relatively myocardial-specific, lacking significant vasoconstrictor properties that are present in previous compounds in this class of drugs, such as BAY k 8644 (Bechem et al., 1997; Huetter et al., 1994). A recent study has demonstrated that in normal conscious dogs, the positive inotropic effects of BAY y 5959 are comparable to those of two other traditional inotropic agents, dobutamine and milrinone (Sato et al., 1997). It remains to be determined whether the positive inotropic effect of BAY y 5959 exists in the heart failure state and whether tolerance, defined as a reduced inotropic response after prolonged exposure, develops with the continuous use of BAY y 5959. Because myofilament responsiveness to calcium is preserved in the heart failure state (Hajjar and Gwathmey, 1992), it is hypothesized that the inotropic responsiveness to this compound should be similar to that observed in the normal heart and that tolerance should not develop after long-term treatment.
Tags: BAY y 5959, calcium, calcium channels, dogs, heart failure, hemodynamics, ischemic