Hemodynamic effects of a calcium channel promoter, BAY y 5959, are preserved after chronic administration in ischemic heart failure in conscious dogs.
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. Because myofilament responsiveness to calcium is preserved in congestive heart failure (CHF), the inotropic responsiveness to this compound should be preserved in CHF, and tolerance should not develop despite long-term treatment. To test these hypotheses, CHF was induced in 14 chronically instrumented dogs by daily (30 +/- 5 days) intracoronary microsphere injections. The effects of BAY y 5959 (2-h i.v. infusions of 3 microg/kg/min and 10 microg/kg/min) were determined before heart failure, after heart failure was established and then 2 h after the end of a 5-day continuous BAY y 5959 intra-atrial infusion. Before CHF, the positive inotropic effect of BAY y 5959 at a dose of 10 microg/kg/min [left ventricular dP/dt (LVdP/dt) increased from 2955 +/- 132 mmHg to 4897 +/- 426 mmHg, P < .05] was associated with bradycardia (HR decreased from 92 +/- 4 to 78 +/- 6 b/min, P <.05), slight increases in mean arterial pressure (it increased from 100 +/- 2 mmHg to 113 +/- 5 mmHg, P <.05) and did not alter left ventricular end-diastolic pressure. In CHF, BAY y 5959 continued to induce dose-dependent increases in left ventricular systolic pressure, LVdP/dt and mean arterial pressure, as well as causing bradycardia and a significant decrease in left ventricular end-diastolic pressure. After a 5-day infusion of BAY y 5959, base-line LVdP/dt and left ventricular end-diastolic pressure improved. The responses of LVdP/dt and mean arterial pressure to BAY y 5959 were similar to those of the control state. The sustained responses in CHF and after long-term infusion suggest that BAY y 5959 may be an effective and potent inotropic agent for treatment of CHF that does not lead to tolerance to its positive inotropic effects.
Division of Circulatory Physiology, Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
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Yi
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Burkhoff
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Zhang
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Zhu
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Zwas
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Wang
D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D004095:Dihydropyridines / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology*; D013997:Time Factors
C109289:BAY y 5959; D002120:Calcium Channel Agonists; D004095:Dihydropyridines