title: Lack of desensitization and enhanced efficiency of calcium channel promoter in conscious dogs with heart failure.
abstract: The goal of this study was to compare responses to a calcium promoter, BAY y 5959, and dobutamine (Dob) in heart failure (HF). Dogs (n = 9) were chronically instrumented and studied in the conscious state before and after pacing-induced HF. In the control state, BAY y 5959 (20 microgram. kg-1. min-1) increased the first derivative of left ventricular (LV) pressure (dP/dt) by 83 +/- 8% and mean arterial pressure (MAP) by 8 +/- 2% and decreased heart rate (HR) by 30 +/- 3%. With Dob (10 microgram. kg-1. min-1) LV dP/dt rose similarly (+80 +/- 6%), but HR also rose (+25 +/- 4%) (P < 0.05 vs. BAY y 5959). After HF developed, BAY y 5959 still increased LV dP/dt by 108 +/- 8% and MAP by 21 +/- 2% and decreased HR by 28 +/- 4%, whereas Dob increased LV dP/dt by only 50 +/- 7% (P < 0.05 vs. BAY y 5959) and MAP by 7 +/- 3%, and HR did not change (+3 +/- 3%) (P < 0.05 vs. BAY y 5959). In HF, cardiac work increased more (P < 0. 05) with BAY y 5959 (+105 +/- 13%) compared with Dob (+47 +/- 11%), yet myocardial oxygen consumption increased similarly with the two drugs. Accordingly, mechanical efficiency increased more (P < 0.05) with BAY y 5959 (+73 +/- 14%) than with Dob (+17 +/- 12%). These data indicate that 1) increases in contractility mediated directly by Ca2+ are relatively resistant to desensitization in HF; and 2) the calcium-channel promoter can produce increases in myocardial contractility and cardiac work similar to those of Dob at a significantly lower oxygen cost, thereby enhancing mechanical efficiency in HF.
authors.affiliation: Cardiovascular and Pulmonary Research Institute, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212, USA.
authors.forename: K
authors.initials: K
authors.lastname: Asai
authors.forename: M
authors.initials: M
authors.lastname: Uechi
authors.forename: N
authors.initials: N
authors.lastname: Sato
authors.forename: W
authors.initials: W
authors.lastname: Shen
authors.forename: T
authors.initials: T
authors.lastname: Meguro
authors.forename: M A
authors.initials: MA
authors.lastname: Mathier
authors.forename: R P
authors.initials: RP
authors.lastname: Shannon
authors.forename: S F
authors.initials: SF
authors.lastname: Vatner
mesh_terms: D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D002302:Cardiac Output / Q000187:drug effects; D002303:Cardiac Output, Low / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002395:Catecholamines / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004280:Dobutamine / Q000494:pharmacology; D004285:Dogs; D004351:Drug Resistance / Q000502:physiology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: C109289:BAY y 5959; D002120:Calcium Channel Agonists; D015220:Calcium Channels; D002316:Cardiotonic Agents; D002395:Catecholamines; D004095:Dihydropyridines; D004280:Dobutamine