title: Ryanodine and left ventricular function in intact dogs: dissociation of force-based and velocity-based indexes.
abstract: After anesthesia and autonomic blockade, nine dogs chronically instrumented with left ventricular (LV) micromanometers and piezoelectric dimension crystals were studied before and after the intravenous administration of 4 micrograms/kg ryanodine, a specific inhibitor of the sarcoplasmic reticulum Ca2+ release channel. Ryanodine prolonged LV contraction and relaxation (P < 0.001) without changing heart rate, end-diastolic volume (EDV), or end-systolic pressure. Velocity-dependent mechanical parameters were significantly depressed, including the maximal rate of LV pressure rise (dP/dtmax; P < 0.002), the mean velocity of circumferential fiber shortening (P < 0.002), the slope of the dP/dtmax-EDV relation (P < 0.05), and the time constant of LV relaxation (P < 0.01). In contrast, the slopes of the end-systolic pressure-volume (PES-VES) and stroke work (SW)-EDV relations, both force-based parameters, were increased (P < 0.05) or maintained, respectively. Ryanodine reduced overall LV contractile performance, evidenced by significant rightward shifts of the PES-VES, dP/dtmax-EDV, and SW-EDV relations and reduced SW at constant preload (P < 0.02). Thus, in the closed-chest dog, low-dose ryanodine resulted in 1) generalized slowing of LV mechanical events without changes in heart rate or load, 2) dissociation of velocity-based and force-based measures of LV function, with depression of the former but enhancement or maintenance of the latter, and 3) reduced overall LV inotropic performance. These effects are consistent with ryanodine-induced alterations of the Ca2+ transient and altered sarcoplasmic reticulum Ca2+ availability.
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Prabhu
authors.forename: M M
authors.initials: MM
authors.lastname: Rozek
authors.forename: D R
authors.initials: DR
authors.lastname: Murray
authors.forename: G L
authors.initials: GL
authors.lastname: Freeman
mesh_terms: D000818:Animals; D003971:Diastole / Q000187:drug effects; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D007275:Injections, Intravenous; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D012433:Ryanodine / Q000008:administration & dosage / Q000494:pharmacology*; D013599:Systole / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D012433:Ryanodine