RYANODINE AND LEFT-VENTRICULAR FUNCTION IN INTACT DOGS - DISSOCIATIONOF FORCE-BASED AND VELOCITY-BASED INDEXES

After anesthesia and autonomic blockade, nine dogs chronically instrum ented with left ventricular (LV) micromanometers and piezoelectric dim ension crystals were studied before and after the intravenous administ ration of 4 mu g/kg ryanodine, a specific inhibitor of the sarcoplasmi c reticulum Ca2+ release channel. Ryanodine prolonged LV contraction a nd relaxation (P < 0.001) without changing heart rate, end-diastolic v olume (EDV), or end-systolic pressure. Velocity-dependent mechanical p arameters were significantly depressed, including the maximal rate of LV pressure rise (dP/dt(max); P < 0.002), the mean velocity of circumf erential fiber shortening (P < 0.002), the slope of the dP/dt(max)-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 (P-ES-V -ES) and stroke work (SW)-EDV relations, both force-based parameters, were increased (P < 0.05) or maintained, respectively. Ryanodine reduc ed overall LV contractile performance, evidenced by significant rightw ard shifts of the P-ES-V-ES, dP/dt(max)-EDV, and SW-EDV relations and reduced SW at constant preload (P < 0.02). Thus, in the dosed-chest do g, low-dose ryanodine resulted in 1) generalized slowing of LV mechani cal events without changes in heart rate or load, 2) dissociation of v elocity-based and force-based measures of LV function, with depression of the former but enhancement or maintenance of the latter, and 3) re duced overall LV inotropic performance. These effects are consistent w ith ryanodine-induced alterations of the Ca2+ transient and altered sa rcoplasmic reticulum Ca2+ availability.