A COMPARISON OF CYCLOPIAZONIC ACID AND RYANODINE EFFECTS ON CARDIAC-MUSCLE RELAXATION

We investigated cardiac muscle behavior after inhibition of either sar coplasmic reticulum (SR) Ca2+ release or SR Ca2+ uptake. Mechanics of 35 rat papillary muscles were studied after either ryanodine 10(-7)M ( n = 11) or cyclopiazonic acid (CPA) 10(-5)M (n = 14) and compared with a control group containing the solvent alone (n = 10). We measured th e maximum extent of shortening (DELTAL) of the preloaded twitch (DELTA L(p)), and the normalized total force (TF) of the fully isometric twit ch (TF(i)). The peak lengthening velocity (Vl) of the preloaded twitch (Vl(p)) and the normalized negative peak force derivative of the full y isometric twitch (-DF(i)) tested the lusitropic state. With the infl uence of shortening and/or load on relaxation taken into account, anal ysis of relaxation was performed using 1) Vl(p)-to-DELTAL(p) and \-DF( i)\ -to-TF(i) ratios and 2) slopes of the Vl-DELTAL and \-DF\ -TF rela tionships over the entire continuum of load. Ca2+-release inhibition w ith ryanodine induced a negative inotropic effect and a decrease in Vl (p) from 2.7 +/- 0.2 to 1.4 +/- 0.2 L(max)/s, where L(max) is the init ial length at the peak of the length-active tension curve (P < 0.001). The Vl(p)-to-DELTAL(p) ratio and the slope of the Vl-DELTAL relations hip were preserved, indicating that ryanodine was devoid of intrinsic relaxant effect under isotonic conditions. Ca2+-uptake inhibition with CPA had no inotropic effect but decreased Vl(p) from 2.9 +/- 0.1 to 2 .2 +/- 0.1 L(max)/s (P < 0.001). The Vl(p)-to-DELTAL(p) ratio and the slope of the Vl-DELTAL relationship were significantly decreased (P < 0.001), attesting to the negative relaxant effect of CPA under isotoni c conditions. This effect was confirmed using the isometric-isotonic s equence of relaxation. Under isometric conditions, no intrinsic relaxa nt effect was observed under either ryanodine or CPA. This in vitro st udy demonstrated that a specific mechanical behavior could characteriz e the cardiac performance after alteration of either SR Ca2+ release o r SR Ca2+ uptake.