RELATIONSHIP BETWEEN ACTION-POTENTIAL, CONTRACTION-RELAXATION PATTERN, AND INTRACELLULAR CA2-FAILURE( TRANSIENT IN CARDIOMYOCYTES OF DOGS WITH CHRONIC HEART)

Abnormalities of contractile function have been identified in cardiomy ocytes isolated from failed human hearts and from hearts of animals wi th experimentally induced heart failure (HF). The mechanism(s) respons ible for these functional abnormalities are not fully understood. In t he present study, we examined the relationship between action potentia l duration, pattern of contraction and relaxation, and associated intr acellular Ca2+ transients in single cardiomyocytes isolated from the l eft ventricle (LV) of dogs (n = 7) with HF produced by multiple sequen tial intracoronary micro-embolizations. Comparisons were made with LV cardiomyocytes isolated from normal dogs. Action potentials were measu red in isolated LV cardiomyocytes by perforated patch clamp, Ca2+ tran sients by flue 3 probe fluorescence, and cardiomyocyte contraction and relaxation by edge movement detector. HF cardiomyocytes exhibited an abnormal pattern of con traction and relaxation characterized by an at tenuated initial twitch (spike) followed by a sustained contracture (' dome') of 1 to 8 s in duration and subsequent delayed relaxation. This pattern was more prominent at low stimulation rates (58% at 0.2 Hz, n = 211, 21% at 0.5 Hz, n = 185). Measurements of Ca2+ transients in HF cardiomyocytes at 0.2 Hz manifested a similar spike and dome configur ation. The dome phase of both the contraction/relaxation pattern and C a2+ transients seen in HF cardiomyocytes coincided with a sustained pl ateau of the action potential. Shortening of the action potential dura tion by administration of saxitoxin (100 nM) or lidocaine (30 mu M) re duced the duration of the dome phase of both the contraction/relaxatio n profile as well as that of the Ca2+ transient profile. An increase o f stimulation rate up to 1 Hz caused shortening of the action potentia l and disappearance of the spike-dome profile in the majority of HF ca rdiomyocytes. Tn HE cardiomyocytes, the action potential and Ca2+ tran sient duration were not significantly different from those measured in normal cells. However, the contraction-relaxation cycle was significa ntly longer in HF cells (314 +/- 67 ms, n = 21, vs. 221 +/- 38 ms, n = 46, mean +/- SD), indicating impaired excitation-contraction uncoupli ng in HF cardiomyocytes. The results show that, in cardiomyocytes isol ated from dogs with HF, contractile abnormalities and abnormalities of intracellular Ca2+ transients at low stimulation rates are characteri zed by a spike-dome configuration. This abnormal pattern appears to re sult from prolongation of the action potential.