ryanodine and Heart-Diseases

Topics: Animals; Binding, Competitive; Calcium; Calcium Channels; Calmodulin-Binding Proteins; Heart Diseases; Humans; Isotope Labeling; Malignant Hyperthermia; Muscle Proteins; Musculoskeletal Diseases; Ryanodine; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Xenobiotics

The ryanodine receptor (RyR) is a Ca

Topics: Biological Assay; Calcium; Calcium Channel Blockers; Drug Discovery; Heart Diseases; HEK293 Cells; Humans; Microsomes; Muscle, Skeletal; Ryanodine; Ryanodine Receptor Calcium Release Channel

Doxorubicin treatment causes delayed development of cardiotoxicity. Whether the doxorubicin-induced impairment of cardiac functions reverses or progresses with time after the cessation of the treatment was examined. The rats were injected with doxorubicin (2.5 mg/kg, i.v., once a week for 3 weeks) and sacrificed at 1 (1W), 13 (13W), or 18 (18W) weeks after the final doxorubicin administration. The time to peak of twitch contraction observed at 2-Hz stimulation was not altered in left atrial or ventricular muscle preparations isolated from 1W rats, but it was prolonged in those from 13W and 18W rats. The reduction of the magnitude of postrest contraction and the alteration of force-frequency relationships in left atrial muscle preparations in 1W rats were not significant, but were intensified in the 13W and 18W groups. Alterations in the postrest contraction and the force-frequency relationships in ventricular muscle preparations isolated from doxorubicin-treated rat hearts were weaker, but the pattern of alteration was similar to that observed in left atrial muscle preparations. Caffeine-induced contraction observed in skinned fibers that were isolated from the 1W rats was not altered, but it was reduced in the 18W rats. The Ca2+ sensitivity of contractile proteins was not altered in doxorubicin-treated rat hearts in any of the groups. The K(d) values estimated from a [3H]ryanodine binding study were not altered, but the B(max) values were significantly lower in the 13W and 18W groups than those observed in control rats. These results suggest that the dysfunction of the sarcoplasmic reticulum progresses after the completion of doxorubicin treatment and contributes to the doxorubicin-induced late cardiotoxicity.

Topics: Animals; Antibiotics, Antineoplastic; Caffeine; Calcium; Doxorubicin; Heart Atria; Heart Diseases; Heart Ventricles; Male; Muscle Fibers, Skeletal; Myocardial Contraction; Phosphodiesterase Inhibitors; Rats; Rats, Wistar; Ryanodine; Saponins; Sarcoplasmic Reticulum; Time Factors

Fifty human atrial specimens removed at time of cardiac surgery were studied in vitro. Thirty-four samples were selected as presenting partial cell depolarization and exhibiting slow response action potentials. Twenty of these preparations were automatic whereas 14 were not. Neither mean maximum diastolic potential (-52.8 +/- 1.3 mV and -49.3 +/- 2.2 mV respectively) nor maximum rate of depolarization (Vmax) (1.1 +/- 0.1 V/s and 1.3 +/- 0.8 V/s) significantly differed between these two groups. Abnormal automaticity due to phase 4 depolarization occurred in 12/13 preparations dissected from markedly dilated atria whereas it occurred in only 2/10 preparations sampled from non-dilated atria. A statistically significant relationship between in vitro abnormal pacemaking and atrial dilatations was found. We investigated the effects on abnormal pacemaker depolarization and automaticity of a reduction in the extracellular Na and Ca and of sarcoplasmic reticulum (SR) inhibitors. Abnormal pacemaker depolarization appeared to be much more sensitive to a reduction in the extracellular Na than in the extracellular Ca. Both Sr and Mg slowed the automatic rate. Ryanodine 3 X 10(-6) M, a specific SR inhibitor, irreversibly lengthened the spontaneous basic cycle duration to about 300% of control. Epinephrine up to 10(-4) M was ineffective in accelerating the residual spontaneous rhythm that persists after ryanodine action, although epinephrine markedly enhanced the overshoot and Vmax of the slow responses. It is concluded that, in the human atrial myocardium, abnormal pacemaking that develops at low level of membrane potential: is promoted by chamber dilatation; is strongly modulated by SR-dependent processes.

Topics: Adolescent; Adult; Calcium; Child; Child, Preschool; Dilatation, Pathologic; Electrophysiology; Heart Atria; Heart Conduction System; Heart Diseases; Humans; In Vitro Techniques; Infant; Infant, Newborn; Middle Aged; Ryanodine; Sarcoplasmic Reticulum