ryanodine and Hyperkalemia

Studies using isolated sinoatrial node (SAN) cells indicate that rhythmic spontaneous sarcoplasmic reticulum calcium release (Ca clock) plays an important role in SAN automaticity. In the intact SAN, cross-contamination of optical signals from the SAN and the right atrium (RA) prevent the definitive testing of Ca clock hypothesis. The aim of this study was to use a novel approach to selectively mapping the intact SAN to examine the Ca clock mechanism.. We simultaneously mapped intracellular Ca (Ca(i)) and membrane potential (V(m)) in 10 isolated, Langendorff-perfused normal canine RAs. The excitability of the RA was suppressed with high-potassium Tyrode's solution, allowing selective optical mapping of V(m) and Ca(i) of the SAN. Isoproterenol (ISO, 0.03 µmol/L) decreased the cycle length of the sinus beats, and shifted the leading pacemaker site from the middle or inferior SAN to the superior SAN in all RAs. The Ca(i) upstroke preceded the V(m) in the leading pacemaker site by up to 18 ± 2 ms. ISO-induced changes to SAN were inhibited by ryanodine (3 µmol/L), but not ZD7288 (3 µmol/L), a selective I(f) blocker.. We conclude that, in the isolated canine RA, a high extracellular potassium concentration can suppress atrial excitability thus leading to SAN-RA conduction block, allowing selective optical mapping of the intact SAN. Acceleration of Ca cycling in the superior SAN underlies the mechanism of sinus tachycardia during sympathetic stimulation.

Topics: Animals; Biological Clocks; Calcium; Cardiotonic Agents; Dogs; Heart Atria; Heart Rate; Hyperkalemia; Isoproterenol; Isotonic Solutions; Male; Membrane Potentials; Perfusion; Potassium; Pyrimidines; Ryanodine; Sarcoplasmic Reticulum; Sinoatrial Node; Sympathetic Nervous System; Tachycardia, Sinus

The effects of the L-type (nifedipine and verapamil) and the T-type (mibefradil) Ca2+ channel blockers on the increase in intracellular Ca2+ concentration ([Ca2+]i) induced by NaCN metabolic inhibition and hyperkalemia were examined in chicken cardiomyocytes using fluorescence imaging with Fura-2. NaCN induced a slow and sustained rise in [Ca2+]i, which was not affected by pretreating the cells for 5 min with nifedipine, verapamil, or mibefradil at 100 nM or 10 microM. Pretreatment of the cells with 10 microM nifedipine, verapamil, or mibefradil for 5 min remarkably inhibited the K+-induced increase in [Ca2+]i. These inhibitory effects diminished after 48-h pretreatment with nifedipine or verapamil but not with mibefradil. Ryanodine also induces an increase in [Ca2+]i, and this effect was enhanced by 48-h pretreatment of the cells with 10 microM verapamil but not with 10 microM mibefradil. We conclude that the NaCN-induced increase in [Ca2+]i is independent of the Ca2+ influx though the L-type or T-type Ca2+ channels. Chronic inhibition of the L-type Ca2+ channels but not T-type channels may enhance the ryanodine receptor-mediated Ca2+ release, which may be responsible for the development of tolerance to their inhibitory effects on K+-induced increase in [Ca2+]i.

Topics: Animals; Benzimidazoles; Calcium; Calcium Channel Blockers; Cells, Cultured; Chickens; Cyanides; Hyperkalemia; Mibefradil; Myocardium; Potassium; Potassium Chloride; Ryanodine; Tetrahydronaphthalenes; Verapamil