ryanodine and Brain-Ischemia

The mechanisms of myocardial dysfunction and calcium handling disturbance underlying cerebral ischemia remain obscure. Here we for the first time report that acute cerebral ischemia significantly increased left ventricular end diastolic pressure (LVEDP), but decreased +dP/dt, -dP/dt, and left ventricular systolic pressure (LVSP). Significant increase in either the resting or KCl-induced [Ca2+](i)in ventricular myocytes was also detected by scanning confocal microscopy at 2 and 24 hours after cerebral ischemia. Verapamil as a blocker of I(Ca,L), ryanodine as a specific inhibitor of RyR, thapsigargin as a highly specific inhibitor of sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) and SEA0400 as a selective NCX inhibitor changed the area under the curve of averaged ratio of fluorescence (FI/F(0)I) induced by KCl. Cardiac expression of Ca(v)1.2 was significantly up-regulated at 2 and 24 hours after cerebral ischemia, whereas cardiac expression of SERCA2a and Na(+)-Ca(2+) exchanger (NCX) was significantly down-regulated at the same time period after cerebral ischemia. Cardiac expression of phospholamban (PLB) was significantly elevated at 2 hours after cerebral ischemia but was restored to about normal level at 24 hours after injury. These data suggest that acute cerebral ischemia may specifically disturb cardiac function and calcium homeostasis, which are related to increase of Ca(v)1.2 and decrease of through up-regulating Ca(v)1.2 and PLB, down-regulating SERCA2a and NCX, subsequently leading to Ca2+ overload by the enhancement of Ca2+ influx and inhibition of intracellular Ca2+ extrusion and cerebral ischemia-induced myocardial dysfunction.

Topics: Aniline Compounds; Animals; Brain Ischemia; Calcium; Calcium Channel Blockers; Calcium Channels, L-Type; Enzyme Inhibitors; Heart Ventricles; Male; Muscle Contraction; Myocytes, Cardiac; Phenyl Ethers; Potassium Chloride; Rats; Rats, Wistar; Ryanodine; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sodium-Calcium Exchanger; Thapsigargin; Time Factors; Verapamil

Ca2+-activated K+ currents in rat locus coeruleus neurons induced by experimental ischemia, anoxia, and hypoglycemia. J. Neurophysiol. 78: 2674-2681, 1997. The effects of metabolic inhibition on membrane currents and N-methyl--aspartic acid (NMDA)-induced currents were investigated in dissociated rat locus coeruleus (LC) neurons by using the nystatin perforated patch recording mode under voltage-clamp conditions. Changes in the intracellular Ca2+ concentration ([Ca2+]i) during the metabolic inhibition were also investigated by using the microfluometry with a fluorescent probe, Indo-1. Removal of both the oxygen and glucose (experimental ischemia), deprivation of glucose (hypoglycemia), and a blockade of electron transport by sodium cyanide (NaCN) or a reduction of the mitochondrial membrane potential with carbonyl cyanide-p-trifluoromethoxyphenyl-hydrazone(FCCP) as experimental anoxia all induced a slowly developing outward current (IOUT) at a holding potential of -40 mV. The application of 10(-4) M NMDA induced a rapid transient peak and a successive steady state inward current and a transient outward current immediately after washout. All treatments related to metabolic inhibition increased the NMDA-induced outward current(INMDA-OUT) and prolonged the one-half recovery time of INMDA-OUT. The reversal potentials of both IOUT and INMDA-OUT were close to the K+ equilibrium potential (EK) of -82 mV. Either charybdotoxin or tolbutamide inhibited the IOUT and INMDA-OUT, suggesting the contribution of Ca2+-activated and ATP-sensitive K+ channels, even though the inhibitory effect of tolbutamide gradually diminished with time. Under the metabolic inhibition, the basal level of [Ca2+]i was increased and the one-half recovery time of the NMDA-induced increase in [Ca2+]i was prolonged. The IOUT induced by NaCN was inhibited by a continuous treatment of thapsigargin but not by ryanodine, indicating the involvement of inositol 1,4, 5-trisphosphate (IP3)-induced Ca2+ release (IICR) store. These findings suggest that energy deficiency causes Ca2+ release from the IICR store and activates continuous Ca2+-activated K+ channels and transient ATP-sensitive K+ channels in acutely dissociated rat LC neurons.

Topics: Animals; Brain Ischemia; Calcium; Calcium Channels; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Charybdotoxin; Glucose; Glyburide; Hypoglycemia; Hypoxia, Brain; In Vitro Techniques; Locus Coeruleus; Membrane Potentials; N-Methylaspartate; Neurons; Oxygen; Partial Pressure; Rats; Rats, Wistar; Ryanodine; Sodium Cyanide; Thapsigargin; Tolbutamide