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Yuji Wakayama

Publications and source records attributed to Yuji Wakayama.

9 recordsLinked to original sources
PubMed2006

Reduced inotropic effect of nifekalant in failing hearts in rats.

Class III antiarrhythmic agents have been widely used to suppress ventricular tachyarrhythmias in patients with heart failure because they have been shown to have positive inotropic effects as well. However, it remains to be examined whether those agents also exert positive inotropic effects in failing hearts. We addressed this important issue in a rat model of heart failure. We used Nifekalant as a representative class III antiarrhythmic agent. Four weeks after a s.c. injection of 60 mg/kg monocrotaline (MCT) or vehicle (Ctr) into rats, we obtained trabeculae from right ventricles and measured the developed force and intracellular Ca(2+) ([Ca(2+)](i)) by the fura-2 microinjection method. The sarcoplasmic reticulum (SR) Ca(2+) content was assessed by the rapid-cooling contracture (RCC) technique. MCT rats exhibited right ventricular hypertrophy induced by pressure overload. The protein expression of SR Ca(2+) ATPase type 2 (SERCA2) and the SERCA2/phospholamban ratio in MCT rats was lower with a slower decline of Ca(2+) transients and a reduced amplitude of RCCs. Nifekalant concentration-dependently increased the force, peak [Ca(2+)](i), and the amplitude of RCCs in Ctr rats but not in MCT rats with identical prolongation of the action potential. Under the SR inhibited with cyclopiazonic acid and ryanodine, Nifekalant increased the force in Ctr rats but not in MCT rats. These results indicate that the positive inotropic effects of Nifekalant is reduced in failing hearts, probably due to the depressed SR Ca(2+) uptake and reduced reserve of the trans-sarcolemmal Ca(2+) transport, warranting a caution in the antiarrhythmic therapy with a class III antiarrhythmic agent in heart failure.

Action Potentials↗
PubMed2006

Role of sarcomere mechanics and Ca2+ overload in Ca2+ waves and arrhythmias in rat cardiac muscle.

Ca(2+) release from the sarcoplasmic reticulum (SR) depends on the sarcoplasmic reticulum (SR) Ca(2+) load and the cytosolic Ca(2+) level. Arrhythmogenic Ca(2+) waves underlying triggered propagated contractions arise from Ca(2+) overloaded regions near damaged areas in the cardiac muscle. Ca(2+) waves can also be induced in undamaged muscle, in regions with nonuniform excitation-contraction (EC) coupling by the cycle of stretch and release in the border zone between the damaged and intact regions. We hypothesize that rapid shortening of sarcomeres in the border zone during relaxation causes Ca(2+) release from troponin C (TnC) on thin filaments and initiates Ca(2+) waves. Elimination of this shortening will inhibit the initiation of Ca(2+) waves, while SR Ca(2+) overload will enhance the waves. Force, sarcomere length (SL), and [Ca(2+)](i) were measured and muscle length was controlled. A small jet of Hepes solution with an extracellular [Ca(2+)] 10 mM (HC), or HC containing BDM, was used to weaken a 300 mum long muscle segment. Trains of electrical stimuli were used to induce Ca(2+) waves. The effects of small exponential stretches on triggered propagatory contraction (TPC) amplitude and propagation velocity of Ca(2+) waves (V(prop)) were studied. Sarcomere shortening was uniform prior to activation. HC induced spontaneous diastolic sarcomere contractions in the jet region and attenuated twitch sarcomere shortening; HC+ butanedione monoxime (BDM) caused stretch only in the jet region. Stimulus trains induced Ca(2+) waves, which started inside the HC jet region during twitch relaxation. Ca(2+) waves started in the border zone of the BDM jet. The initial local [Ca(2+)](i) rise of the waves by HC was twice that by BDM. The waves propagated at a V(prop) of 2.0 +/- 0.2 mm/sec. Arrhythmias occurred frequently in trabeculae following exposure to the HC jet. Stretch early during relaxation, which reduced sarcomere shortening in the weakened regions, substantially decreased force of the TPC (F(TPC)) and delayed Ca(2+) waves, and reduced V(prop) commensurate with the reduction F(TPC). These results are consistent with the hypothesis that Ca(2+) release from the myofilaments initiates arrhythmogenic propagating Ca(2+) release. Prevention of sarcomere shortening, by itself, did not inhibit Ca(2+) wave generation. SR Ca(2+) overload potentiated initiation and propagation of Ca(2+) waves.

Animals↗
PubMed2005

Arrhythmogenic Ca(2+) release from cardiac myofilaments.

We investigated the initiation of Ca(2+)waves underlying triggered propagated contractions (TPCs) occurring in rat cardiac trabeculae under conditions that simulate the functional non-uniformity caused by mechanical or ischemic local damage of the myocardium. A mechanical discontinuity along the trabeculae was created by exposing the preparation to a small constant flow jet of solution with a composition that reduces excitation-contraction coupling in myocytes within that segment. Force was measured and sarcomere length as well as [Ca(2+)](i) were measured regionally. When the jet-contained Caffeine, BDM or Low-[Ca(2+)], muscle-twitch force decreased and the sarcomeres in the exposed segment were stretched by shortening of the normal regions outside the jet. During relaxation the sarcomeres in the exposed segment shortened rapidly. Short trains of stimulation at 2.5 Hz reproducibly caused Ca(2+)-waves to rise from the borders exposed to the jet. Ca(2+)-waves started during force relaxation of the last stimulated twitch and propagated into segments both inside and outside of the jet. Arrhythmias, in the form of non-driven rhythmic activity, were triggered when the amplitude of the Ca(2+)-wave increased by raising [Ca(2+)](o). The arrhythmias disappeared when the muscle uniformity was restored by turning the jet off. We have used the four state model of the cardiac cross bridge (Xb) with feedback of force development to Ca(2+) binding by Troponin-C (TnC) and observed that the force-Ca(2+) relationship as well as the force-sarcomere length relationship and the time course of the force and Ca(2+) transients in cardiac muscle can be reproduced faithfully by a single effect of force on deformation of the TnC.Ca complex and thereby on the dissociation rate of Ca(2+). Importantly, this feedback predicts that rapid decline of force in the activated sarcomere causes release of Ca(2+) from TnC.Ca(2+),which is sufficient to initiate arrhythmogenic Ca(2+) release from the sarcoplasmic reticulum. These results show that non-uniform contraction can cause Ca(2+)-waves underlying TPCs, and suggest that Ca(2+) dissociated from myofilaments plays an important role in the initiation of arrhythmogenic Ca(2+)-waves.

Actin Cytoskeleton↗
PubMed2005

Spatial nonuniformity of excitation-contraction coupling causes arrhythmogenic Ca2+ waves in rat cardiac muscle.

Ca2+ waves underlying triggered propagated contractions (TPCs) are initiated in damaged regions in cardiac muscle and cause arrhythmias. We studied Ca2+ waves underlying TPCs in rat cardiac trabeculae under experimental conditions that simulate the functional nonuniformity caused by local mechanical or ischemic local damage of myocardium. A mechanical discontinuity along the trabeculae was created by exposing the preparation to a small jet of solution with a composition that reduces excitation-contraction coupling (ECC) in myocytes within that segment. The jet solution contained either caffeine (5 mmol/L), 2,3-butanedione monoxime (BDM; 20 mmol/L), or low Ca2+ concentration ([Ca2+]; 0.2 mmol/L). Force was measured with a silicon strain gauge and sarcomere length with laser diffraction techniques in 15 trabeculae. Simultaneously, [Ca2+]i was measured locally using epifluorescence of Fura-2. The jet of solution was applied perpendicularly to a small muscle region (200 to 300 microm) at constant flow. When the jet contained caffeine, BDM, or low [Ca2+], during the stimulated twitch, muscle-twitch force decreased and the sarcomeres in the exposed segment were stretched by shortening normal regions outside the jet. Typical protocols for TPC induction (7.5 s-2.5 Hz stimulus trains at 23 degrees C; [Ca2+]o=2.0 mmol/L) reproducibly generated Ca2+ waves that arose from the border between shortening and stretched regions. Such Ca2+ waves started during force-relaxation of the last stimulated twitch of the train and propagated (0.2 to 2.8 mm/sec) into segments both inside and outside of the jet. Arrhythmias, in the form of nondriven rhythmic activity, were induced when the amplitude of the Ca2+-wave was increased by raising [Ca2+]o. Arrhythmias disappeared rapidly when uniformity of ECC throughout the muscle was restored by turning the jet off. These results show, for the first time, that nonuniform ECC can cause Ca2+ waves underlying TPCs and suggest that Ca2+ dissociated from myofilaments plays an important role in the initiation of Ca2+ waves.

Animals↗
PubMed2005

Spatial nonuniformity of contraction causes arrhythmogenic Ca2+ waves in rat cardiac muscle.

Landesberg and Sideman's four state model of the cardiac cross-bridge (XB) hypothesizes a feedback of force development to Ca(2+) binding by troponin C (TnC). We have further modeled this behavior and observed that the force (F)-Ca(2+) relationship as well as the F-sarcomere length (SL) relationship and the time course of F and Ca(2+) transients in cardiac muscle can be reproduced faithfully by a single effect of F on deformation of the TnC-Ca complex and, thereby, on the dissociation rate of Ca(2+). Furthermore, this feedback predicts that rapid decline of F in the activated sarcomere causes release of Ca(2+) from TnC-Ca(2+), which is sufficient to initiate arrhythmogenic Ca(2+) release from the sarcoplasmic reticulum (SR). This work investigated the initiation of Ca(2+) waves underlying triggered propagated contractions (TPCs) in rat cardiac trabeculae under conditions that simulate functional nonuniformity caused by mechanical or ischemic local damage of the myocardium. A mechanical discontinuity along the trabeculae was created by exposing the preparation to a small constant flow jet of solution that reduces excitation-contraction coupling in myocytes within that segment. Force was measured, and SL as well as [Ca(2+)](i) were measured regionally. When the jet contained caffeine, 2,3-butanedione monoxime or low-[Ca(2+)], muscle-twitch F decreased and the sarcomeres in the exposed segment were stretched by shortening the normal regions outside the jet. During relaxation, the sarcomeres in the exposed segment shortened rapidly. Short trains of stimulation at 2.5 Hz reproducibly caused Ca(2+) waves to rise from the borders exposed to the jet. Ca(2+) waves started during F relaxation of the last stimulated twitch and propagated into segments both inside and outside of the jet. Arrhythmias, in the form of nondriven rhythmic activity, were triggered when the amplitude of the Ca(2+) wave increased by raising [Ca(2+)](o). The arrhythmias disappeared when the muscle uniformity was restored by turning the jet off. These results show that nonuniform contraction can cause Ca(2+) waves underlying TPCs, and suggest that Ca(2+) dissociated from myofilaments plays an important role in the initiation of arrhythmogenic Ca(2+) waves.

Animals↗
PubMed2005

Effect of nifekalant, a class III anti-arrhythmic agent, on Ca2+ waves in rat intact trabeculae.

BACKGROUND: Nifekalant, a class III anti-arrhythmic agent, has been used clinically at serum concentrations of 1-10 micromol/L in patients with ventricular arrhythmias. However, the effect of nifekalant on triggered arrhythmias has not yet been established. METHODS AND RESULTS: Trabeculae were dissected from the right ventricles of 16 rat hearts. The force was measured using a silicon strain gauge, the membrane potential using ultra-compliant microelectrodes, and the regional intracellular Ca2+ ([Ca2+]i) using electrophoretically microinjected fura-2 and an image intensified CCD camera at a sarcomere length of 2.1 microm. Rapid cooling contractures (RCCs) were measured to estimate the Ca2+ content in the sarcoplasmic reticulum. Ca2+ waves and aftercontractions were measured after the induction of reproducible Ca2+ waves. Nifekalant at 1, 10 and 250 micromol/L increased significantly the action potential duration, the peak [Ca2+]i, the developed force and the amplitude of RCCs in a concentration-dependent manner (stimulus interval = 2 s, [Ca2+]o = 0.7 mmol/L, 26.0+/-0.2 degrees C). Nifekalant at 10 and 250 micromol/L increased significantly the velocity of Ca2+ waves with an enhancement of the aftercontractions (stimulus interval = 0.5 s for 7.5 s, [Ca2+]o = 1.8+/-0.1 mmol/L, 22.3+/-0.5 degrees C). CONCLUSIONS: Nifekalant, even at a therapeutic concentration, can increase muscle contraction, but may worsen triggered arrhythmias because of the acceleration of Ca2+ waves under Ca2+-overloaded conditions.

Animals↗
PubMed2004

Use of an extracorporeal left ventricular assist system after acute myocardial infarction due to occlusion of the left main coronary artery.

A 35-year-old man presented to our institution one day after the onset of dyspnea. Coronary angiography revealed the occlusion of the left main trunk. The left main coronary artery and the left circumflex artery were recanalized, but he was hypotensive with low cardiac output. Even after he was placed on circulatory support with veno-arterial extracorporeal membrane oxygenation (ECMO), hemodynamic deterioration could not be reversed, and lung edema developed. The decision was made to use Toyobo LVAS. With institution of left ventricular assist system (LVAS), however, the patient's arterial saturation decreased. Peripheral veno-venous (V-V) ECMO was promptly established, and the patient's arterial saturation improved. On postoperative day 3, the patient was successfully weaned from V-V ECMO. He was extubated on postoperative day 28. The patient was recovered without any serious complications. Although echocardiography showed no substantial improvement in left ventricular function, his general condition is doing quite well with the assist of Toyobo LVAS. He is on rehabilitation program and awaiting heart transplantation.

Adult↗
PubMed2003

Deficit of CD38/cyclic ADP-ribose is differentially compensated in hearts by gender.

To elucidate whether myocardial CD38/cyclic ADP-ribose (cADPR) signaling plays a physiological role, we investigated the heart of CD38 knockout mice (CD38KO). In CD38KO, the myocardial cADPR content was reduced by 85% compared with wild-type mice (WT). Cardiac hypertrophy developed only in males. At 36 degrees C, none of the parameters for Ca(2+) transients and forces of the papillary muscles differed between WT and CD38KO. In contrast, at 27 degrees C, at which cADPR does not work, the peak [Ca(2+)](i) was increased and the decline in [Ca(2+)](i) was accelerated in CD38KO compared with WT. In CD38KO, the protein expression of SR Ca(2+) ATPase type2 (SERCA2) and the SERCA2-to-phospholamban ratio were increased compared with WT. The ryanodine receptor protein was increased only in female CD38KO compared with WT. These data suggest that the CD38/cADPR signaling plays an important role in intracellular Ca(2+) homeostasis in cardiac myocytes in vivo. Its deficiency was compensated differentially according to gender.

ADP-ribosyl Cyclase↗