Simulated ischemia enhances L-type calcium current in pacemaker cells isolated from the rabbit sinoatrial node.

Ischemic-like conditions (a glucose-free, pH 6.6 Tyrode solution bubbled with 100% N(2)) enhance L-type Ca current (I(Ca,L)) in single pacemaker cells (PCs) isolated from the rabbit sinoatrial node (SAN). In contrast, studies of ventricular myocytes have shown that acidic extracellular pH, as employed in our "ischemic" Tyrode, reduces I(Ca,L). Therefore, our goal was to explain why I(Ca,L) is increased by "ischemia" in SAN PCs. The major findings were the following: 1) blockade of Ca-induced Ca release with ryanodine, exposure of PCs to BAPTA-AM, or replacement of extracellular Ca(2+) with Ba(2+) failed to prevent the ischemia-induced enhancement of I(Ca,L); 2) inhibition of protein kinase A with H-89, or calcium/calmodulin-dependent protein kinase II with KN-93, reduced I(Ca,L) but did not prevent its augmentation by ischemia; 3) ischemic Tyrode or pH 6.6 Tyrode shifted the steady-state inactivation curve in the positive direction, thereby reducing inactivation; 4) ischemic Tyrode increased the maximum conductance but did not affect the activation curve; 5) in rabbit atrial myocytes isolated and studied with exactly the same techniques used for SAN PCs, ischemic Tyrode reduced the maximum conductance and shifted the activation curve in the positive direction; pH 6.6 Tyrode also shifted the steady-state inactivation curve in the positive direction. We conclude that the acidic pH of ischemic Tyrode enhances I(Ca,L) in SAN PCs, because it increases the maximum conductance and reduces inactivation. Furthermore, the opposite results obtained with rabbit atrial myocytes cannot be explained by differences in cell isolation or patch-clamp techniques.

Ionic basis of ischemia-induced bradycardia in the rabbit sinoatrial node.

To investigate the basis of ischemia-induced bradycardia (<60 beats/min), we isolated pacemaker cells from the rabbit sinoatrial node and exposed them to ischemic-like conditions, including omission of glucose, pH 6.6, and either 5.4 or 10 mM KCl to evaluate the role of increased serum [K]. A perforated-patch technique was employed to test the hypothesis that the arrhythmia is caused by attenuation of inward currents that contribute to the diastolic depolarization. After exposure to "ischemic" Tyrode containing 5.4 mM KCl, the pacemaker cells exhibited 13% slower beat rates and action potentials with 6-mV greater overshoots and 44% longer durations. In contrast, after exposure to "ischemic" Tyrode containing 10 mM KCl, the pacemaker cells exhibited a 7-mV depolarization of the maximum diastolic potential but no significant change in the overshoot. Beat rates were slowed by 43%, and the action potentials were prolonged by 46%. "Ischemic" Tyrode containing 5.4 mM KCl increased L-type Ca current, decreased T-type Ca current and reduced Ni-sensitive inward current tails (presumably Na-Ca exchange current), even after treatment with 40 muM ryanodine to block Ca release from the sarcoplasmic reticulum. "Ischemic" Tyrode containing 10 mM KCl increased hyperpolarization-activated inward current at diastolic potentials and reduced the slowly activating component, but not the rapidly activating component, of delayed rectifier K current. Our results suggest that reductions of inward Na-Ca exchange current and T-type Ca current contribute to "ischemia"-induced "bradycardia" in sinoatrial node pacemaker cells.

Recovery of stroke hemiplegia through neurosurgical intervention in the chronic stage.

Objective: We evaluated quantitatively the further recovery from impairment and disability in the hemiplegic stroke survivors who required neurosurgical intervention, i.e. cranioplasty or ventriculoperitoneal (V-P) shunt, in chronic stage. Setting: Rehabilitation (RH) ward affiliated with university hospitals. Patients: Eleven first-ever stroke patients with hemiplegia (mean age, 56.3+/-2.5 years) out of 498 survivors required delayed (between 4 and 10 months after the onset) neurosurgical intervention during continuous RH therapy. Six patients received cranioplasty for preexisting hemicraniectomy, and five required V-P shunt for normal pressure hydrocephalus with later complications. Main outcome measures: Recovery grade (1--12) of hemiplegia and Barthel index were assessed monthly before (the 1st RH) and after the intervention (the 2nd RH). Results: The recovery grade of upper and lower extremity movements significantly increased both in the 1st and 2nd RH. Changes in the upper and lower extremity grades were significantly larger in the 2nd RH (0.5+/-0.3 in the 1st vs. 2.5+/-0.6 in the 2nd RH for upper extremity, p<0.005; 0.9+/-0.3 in the 1st vs. 3.4+/-0.5 in the 2nd RH for lower extremity, p<0.001). Barthel index increased significantly only in the 2nd RH (from 48+/-7 to 90+/-3, p<0.001); all patients regained the ability to walk independently. Conclusions: Significant recovery of functional grade and recovery from disability occurred after the neurosurgical intervention in the chronic stage (geq 4 months) of stroke.