Background and Purpose-Synaptic transmission is highly vulnerable to metabolic perturbations. However, the long-term consequences of transient metabolic perturbations on synapses are not clear. We studied the long-lasting changes in synaptic transmission and phosphorylation of presynaptic proteins in penumbral cortical neurons after transient moderate ischemia. Methods-Rats were subjected to 1 hour of middle cerebral artery occlusion. After reperfusion, electric activity of neurons in the peri-infarct region was recorded intracellularly and extracellularly in situ. Phosphorylation of synapsin-I and tyrosine residues was studied by immunohistochemistry. Results-Neurons in the penumbra displayed no postsynaptic potentials 1 to 3 hours after recirculation. However, these cells were able to generate action potentials and were responsive to glutamate, suggesting that postsynaptic excitability was preserved but the synaptic transmission was blocked because of a presynaptic defect. The synaptic transmission was still depressed 24 hours after recirculation in neurons in the peri-infarct area that survived ischemia. The amount of immunoreactive synapsin-I, synaptophysin, and synaptotagmin was not appreciably changed for 72 hours after reperfusion. However, phosphorylation of synapsin-l was significantly decreased, whereas phosphotyrosine immunoreactivity was increased, suggesting a selective defect in synapsin-I phosphorylation. Conclusions-These data demonstrate that synaptic transmission may be permanently impaired after transient moderate brain injury. Since postsynaptic excitability is preserved, the transmission failure is likely to be caused by presynaptic mechanisms, one of which may be impaired phosphorylation of presynaptic proteins.

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Congestive heart failure (CHF) is associated with exercise intolerance that cannot be entirely explained by hypoperfusion of the skeletal muscles. We studied the contractile properties of fast-twitch (extensor digitorum longus; EDL) and slow-twitch (soleus; SOL) skeletal muscles in doxorubicin-induced CHF in rats, and evaluated the defective steps of excitation-contraction coupling. Both types of muscles-obtained from CHF rats displayed significant reduction in twitch and tetanic contractions. Twitch half-relaxation times of CHF SOL muscles were prolonged while there was no significant difference in EDL muscles. High K⁺ application induced lower contracture amplitudes in CHF muscles. Caffeine-induced contractures were significantly diminished in CHF SOL. Verapamil application depressed tetanic contractions in all preparations while depression was more pronounced in CHF SOL. Immunohistochemistry revealed reduced expression of sarcoplasmic reticulum Ca²⁺-ATPase-1 and -2 in CHF EDL and in CHF SOL, respectively. Sarcolemmal excitability and spontaneous neurotransmitter release were unaffected since resting membrane potential, action potential and miniature end-plate potentials were unaltered in CHF muscles. We conclude that CHF induces contractile impairment that occurs predominantly in rat slow-twitch skeletal muscles. Our results suggest that this muscle-type-specific effect of CHF is related to the defective intracellular Ca²⁺ release and uptake mechanisms and reduced sarcolemmal-dihydropyridine-sensitive Ca²⁺ channel activity.