To the Editor:—The L-type voltage-sensitive calcium channel (VSCC) mediates changes in excitable cell function in many tissues, including the heart, skeletal, and smooth muscles and the central nervous system. The processes of ischemia and reperfusion have been shown, in the heart and the central nervous system, to be associated with an increase in intracellular Calcium2+. One possible mechanism for increased intracellular calcium, discussed in the paper by Drenger et al., is that of influx of calcium from the extracellular space through new VSCC. [1] Drenger et al. demonstrate in the heart that the number of VSCCs, as measured by radioligand binding, is increased immediately after a brief period of ischemia. [1] This phenomenon has been observed in the CNS and reported by several laboratories, including our own. [2–4] Our previous studies, using a dog model of global cerebral ischemia, showed a 350% increase in the Bmaxof L-type Calcium2+ channels without a change in Kdafter 10 min of ischemia. The increase persisted for several hours and still differed from control after 24 h of reperfusion.

Drenger et al. state that ischemia causes “a growth in the number of available VSCC in the sarcolemma” and suggest that “the increase in available VSCC is explained by a mechanism of differential unmasking of latent channels in the cell membrane and was related to a methylation process of the membrane phospholipids.” No data are presented to support this statement. Another possibility not considered by the authors is that the membrane population isolated after ischemia differs from that isolated from control tissue.

Our own unpublished data using a similar binding technique in a regionally ischemic model demonstrated wide variability from animal to animal, preventing us from drawing conclusions with regard to a change in Bmax. However, we found that 15 min of global cardiac ischemia results in a marked increase in the Bmaxfor isradipine binding to porcine cardiac sarcolemma and also found an equivalent increase in the activity of the enzyme 5′-nucleotidase, widely used as a marker for sarcolemmal membranes. Our unpublished data suggest that the increase observed in [sup 3 Hydrogen]-isradipine binding might be due to an artifact of the purification process that occurs in ischemic tissue. Because the time from the initiation of ischemia to the assay for VSCC is too short for de novo synthesis of VSCC, the appearance of new binding sites with the same affinity as native channels suggests that the cell contains an excess of previously sequestered channels that may be functional but are revealed from a hidden membrane pool along with other sarcolemmal components, e.g., 5′-nucleotidase.

The important observation by Drenger et al. that halothane decreases [sup 3 Hydrogen]-isradipine binding in ischemic membranes in vitro suggests a therapeutic possibility for the use of halothane during ischemia but requires in vivo corroboration and careful consideration of the synergistic negative inotropic effects of ischemia and volatile anesthetics.

The experiments described above were performed by William Curtiss, M.D., Satoshi Yasukohchi, M.D., and Mary Quigg, M.S., at the Johns Hopkins University, Baltimore, Maryland.

Thomas J. J. Blanck, M.D., Ph.D., Professor of Anesthesiology, Pharmacology, Physiology, and Biophysics, Department of Anesthesiology, Cornell University Medical College 1300 York Avenue, New York, New York 10021.

Timothy J. Gardner, M.D., Professor of Cardiothoracic Surgery, Department of Cardiac Surgery, Hospital of the University of Pennsylvania, 37th and Spruce Streets, Philadelphia, Pennsylvania 19104.

(Accepted for publication February 23, 1995.)

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