Calcium entry blockade prevents leakage of macromolecules induced by ischemia-reperfusion in skeletal muscle.
Calcium kinetics and its intracellular mobilization are important in all biological processes. We used verapamil to examine the effect of calcium entry blockade on microvascular transport of macromolecules in ischemia-reperfusion injury. The rat cremaster muscle was splayed, placed in a Lucite intravital chamber, and suffused with bicarbonate buffer. The clearance of fluorescein isothiocyanate-conjugated dextran (FITC-dextran 150) was measured as an index of microvascular transport. After determination of baseline data (clearance of FITC-dextran 150, 3.0 +/- 0.5 microliters/5 min/g), the muscle was made ischemic for 2 hours by clamping its vascular pedicle and subsequently was reperfused for 2 hours. Ischemia-reperfusion produced a marked increase in FITC-dextran clearance. After a peak of 12 +/- 2-fold increase observed in the first 15 minutes into reperfusion, FITC-dextran 150 clearance decreased in magnitude and stabilized at about sixfold above baseline. Verapamil did not change the baseline clearance values. Importantly, verapamil inhibited the ischemia-induced increase in clearance and maintained the values at or near the baseline levels. We simultaneously determined the rate of release of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TXB2) into the suffusate. Verapamil decreased the baseline values of 6-keto-PGF1 alpha and increased those of TXB2. Verapamil inhibited the ischemia-reperfusion-induced increase in 6-keto-PGF1 alpha but did not alter the effect of ischemia-reperfusion on TXB2. Our main results demonstrate the effectiveness of verapamil in preventing microvascular alterations leading to increased leakage of macromolecules.
Department of Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark 07103-2757.
J
J
Paul
A Y
AY
Bekker
W N
WN
Durán
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003911:Dextrans / Q000493:pharmacokinetics; D015777:Eicosanoids / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives*; D005452:Fluoresceins / Q000493:pharmacokinetics; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology; D046911:Macromolecular Substances; D008297:Male; D009132:Muscles / Q000098:blood supply*; D010539:Permeability; D051381:Rats; D011920:Rats, Inbred WF; D015424:Reperfusion
D002121:Calcium Channel Blockers; D003911:Dextrans; D015777:Eicosanoids; D005452:Fluoresceins; D046911:Macromolecular Substances; C015219:fluorescein isothiocyanate dextran; D016650:Fluorescein-5-isothiocyanate