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The pulmonary microcirculation of the rat: differential ultrastructural responses of the endothelia to protamine sulfate.

Protamine sulfate is used clinically to reverse the anti-coagulant effects of heparin and in certain cases high protein, non-cardiogenic pulmonary edema develops. In the present study an initial stage of edema formation, namely, interstitial fluid accumulation around partially muscular extra-alveolar microvessels was observed in rats in situ after right ventricular injections of protamine. In addition, the endothelium of these microvessels displayed marked increases in plasmalemmal vesicles; however, disruption of the endothelium was not observed. Further, endothelial vesicle densities were unchanged and perivascular cuffs were not observed in either the nonmuscular extra-alveolar microvessels or the alveolar capillaries. Left ventricular injections of protamine failed to elicit the ultrastructural responses to protamine. Predosing the pulmonary microcirculation with heparin also served to prevent protamine-induced changes in the partially muscular microvessels. If it is assumed that heparin lowers the threshold for protamine-mediated responses in patients who develop edema, inhibition of protamine-induced changes by heparin predosing cannot be explained by the present data. Although evidence of increased endothelial vesiculation in the partially muscular microvessels was obtained, relative contributions of vesicles or of the junctional clefts to efflux from the pulmonary microvessels is not known. Thus, the mechanisms associated with a reduction of endothelial selectivity to macromolecular efflux after protamine administration remain to be defined.