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HANDBOOK OF PHYSIOLOGY 



CIRCULATION I 



coprecipitation of another molecule), since no binding 

 to albumin can be demonstrated using starch block 

 electrophoresis for separation (284). 



There is no certainty, however, that the glycosides 

 enter the cell. The only studies available involve 

 fractionation of cellular components by homogeniza- 

 tion and differential centrifugation, with estimation of 

 the amount of glycoside associated with each fraction 

 (126-, 257, 285). No conclusions can be drawn, since 

 the results are conflicting. (See ref. 1 13.) 



The solution to this problem would appear to re- 

 quire another approach, such as an attempt to de- 

 termine the cellular locus of digitoxin i:)y ra- 

 dioautography. 



Membrane Transport 



In contrast to the variable effects of cardiac glyco- 

 sides on separated cellular protein components, there 

 is a consistent body of evidence showing that glyco- 

 sides have a profound eflTect on the plasma membrane 

 of intact cells. 



GLYCOSIDE-INDUCED NET POTASSIUM LOSS FROM MUSCLE. 



It was shown by Wood & Moe (336) that administra- 

 tion of lanatoside increased the cardiac potassium 

 A-V difference in dog heart-lung preparations. They 

 showed that potassium was lost slowly from both the 

 heart and lungs during the control period, and that 

 the rate of potassium loss was increased significantly 

 by lanatoside, not only in toxic but also in therapeutic 

 doses. Furthermore, there was a positive correlation 

 between the increase in mechanical efficiency caused 

 by the glycoside and the rate of increase of potassium 

 concentration in the venous blood. A net tissue po- 

 tassium loss induced by glycosides has since been 

 demonstrated for isolated frog (iio, 164) and guinea 

 pig (289, 304) hearts by measuring the resultant in- 

 crease in potassium concentration in the perfusion 

 solution. Comparable results in intact animals and 

 human subjects have been obtained, now that the 

 technique of coronary sinus catheterization makes it 

 possible to measure coronary arteriovenous potassium 

 concentration diff"erences without exposing the heart. 

 Studies utilizing this method have not included meas- 

 urement of coronary blood flow, estimates of cardiac 

 net potassium changes being leased on the coronary 

 arteriovenous concentration difference alone. Harris 

 and co-workers (115) showed that the administration 

 of K-strophanthoside to intact dogs was followed by a 

 rise in both arterial and coronary sinus iilood po- 

 tassium concentration; in some but not all cases the 



potassium increase in coronary sinus blood was said 

 to be significantly greater than in the arterial blood. 

 Since the chances of detecting a net cardiac potassium 

 loss by this method would be best if the drug induced 

 an intense loss over a short period of time, Regan et al. 

 (238) administered to dogs the fast-acting acetyl- 

 strophanthidin which caused a peak effect on ion 

 movements at about 6 min. They consistently found a 

 potassium loss from the heart under these conditions, 

 and Hellems et al. (132) from the same laboratory 

 reported similar findings in seven patients with car- 

 diac failure. With slower acting glycosides such con- 

 sistent differences have not been found (100). 



MECHANISM OF THE POTASSIUM LOSS. The glycosidc-iu- 

 duced potassium loss could be caused by an inhibition 

 of the active process which normally transports po- 

 tassium into the cell, or it could be due to an increased 

 potassium leakage out of the cell. Based on a com- 

 parison of the action of digitalis and veratrum on the 

 isolated frog heart, Hajdu (iio, iii) suggested that 

 the glycosides decreased the rate of pota.ssium re- 

 entry during the recovery phase of the contraction 

 cycle. Similar conclusions were reached by Vick & 

 Kahn (304) in studies of the potassium release 

 from guinea pig hearts during alternating periods of 

 rapid and slow beating in the presence of ouabain or 

 veratridine. Support for this view has recently been 

 obtained by means of potassium tracer measurements, 

 a decrease in the influx with no change in efflux being 

 reported for both frog ventricle (266) and guinea pig 

 auricle (235) when glycosides are administered. These 

 studies, in which influx is found to be slowed while 

 efflux remains unchanged, were of course made in the 

 unsteady state when a net loss of potassium from the 

 cell must have been occurring as a result of the action 

 of the glycosides. Eventually a new steady state must 

 be reached in which efflux and influx are equal and 

 intracellular potassium concentration is stabilized 

 at a new level. Conn (51a) has measured potassium 

 flu.x across the cell membrane in the heart of an intact 

 animal after .such a presumed new steady state has 

 been reached during a period of continuing glycoside 

 action in which digitoxin was administered to dogs 

 in a dosage of 0.2 to 0.4 mg daily for 10 to 14 days. 

 K''- transfer rates between cell and interstitial fluid 

 in these digitalizcd dogs were significantly below 

 normal, l)eing 4.25 ± 0.25 (sem) meq K per kg per 

 min for the controls and 3.74 ±0.15 for the experi- 

 mental group. The combined results of the isotope 

 studies, then, show that potassium influx is diminished 

 as a result of digitalis administration, and that after 



