EFFECTS OF IONS ON VASCULAR SMOOTH MUSCLE 



I 153 



sodium transfer systems, broadly defined. The rise in 

 plasma K following Pitressin administration was 

 considered an integral part of the phenomenon, but 

 left aside from this first theoretical approximation for 

 later consideration. 



In these first studio uc overestimated the absolute 

 magnitude of the water shift that follows Pitressin 

 administration. This was corrected in subsequent 

 studies. The effects of norepinephrine on Xa, K, and 

 inulin space in the nephrectomized rat were then com- 

 pared with those produced by Pitressin and again a 

 net loss of extracellular Na was observed in association 

 with the blood pressure rise (75). Pitressin in the large 

 doses used caused a measurable fall in plasma Na 

 indicating that Na moved in excess of water. With the 

 techniques at hand (flame photometry, arterial blood 

 sampling) no clear fall in plasma Na concentration 

 taken alone was observed with norepinephrine, but a 

 shift of Na and water was claimed on the basis of 

 replicate experiments in which extracellular sodium 

 was calculated. Angiotensin was then compared with 

 Pitressin in the nephrectomized rat (76). Both agents 

 given intravenously produced a measurable fall in 

 plasma Na concentration and a fall in extracellular 

 fluid volume (inulin) associated with the rapid rise 

 of blood pressure. While Pitressin produced a meas- 

 urable increase in extracellular K, angiotensin did 

 not. 



It was clear at this time, at least for norepinephrine, 

 that the fall in Na and water and the rise in K which 

 we were measuring in the extracellular compartment 

 of the rat corresponded qualitatively to the gain in 

 Na and loss in K which Tobian & Fox (197) had 

 measured in the femoral arterv of the dog. Daniel et 

 al. (41 ) then injected a pressor dose of norepinephrine 

 within the physiological range, 1 /xg per kg, in the rat. 

 They found that the aorta was rapidly depleted of K 

 while Na tended to increase. This is surprisingly good 

 confirmation in view of the fact that the Na shift is 

 probably partly obscured by a movement of water 

 which these workers could not measure. 



Subsequently, this group (42) studied the effects of 

 Pitressin and isoproterenol (isopropyl norepinephrine, 

 a peripheral vasodilator) on aorta electrolytes in the 

 rat. They concluded from the variations in aorta 

 sodium that during blood pressure changes, Na 

 moves into (rising blood pressure) and out of (falling 

 blood pressure) vascular muscle cells. Since they were 

 dealing with the aorta, an outward movement of K 

 occurred only with those drugs known to cause an 

 aorta strip to contract. They pointed out, however, 

 that the total amount of Na which we had reported to 



leave the extracellular space could not possibly be 

 accommodated within the cells of the vascular tree. 

 This difficulty has now been satisfactorily resolved by 

 our observation that skeletal muscle also takes up 

 sodium under the influence of Pitressin (85). 



In the rat, studies of changes in plasma Na, K, and 

 inulin space during changes in blood pressure are 

 technically difficult, since each step in drug, dose, or 

 time interval requires the use of separate groups of 

 animals. To circumvent this, as well as to extend the 

 observations to the dog, we studied the problem in the 

 bilaterally nephrectomized dog using norepinephrine, 

 isoproterenol, angiotensin, and Pitressin (73). We 

 found that the calculated extracellular Na (product of 

 inulin space and plasma Na) declined as pressure rose 

 and increased as it fell; the two measurements con- 

 sistently formed mirror images. Calculated extracellu- 

 lar K in general moved inversely to Na and hence in 

 parallel with the pressure except in the case of angio- 

 tensin where, as in the rat, no K shift was found. 



In the case of norepinephrine, the simple measure- 

 ment of plasma Na was an inconsistent index of Na 

 movement, since the real decrease in this ion is 

 partially masked by a movement of water in the same 

 direction. For the same reason, K concentration is a 

 consistent but inaccurate estimate of K movement, 

 since the change is magnified by inverse movement of 

 water. In the case of Pitressin, although both Na and 

 water move out of the extracellular compartment, the 

 Na shift is well in excess of the water so that, if the 

 dose is adequate, a fall in plasma Na is readily ob- 

 served. These findings are remarkably similar to those 

 obtained in the rat. 



Warren (205) has recently studied the effect of 

 Pitressin on Na, K, and inulin space in the trained, 

 conscious, intact dog. He observed similar exchanges 

 to those previously reported in the nephrectomized 

 dog even though he used considerably smaller doses 

 of Pitressin (30 mU kg as a single i.v. injection versus 

 200 mU/kg/min for 10 min by infusion). 



Recently the Na and K. electrodes have been ap- 

 plied to this problem. In the first experiments we used 

 only a sodium electrode interposed into the femoral 

 artery of the dog (80). The aim was to determine 

 whether pressor and depressor agents actually shift Na 

 levels as blood sampling procedures indicated. The 

 result was unequivocal; the pressor response to nor- 

 epinephrine, epinephrine, and angiotensin was regu- 

 larly accompanied by a fall in electrode potential 

 indicating a fall in sodium concentration, or more 

 precisely, sodium activity. In terms of degree of 

 change, time course, and duration of effect, each agent 



