1152 



HANDBOOK OF PHYSIOLOGY 



CIRCULATION II 



IWJECTIOM 



(.005 mg/>g EPIWEPHRIIIE) 

 CYCLOPROPANE 

 NEMBUTAL 

 UNANESTHETIZED 

 D— O ETHER 



40 SO 



imecTioi (b) 

 i iv I ^ 



VT 



JOIVEIS. 



CYCLOPROPANE 30 MINUTES 

 EPINEPHRINE 

 •— • ARANTHOL 

 a — □ NEOSYNEPHRIN 

 O— O EPHEORIBE 





SECONDS 



40 80 



120 



110 



240 



300 



fig. 6. A: influence of anesthesia on plasma [K + j rise induced 

 by epinephrine in the dog. Arrhythmias and time of their 

 occurrence shown by horizontal lines at top of figure. VT 

 = ventricular tachycardia. B: effect of a series of sympatho- 

 mimetic amines on plasma [K + ] in the dog. VT = ventricular 

 tachycardia, NVEXS — numerous ventricular extrasystoles. 

 [From O'Brien et al. (155).] 



of the injections rather than to the blood pressure 

 effect. This explanation for the rise of K remained 

 unchallenged and uncritically accepted for almost two 

 decades. 



O'Brien et al. (155) in 1953 obtained beautiful 

 curves showing the rise of plasma K after rather lower 

 doses of norepinephrine, 5 ng per kg, in dogs. Although 

 norepinephrine does not have any marked effect on 

 the mobilization of glucose and although these authors 

 pointed out that it is blocked by Dibenamine, which 

 would not block a glycogenolytic effect, the original 

 explanation still persisted. O'Brien and his associates 

 also pointed out that the choice of anesthetic modified 

 the effects, ether being the worst for blurring the 

 effect, cyclopropane affecting it least, Nembutal 

 almost as good as cyclopropane. These important 

 observations were unfortunately ignored by most 

 later workers including ourselves. (In our more 



recent studies we have found the effects considerably 

 sharpened if a barbiturate mixture is used instead of 

 ether. ) 



Muirhead et al. (153) in the next year restudied the 

 problem. They gave norepinephrine by infusion in 

 total doses of 1 to 7 mg per kg in 50 to 180 ml of 

 saline over periods ranging from 20 to 50 min. Con- 

 cerning their results they wrote: "In many of the 

 experiments the sodium curve represents an approxi- 

 mate mirror image of the blood pressure curve. In 

 most of the experiments the changes of potassium 

 were not as pronounced as those of sodium. In 

 addition there seemed to be little if any correlation 

 between blood pressure and plasma potassium. The 

 latter is in contrast to the variations in sodium levels 

 which reflected even sudden changes in blood pres- 

 sure." No real change in radiosulfate space or in 

 chloride concentration was observed. These observa- 

 tions did not have the impact they ought to have had 

 for the doses used were very large. 



Tobian & Fox (197) then approached the problem 

 directly and analyzed segments of dog femoral 

 artery before and after infusing norepinephrine 

 sufficient to maintain a blood pressure elevation for 

 30 min. A consistent fall in artery K and a less con- 

 sistent gain in Na was observed. These changes were 

 believed to represent a fall in K, and rise in Na„ but 

 the authors tended to underestimate the importance 

 of the Na change since it was less consistent. In our 

 view, the difficulties inherent in such tissue anah sis 

 and their basic range of error make it highly sig- 

 nificant that even this trend for a sodium increase was 

 observed; in fact, a sizeable Na gain was found in 9 

 of 12 dogs. In the light of later evidence, we must 

 conclude that a fall in K, and a real gain in Na„ 

 probably with water, actually did occur. 



Shortly thereafter, following up the possibility 

 that Pitressin might have an extrarenal action, we 

 observed that this agent caused a shift of water out 

 of the extracellular space in the bilaterally nephrecto- 

 mized rat. In a more detailed study, we found that 

 Na also left the extracellular space in association 

 with, but in excess of, water so that there was a 

 measurable fall in plasma Na concentration (82). The 

 relation of dose to response was presented at this time 

 and the correlation of the shifts with blood pressure 

 noted. In interpreting these exchanges of salt and 

 water, we took into account the changes which 

 other workers had previously observed to follow 

 norepinephrine administration and hypothesized thai 

 both sets of observations could be related by a general 

 rule that blood pressure regulation depends on the 



