i i6o 



HANDBOOK OF PHYSIOLOGY 



cikcn.ATION II 



by several workers Raab ( i • > _• i has suggested that the 

 amount of sodium in the smooth muscle cell deter- 

 mines its responsiveness to catecholamines which he 

 considers important in the pathogenesis of hyperten- 

 sive states Tobian & Redleaf (200) suggest that the 

 amount of both sodium and potassium increases in 

 the vascular smooth muscle cell in chronic hyperten- 

 sion and, by osmotic attraction, causes cell swelling 

 and water logging. Tobian has recently reviewed this 

 position (193, 194)- VVe have presented the theory 

 that the sodium transfer systems, broadly defined, 

 and expressed in the sodium gradient, determine 

 vascular tone (78). Raab (163) has recently revised his 

 position to incorporate the sodium gradient into his 

 basic thesis ol catecholamine sensitivity. 



Insofar as the cell is concerned, neither the amount 

 nor the concentration of Na or K enclosed by its 

 membrane has any meaning apart from their relation 

 to the external environment as the gradients Na„/Na, 

 and K, K.„. An increase in Na,-, for example, attracts 

 water into the cell until osmotic equilibrium is estab- 

 lished only if Na, has increased relative to Na„. Again, 

 an increase in K„ will redistribute itself so as to pro- 

 duce no osmotic effect at equilibrium if Na„ Na, is 

 kept constant. Or again, insofar as membrane poten- 

 tials are concerned, an increase in K, hyperpolarizes 

 the cell only if K, K.„ is made steeper thereby. 



We need not belabor the point implicit in the basic 

 principles of the introduction to this chapter but only 

 urge that a satisfactory theory must be based on con- 

 centration (or activity) gradients and not stress either 

 cell or environment alone in isolation. It is equally 

 apparent from the evidence presented that a satisfac- 

 tory theory must embrace both sodium and potassium. 

 We believe that the following theoretical interpreta- 

 tion will lit many of the presently known facts and 

 will perhaps serve to stimulate further thought. It will 

 be presented in the form of generalizations with some 

 supporting evidence. The remainder of the evidence 

 is contained in the body of this chapter. 



/ ) Vascular smooth muscle tension is inversely pro- 

 portional to the membrane potential, that is, to the 

 sum of the equilibrium potentials of Na + and K + 

 where, in the basal state, the permeability of the cell 

 lo K 4 considerably exceeds its permeability to Na + . 

 Laborit & Huguenard (130) and Furchgott (87) have 

 already expressed this view. 



The simple shift of water from cells to environment 

 which can be induced b\ increasing the external 

 tonicity will increase both Na, and K,, hyperpolarize 

 the membrane and relax the cell. This explains the 



vasodilatation which consistently follows the infusion 

 of hyperosmotic solutions. Sustained exposure to hy- 

 perosmotic solutions containing particles other than 

 Na + will not only lower Na but induce a flow of K+ 

 from cells to medium so that at equilibrium the mem- 

 brane potential will be reduced and tension increased. 

 This may explain postnephrectomy hypertension (83). 



2) Acute change in vascular smooth muscle tension 

 is ordinarily accomplished by agents which alter the 

 permeability of the membrane to Na + . An agent 

 which increases the permeability to Na + will produce 

 an immediate depolarization and increase in tension 

 followed by a flow of sodium from environment to cells. 

 Such a flow of sodium has been consistently induced 

 in vivo by all vasoconstrictors. 



If cell volume is to be maintained unchanged during 

 this process, potassium must leave the cell as sodium 

 enters. The expected increase in K„ does not occur 

 with all vasoconstrictors. In this case we must assume 

 that some cell swelling occurs. Fending further data 

 we recognize that real changes in cell volume may 

 also be involved in changes of tension in vascular 

 smooth muscle (65, 195). 



■-;) Sustained change in vascular smooth muscle 

 tension may be accomplished by agents which ad- 

 just and sustain the membrane permeability to Na. 

 The equilibrium state fora given permeability is mani- 

 fest in the Na gradient. Since the entrance and exit 

 mechanisms for sodium are not necessarily the same 

 (see Goldman equation) the same result can be 

 achieved by varying either influx or efflux rate. The 

 sodium gradient falls, for example, if influx rate is 

 increased or efflux hindered. If Na, tends to accumu- 

 late in a sustained manner due to either of these 

 changes the cell can, within reason, compensate by 

 increasing its work of extrusion. Presumably the first 

 effort of the cell to compensate will be reflected by an 

 increase in the cell machinery involved in the work of 

 such Na extrusion. This capacity must, however, be 

 limited so that equilibrium will next be attained at a 

 lower gradient, that is, Na, increases until equilibrium 

 is re-established. The resultant accumulation of .Na, 

 must lead to the extrusion of K,, a new and lower 

 membrane potential and an increase of tension. 



We have described the evidence that Na, is actually 

 increased in sustained hypertensive states. It is 

 equally clear that chronic sodium-depleting proce- 

 dures tend to re-establish the basic normal situation. 

 There is also good evidence that mineralocorticoids 

 regulate the permeability of cell membranes to 

 sodium (33, 74, 123). A control system which allows ,i 

 small trickle of sodium to enter the cell and then 



