"44 



HANDBOOK OF PHYSIOLOGY 



CIRCULATION II 



smooth muscle to a sudden reduction of Na concen- 

 tration in the medium, Na„, osmotic pressure being 

 held constant, produces an immediate increase in 

 tension (i 16). This increase in tension is not sustained 

 as equilibration proceeds. Streeten & Vaughan 

 Williams (189) noted an increase in motility of in- 

 testinal loops (dog) during the first stage of Na deple- 

 tion by intraperitoneal lavage. Whitehead (208) 

 noted an increase in tone of isolated ileal or jejunal 

 segments (rabbit). We (78) studied the response in 

 greater detail using a colon strip (rat) suspended in a 

 sensitive strain-gauge tensometer and found that the 

 increase in tension and the duration of response are 

 proportional to the degree of reduction of Na . 

 Dodd & Daniel (49) observed a similar immediate 

 increase in the tension of an aorta strip following a 

 reduction in Na . 



The sudden reduction of Na + in the medium must 

 at once unbalance ionic equilibrium across the smooth 

 muscle cell membrane. The restoration of equilibrium, 

 while still retaining electroneutrality in each com- 

 partment, may require a migration of positive ions 

 from within the cell to the exterior. Since K. ions 

 are the only ones freely available for this they must 

 shift outward (31, 32). The increase in tension re- 

 corded may be primarily related to the applied re- 

 duction of the Na gradient, Na„/Na, , or perhaps to 

 an induced K + efflux from the cell. 



We may suppose that, with time, the Na gradient 

 is gradually built back up toward its basal state as Na 

 is actively but relatively slowly extruded. Thus, when 

 fully equilibrated, tissues in a low Na medium contain 

 a reduced intracellular Na concentration, Na,-. 

 Working with guinea pig taenia coli, Holman (118) 

 has shown that at this stage the tissue still responds 

 normally to stimuli, but Bohr et al. (13) claim hyper- 

 responsiveness for the vascular strip. Daniel's group 

 does not agree with this (49). When such tissues are 

 equilibrated in very low levels of Na„ , however, all 

 agree that they become first hyposensitive and finally 

 unresponsive (49, 116, 118, 147, 188, 189). This sug- 

 gests that the response falls off either because Na, 

 reaches some critical level or that Na„/Na, has itself 

 fallen below some critical value. 



The observation that tone or responsiveness or both 

 decline after equilibration in very low Na„ seems 

 quite uniform. The experiments of Dodd & Daniel 

 (49) and Yamabayashi & Hamilton (214) show that 

 the phenomenon applies equally well to vascular 

 smooth muscle. It appears, however, that a fairly 

 extreme reduction in Na„ is necessary to elicit this 

 change and, since techniques vary, there is no uniform 



answer concerning the absolute level at which the 

 hyporeactivity occurs. Indeed this level may also vary 

 in different types of smooth muscle (43). We shall 

 later see whether the decline in responsiveness after 

 equilibration in low Na media can be related to a 

 reduction in the Na„ Na, gradient. 



The time used by various workers for equilibration 

 of their tissues varies over a wide range. This may 

 well condition the responses obtained, since all tissues 

 incubated in vitro for any length of time (in hours) 

 take up Na and water and may extrude some K (165). 

 Put another way, these tissues fail to maintain a nor- 

 mal sodium gradient. This process is accelerated by 

 cooling and is more marked in artificial than in 

 natural media, for example, plasma. 



Despite the detailed differences between the experi- 

 mental results with various smooth muscle types, we 

 may conclude that, in general, an induced reduction 

 in the sodium gradient produces an immediate in- 

 crease in tension, while the continued presence of 

 such a low gradient leaves the tissue less primed for 

 the next stimulus, that is, hyporesponsive. Several 

 additional observations now fall into line and a few 

 of these may be dealt with at this point. Hughes et al. 

 (120) found that rat uterus immersed in normal 

 Krebs solution for 3 hours gained Na, , as do all 

 tissues, and became less responsive to test doses of 

 histamine. We have incubated dog femoral artery in 

 Krebs solution at o C overnight, a situation in which 

 the cells must gain Na (165), and in the morning find 

 the tissue contracted and totally incapable of respond- 

 ing to drug stimulation. Revvarming to 37 C, the 

 standard procedure for re-extruding Na, relaxes the 

 tissue and restores its responsiveness. McDowall & 

 Zayat (145) have concluded that smooth muscle 

 (uterus) takes up sodium during drug-induced con- 

 traction and in this state is less responsive to stimula- 

 tion. 



McDowall & Soliman (144) suggest that the post- 

 stimulatory refractoriness is due to difficulty in reprint- 

 ing the cell by extruding Na. In brief, they relate 

 unresponsiveness to the simple increase in Xa, and 

 support this idea by the fact that responsiveness can 

 be quickly restored to a refractory uterus strip by 

 reducing Na in the medium. Three facts militate 

 against this oversimplified explanation. In the first 

 place, the acute reduction of Na in the medium can 

 be expected to facilitate Na extrusion but only during 

 the prolonged equilibration period. In fact, however, 

 the reduction of Na„ restores responsiveness at once. 

 In the second place, as we have pointed out earlier, 

 the sudden reduction of Na„ immediately unbalances 



