THE HEPATIC CIRCULATION 



1423 



creased carbon dioxide tension in the blood perfusing 

 splanchnic blood vessels including those of the liver, 

 intestines, and spleen, elicits an arteriolar and venous 

 constrictive response only if the splanchnic nerve 

 supply is intact. After denervation, an elevation in 

 Pa C o, regularly induces vasodilation. Evidently this 

 reflex pathway is relatively unaffected by cholinergic 

 blockade and by light general anesthesia. Whether 

 sufficiently high concentrations of carbon dioxide 

 could overcome the opposing reflex activity and dilate 

 the vessels directly remains unsettled, although Brick- 

 ner et al. (66) have shown that mesenteric vasodilation 

 may occur in the intact animal breathing gas mix- 

 tures that contain more than 8 per cent carbon di- 

 oxide. Splenic contraction induced by hypercapnia 

 appears to involve activity of both splanchnic nerves 

 and adrenals (235). Further work is required to 

 elucidate the role of adrenergic mediators, the re- 

 distribution of blood within the splanchnic bed, and 

 changes in the partition of hepatic inflow during 

 hypercapnia. In addition, the effect of carbon dioxide 

 released locally by metabolizing tissues, in amounts 

 too small to affect the vasomotor centers, deserves 

 investigation. 



histamine. There is no doubt that carbon dioxide is 

 added to the blood perfusing the tissues and that it is 

 present, therefore, in varying concentrations which 

 are certainly in excess of those in the arterial blood at 

 the capillary level. Various other vasoactive materials 

 also appear at approximately the same site, though 

 relatively little is known regarding the mechanisms 

 and character of their release. Electrolyte shifts and 

 the production of hydrogen ion may be particularly 

 important though very little is known about the part 

 they play in the regulation of the microcirculation. 

 Another vasoactive substance which appears in high 

 concentration in all the tissues served by the splanch- 

 nic circulation is histamine (127). Although it has 

 excited intense interest and extensive study for more 

 than a half century, the function of histamine remains 

 puzzling and controversial. Its action upon the hepatic 

 and splanchnic circulations has received special atten- 

 tion. As early as 1899, it was discovered that a striking 

 engorgement of the liver occurs in the dog during 

 anaphylactic shock, and not long afterward the same 

 phenomenon was observed following introduction of 

 histamine into the portal vein (132). Since hepatic 

 venous outflow decreased during engorgement of the 

 liver, it was suggested that contraction of the venous 

 musculature might act as a throttle mechanism to 

 occlude the hepatic veins in the dog. Dale (25) and 



others (12, 132) have confirmed these results, Dale 

 showing that the response could be eliminated by- 

 slitting the hepatic veins of the perfused liver. More- 

 over, hepatic swelling proved to be less marked or 

 absent altogether in animals like the cat, goat, or 

 monkey that have thinly muscled hepatic veins. A 

 diminution in portal inflow as well as in hepatic 

 venous outflow also points to the development of in- 

 creased resistance to perfusion. All these findings, 

 together with the fact that histamine causes contrac- 

 tion of the spleen in most animals (132), point to 

 vasoconstriction as the predominant effect. Else- 

 where in the body, however, histamine causes striking 

 arteriolar vasodilation, and in intact animals the net 

 effect appears to be vasodilator also in the splanchnic 

 bed. An increase in EHBF in the face of arterial hy- 

 potension has been observed in man after intramus- 

 cular injection of histamine phosphate (47). In tin- 

 anesthetized dogs, moreover, Gersmeyer & Gersmeyer 

 (142) have found that the velocity (thermistor) of 

 portal venous blood flow increased sharply, although 

 portal venous pressure rises very little as arterial and 

 inferior vena caval pressures fall. Since it seems likely 

 from what has been said above that outflow resistance 

 is increased, the increments in portal pressure [which 

 are quite marked in other studies (308)] and blood 

 flow are most reasonably explained on the basis of 

 mesenteric vasodilation in excess of augmented intra- 

 hepatic resistance. It is equally possible that hepatic 

 arteriolar dilatation occurs. More precise and detailed 

 information obtained under properly controlled 

 conditions is needed to evaluate the simultaneous 

 changes in splanchnic resistances and in venous 

 capacity. The data at hand are in accord with growing 

 evidence that "histamine may actively dilate arterioles 

 at the same time that it actively constricts veins" 

 (167) not only as a result of a direct action upon the 

 vessels but also as a secondary result of adrenal medul- 

 lary discharge (134, 228, 297). It is also possible that 

 the action of many other substances is mediated 

 through histamine release (228). 



Still another substance released locally is serotonin, 

 or 5-hydroxytryptamine, which has been identified 

 and extensively studied in recent years. Selkurt (269) 

 reports that it behaves like norepinephrine in causing 

 vasoconstriction within the isolated mesenteric vessels 

 of the dog but little is known about its effect upon the 

 intrahepatic resistances or upon the volume of blood 

 held within the total splanchnic bed, liver, or spleen. 

 A steadily growing list of similar activating agents, 

 including a miscellany of amines and peptides pro- 

 duced during tissue injury, is making manifest the 



