Pre- and postcapillary resistances in cat mesentery

The hemodynamic behavior of the isolated autoperfused intestinal loop (including mesenteric segment) of the cat was studied in terms of inflow and outflow pressures (BP and VP), arteriolar and venular pressures (P_a and P_v), and blood flow (Q). The regional vascular resistance [$\text{RR =}\text{(BP ? VP)}\text{Q}$] was subdivided into a precapillary resistance [$\text{P}{}_{\mathrm{<mtext>r</mtext>}}\text{R =}\text{(BP ? P}{}_{\mathrm{a}}\text{)}\text{Q}$], capillary resistance [$\text{CR =}\text{(P}{}_{\mathrm{a}}\text{? P}{}_{\mathrm{v}}\text{)}\text{Q}$], and postcapillary resistance [$\text{P}{}_{\mathrm{<mtext>s</mtext>}}\text{R =}\text{(P}{}_{\mathrm{v}}\text{? VP)}\text{Q}$]. With normal perfusion pressure it was found that: P_rR = 68%, P_sR = 20.5% and CR = 11.5%. Two different responses were noted when perfusion pressure was lowered to 20mm Hg. In the first group, precapillary resistance fell significantly, whereas postcapillary resistance did not change. In the second group, the regional resistance increased due to the increase in precapillary resistance and a significantly greater increase in postcapillary resistance. The regulatory mechanism in the first group is based on local readjustment of the precapillary vasculature with no participation of postcapillary vessels. The second group of responses appears to be related to completely dilated vessels, where regulation is achieved by increasing postcapillary resistance in an attempt to maintain the capillary pressure and homeostatic balance.     

The leukocyte response to fluid stress

Leukocyte migration from a hemopoietic pool across marrow endothelium requires active pseudopod formation and adhesion. Leukocytes rarely show pseudopod formation while in circulation. At question then is the mechanism that serves to minimize leukocyte pseudopod formation in the circulation. We tested the hypothesis that fluid shear stress acts to prevent pseudopod formation. When individual human leukocytes (neutrophils, monocytes) spreading on glass surfaces in vitro were subjected to fluid shear stress (≈1 dyn/cm²), an instantaneous retraction of pseudopods was observed. Removal of the fluid shear stress in turn led to the return of pseudopod projection and cell spreading. When steady shear stress was prolonged over several minutes, leukocyte swelling occurs together with an enhanced random motion of cytoplasmic granules and a reduction of cytoplasmic stiffness. The response to shear stress could be suppressed by K⁺ channel blockers and chelation of external Ca²⁺. In rat mesentery microvessels after occlusion, circulating leukocytes project pseudopods in free suspension or when attached to the endothelium, even though immediately after occlusion only few pseudopods were present. When flow was restored, pseudopods on adhering leukocytes were retracted and then the cells began to roll and detach from the endothelium. In conclusion, plasma shear stress in the circulation serves to reduce pseudopod projection and adhesion of circulating leukocytes and vice versa reduction of shear stress leads to pseudopod projection and spreading of leukocytes on the endothelium.     

RBC velocity profiles in arterioles and venules of the rabbit omentum.

We have shown that in vivo RBC velocity profiles for mammalian arterioles and venules are consistent with comparable in vitro measurements on the basis of vessel diameter and flow rate. In vivo profiles are uniformly nonsymmetric, in particular on the venous side. Irrespective of the site, they are time variant and are more blunted than would be anticipated for Poiseuille flow. The blunted nature of the profiles becomes more pronounced as vessel diameter is decreased. The extent to which the profile is blunted was found not to be related to flow rate per se, except where midstream velocity fell to low levels (1.2 mm/sec). Since the velocity of the RBCs at the outermost edge of the bloodstream were higher than would be the case for a Poiseuille profile, the shear rates at the vessel wall can be much higher, i.e., in the range of 16,400 sec^?1, than have been reported on the basis of in vitro experiments.     

INACTIVATION OF BACTERIAL EXOTOXINS AND ENDOTOXIN BY IRON : IN VITRO STUDIES

After incubation with various agents in vitro, the lethal effects of aqueous solutions of Cl. perfringens alpha toxin, C. diphtheriae toxin, and E. coli endotoxin were tested in mice, guinea pigs, and rabbits, respectively. Iron, copper, cysteine, ascorbic acid, and versene counteracted the lethal effects of alpha toxin in mice, while magnesium, manganese, zinc, and citrate did not. Iron also counteracted the lethal effects of diphtheria toxin in guinea pigs. After incubation of endotoxin with iron, its lethal effects and tissue-necrotizing actions in rabbits were counteracted. However, the pyrogenic properties of the toxin were not affected. The solubilities of perfringens alpha toxin and diphtheria toxin were markedly reduced after incubation with detoxifying metals, and resolubilization of these toxins with chelators resulted in partial restoration of toxicity. Addition of versene to detoxified endotoxin also resulted in partial recovery of lethal effectiveness. The inactivation of bacterial toxins by iron under in vitro conditions is not specific to this metal, is a reversible process, and may be due to desolubilization, reduction, or to competition by the metal for sites on the toxin normally bound by other cations in vivo. Although no evidence is presented in this paper to support the view that there is a relationship between the inactivation of endotoxin and the storage iron in the reticuloendothelial system of shocked animals, the observation of an in vitro inactivation of endotoxin by inorganic iron warrants consideration of such a mechanism.     

PATHOGENESIS OF EXPERIMENTAL SHOCK : IV. STUDIES ON LYSOSOMES IN NORMAL AND TOLERANT ANIMALS SUBJECTED TO LETHAL TRAUMA AND ENDOTOXEMIA

Fatal shock was produced in animals by drum trauma, temporary occlusion of the superior mesenteric artery, and bacterial endotoxin. Measurements were made of release of beta glucuronidase and cathepsins from the large granule fractions of livers, and of levels of circulating beta glucuronidase and acid phosphatase in these animals. Experiments were also carried out with animals rendered tolerant by previous exposure to sublethal amounts of trauma or by pretreatment with cortisone. The results show that release of beta glucuronidase and cathepsins from the large granule fraction of liver was increased during traumatic and endotoxin shock in the rat. Similarly, circulating levels of acid phosphatase and beta glucuronidase were increased during traumatic shock in rats and rabbits, and during endotoxin shock in rats. The data also indicate that tolerance to traumatic injury, induced by prior conditioning, prevented the increase in levels of circulating acid phosphatase normally observed after stress, and may have been associated with an increased stability of hepatic lysosomal particles. In addition, cortisone, which appears to "stabilize" hepatic lysosomes in vivo, also reduced the increase in plasma acid phosphatase brought about by endotoxin and trauma. From the foregoing observations, it is suggested that: (a) Disruption of lysosomes and release of their contained enzymes in free, active form may occur in liver and intestine of shocked animals. (b) The activation of lysosomal hydrolases within cells and their release into the circulation may play an important role in exacerbating tissue injury and accelerating the development of irreversibility during shock. (c) The increased stability of lysosomes of tolerant and of cortisone-treated animals may constitute an important component of the resistance of these animals to shock.