Figure 3 Frequency distribution of Lp of single perfused frog mesenteric capillaries (A, n = 1111) and rat mesenteric venules (B, n = 89). Note nonnormal distribution of values with similar shape in both cases.

for fluid filtration were "pores" with a circular cross-section, a normal distribution of pore radii would result in a skewed distribution of filtration coefficient, varying according to the fourth power of the pore radius. However, ultrastructural evidence of cylindrical pores as a pathway for volume flux is lacking.

Control Lp values in frog mesenteric capillaries demonstrate a gradient of values across the capillary network. Capillaries near arterioles (arteriolar capillaries) typically have the lowest values, followed by midstream capillaries (true capillaries) and then capillaries near postcapillary venules (venular capillaries). This phenomenon is illustrated by our median Lp values (in units of 10-7cmsec-1cmH2O) in the frog mesentery of arteriolar capillaries (Lp = 1.8, n = 192), true capillaries (Lp = 2.9, n = 580), and venular capillaries (Lp = 5.1, n = 339). Since hydrostatic pressure across the capillary network has a decreasing gradient, the gradient of Lp values may attenuate variations in net volume flux across the capillary network. Despite this, the relative Lp and hydrostatic pressure gradients across the network tend to favor filtration across true and venular capillaries.

Active Changes in Hydraulic Conductivity

In Landis' initial experiments, he reported that frog mesenteric capillary Lp increased in response to a variety of insults including ischemia, hypoxia, and increased acidity. More recent work has shown acute increases in microvascu-lar Lp with less injurious stimuli. For example, agonists that increase intracellular levels of cyclic guanosine monophosphate (cGMP) such as atrial natriuretic peptide (ANP), sodium nitroprusside, and 8-bromo-cGMP induce reversible, dose-dependent increases in capillary L The endothelial cell structures responsible for these reversible changes in Lp remain to be determined, though in the case of ANP, the change in permeability is independent of the "protein effect" [9]. These data suggest that the microvascular barrier for volume flux may be regulated independently by different mechanisms. Other agents shown to increase Lp include histamine, bradykinin, serotonin, vascular endothe-lial growth factor (VEGF), adenosine triphosphate and calcium ionophores (see Ref. [2]). Many of these agents enhance intracellular endothelial calcium; temporal correlations between changes in endothelial calcium and microvas-cular Lp have been described [10]. In addition to increases in Lp, several agents have been reported to decrease microvascular Lp, including nitric oxide synthase inhibitors [11] as well as agents that increase endothelial cell cyclic adenosine monophosphate or activate adenylyl cyclase (rolipram, isoproterenol, forskolin; [12]). These studies demonstrate that microvascular volume flux may be subject to regulation by a variety of physiologic as well as pathologic stimuli. Under physiologic conditions, changes in Lp may influence the rate of delivery of water and nutrients to tissues. Pathologic increases in permeability, or hyperpermeability, would favor enhanced fluid filtration and may lead to tissue swelling, or edema. Of interest, on occasion a single inflammatory mediator may result in different changes in permeability in different portions of the microvasculature. For example, the inflammatory agonist bradykinin induced changes in Lp with distinct temporal and spatial variations in frog capillaries [13]. Thus, in addition to the heterogeneous control values of Lp across the network described earlier, the changes in Lp in response to the same agonist may vary across the microvascular network.

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