Mesenteric lymphatic vessels adapt to mesenteric venous hypertension by becoming weaker pumps.

Lymphangions, the segments of lymphatic vessels between two adjacent lymphatic valves, actively pump lymph. Acute changes in transmural pressure and lymph flow have profound effects on lymphatic pump function in vitro. Chronic changes in pressure and flow in vivo have also been reported to lead to significant changes in lymphangion function. Because changes in pressure and flow are both cause and effect of adaptive processes, characterizing adaptation requires a more fundamental analysis of lymphatic muscle properties. Therefore, the purpose of the present work was to use an intact lymphangion isovolumetric preparation to evaluate changes in mesenteric lymphatic muscle mechanical properties and the intracellular Ca(2+) in response to sustained mesenteric venous hypertension. Bovine mesenteric veins were surgically occluded to create mesenteric venous hypertension. Postnodal mesenteric lymphatic vessels from mesenteric venous hypertension (MVH; n = 6) and sham surgery (Sham; n = 6) animals were isolated and evaluated 3 days after the surgery. Spontaneously contracting MVH vessels generated end-systolic active tension and end-diastolic active tension lower than the Sham vessels. Furthermore, steady-state active tension and intracellular Ca(2+) concentration levels in response to KCl stimulation were also significantly lower in MVH vessels compared with those of the Sham vessels. There was no significant difference in passive tension in lymphatic vessels from the two groups. Taken together, these results suggest that following 3 days of mesenteric venous hypertension, postnodal mesenteric lymphatic vessels adapt to become weaker pumps with decreased cytosolic Ca(2+) concentration.

Adaptation of mesenteric lymphatic vessels to prolonged changes in transmural pressure.

In vitro studies have revealed that acute increases in transmural pressure increase lymphatic vessel contractile function. However, adaptive responses to prolonged changes in transmural pressure in vivo have not been reported. Therefore, we developed a novel bovine mesenteric lymphatic partial constriction model to test the hypothesis that lymphatic vessels exposed to higher transmural pressures adapt functionally to become stronger pumps than vessels exposed to lower transmural pressures. Postnodal mesenteric lymphatic vessels were partially constricted for 3 days. On postoperative day 3, constricted vessels were isolated, and divided into upstream (UP) and downstream (DN) segment groups, and instrumented in an isolated bath. Although there were no differences between the passive diameters of the two groups, both diastolic diameter and systolic diameter were significantly larger in the UP group than in the DN group. The pump index of the UP group was also higher than that in the DN group. In conclusion, this is the first work to report how lymphatic vessels adapt to prolonged changes in transmural pressure in vivo. Our results suggest that vessel segments upstream of the constriction adapt to become both better fluid conduits and lymphatic pumps than downstream segments.

Decreased myosin phosphatase target subunit 1(MYPT1) phosphorylation via attenuated rho kinase and zipper-interacting kinase activities in edematous intestinal smooth muscle.

BACKGROUND: Intestinal edema development after trauma resuscitation inhibits intestinal motility which results in ileus, preventing enteral feeding and compromising patient outcome. We have shown previously that decreased intestinal motility is associated with decreased smooth muscle myosin light chain (MLC) phosphorylation. The purpose of the present study was to investigate the mechanism of edema-induced decreases in MLC in a rodent model of intestinal edema. METHODS: Intestinal edema was induced by a combination of resuscitation fluid administration and mesenteric venous hypertension. Sham operated animals served as controls. Contractile activity and alterations in the regulation of MLC including the regulation of MLC kinase (MLCK) and MLC phosphatase (MLCP) were measured. KEY RESULTS: Contraction amplitude and basal tone were significantly decreased in edematous intestinal smooth muscle compared with non-edematous tissue. Calcium sensitivity was also decreased in edematous tissue compared with non-edematous intestinal smooth muscle. Although inhibition of MLCK decreased contractile activity significantly less in edematous tissue compared with non-edematous tissue, MLCK activity in tissue lysates was not significantly different. Phosphorylation of MYPT was significantly lower in edematous tissue compared with non-edematous tissue. In addition, activities of both rho kinase and zipper-interacting kinase were significantly lower in edematous tissue. CONCLUSIONS & INFERENCES: We conclude from these data that interstitial intestinal edema inhibits MLC phosphorylation predominantly by decreasing inhibitory phosphorylation of the MLC targeting subunit (MYPT1) of MLC phosphatase via decreased ROCK and ZIPK activities, resulting in more MLC phosphatase activity.

Evaluating the effects of immediate application of negative pressure therapy after decompression from abdominal compartment syndrome in an experimental porcine model.

PURPOSE: The purpose of this large-animal study was to assess the safety and effects of negative pressure therapy (NPT) when used as temporary abdominal closure in the immediate post-decompression period after abdominal compartment syndrome (ACS). METHODS: Using a hemorrhagic shock/resuscitation and mesenteric venous pressure elevation model, ACS was physiologically induced in 12 female Yorkshire swine. At decompression, animals were allocated to either NPT (n = 6) or Bogota bag (n = 6) as temporary abdominal closure and studied for a period of 48 h or until death. Outcomes measured included morbidity and mortality, as well as hemodynamic parameters, ventilator-related measurements, blood gases, coagulation factors, and organ (liver, kidney, lung, and intestinal) edema and histology at the time of death/sacrifice. RESULTS: All animals developed ACS. Early application of NPT was associated with decreases in mesenteric venous and central venous pressure, and significantly increased drainage of peritoneal fluid. In addition, there was no increase in the incidence of mortality, recurrent intra-abdominal hypertension/ACS, or any deleterious effects on markers of organ injury. CONCLUSIONS: Early application of NPT in this porcine ACS model is safe and does not appear to be associated with an increased risk of recurrent intra-abdominal hypertension. The results of this animal study suggest that the application of NPT following decompression from ACS results in greater peritoneal fluid removal and may translate into augmented intestinal edema resolution secondary to more favorable fluid flux profiles.

Evaluation of gravimetric techniques to estimate the microvascular filtration coefficient.

Microvascular permeability to water is characterized by the microvascular filtration coefficient (K(f)). Conventional gravimetric techniques to estimate K(f) rely on data obtained from either transient or steady-state increases in organ weight in response to increases in microvascular pressure. Both techniques result in considerably different estimates and neither account for interstitial fluid storage and lymphatic return. We therefore developed a theoretical framework to evaluate K(f) estimation techniques by 1) comparing conventional techniques to a novel technique that includes effects of interstitial fluid storage and lymphatic return, 2) evaluating the ability of conventional techniques to reproduce K(f) from simulated gravimetric data generated by a realistic interstitial fluid balance model, 3) analyzing new data collected from rat intestine, and 4) analyzing previously reported data. These approaches revealed that the steady-state gravimetric technique yields estimates that are not directly related to K(f) and are in some cases directly proportional to interstitial compliance. However, the transient gravimetric technique yields accurate estimates in some organs, because the typical experimental duration minimizes the effects of interstitial fluid storage and lymphatic return. Furthermore, our analytical framework reveals that the supposed requirement of tying off all draining lymphatic vessels for the transient technique is unnecessary. Finally, our numerical simulations indicate that our comprehensive technique accurately reproduces the value of K(f) in all organs, is not confounded by interstitial storage and lymphatic return, and provides corroboration of the estimate from the transient technique.

A murine model for the study of edema induced intestinal contractile dysfunction.

BACKGROUND: We have published extensively regarding the effects of edema on intestinal contractile function. However, we have found the need to expand our model to mice to take advantage of the much larger arsenal of research support, especially in terms of transgenic mouse availability and development. To that end, we have developed and validated a hydrostatic intestinal edema model in mice. METHODS: Male C57 Black 6 mice were subjected to a combination of high volume crystalloid resuscitation and mesenteric venous hypertension in an effort to induce hydrostatic intestinal edema. Wet to dry ratios, myeloperoxidase activity, mucosal injury scoring, STAT-3 nuclear activation, phosphorylated STAT-3 levels, NF-κB nuclear activation, myosin light chain phosphorylation, intestinal contractile activity, and intestinal transit were measured to evaluate the effects of the model. KEY RESULTS: High volume crystalloid resuscitation and mesenteric venous hypertension resulted in the development of significant intestinal edema without an increase in myeloperoxidase activity or mucosal injury. Edema development was associated with increases in STAT-3 and NF-κB nuclear activation as well as phosphorylated STAT-3. There was a decrease in myosin light chain phosphorylation, basal and maximally stimulated intestinal contractile activity, and intestinal transit. CONCLUSION & INFERENCES: Hydrostatic edema in mice results in activation of a signal transduction profile that culminates in intestinal contractile dysfunction. This novel model allows for advanced studies into the pathogenesis of hydrostatic edema induced intestinal contractile dysfunction.

Balance point characterization of interstitial fluid volume regulation.

The individual processes involved in interstitial fluid volume and protein regulation (microvascular filtration, lymphatic return, and interstitial storage) are relatively simple, yet their interaction is exceedingly complex. There is a notable lack of a first-order, algebraic formula that relates interstitial fluid pressure and protein to critical parameters commonly used to characterize the movement of interstitial fluid and protein. Therefore, the purpose of the present study is to develop a simple, transparent, and general algebraic approach that predicts interstitial fluid pressure (P(i)) and protein concentrations (C(i)) that takes into consideration all three processes. Eight standard equations characterizing fluid and protein flux were solved simultaneously to yield algebraic equations for P(i) and C(i) as functions of parameters characterizing microvascular, interstitial, and lymphatic function. Equilibrium values of P(i) and C(i) arise as balance points from the graphical intersection of transmicrovascular and lymph flows (analogous to Guyton's classical cardiac output-venous return curves). This approach goes beyond describing interstitial fluid balance in terms of conservation of mass by introducing the concept of inflow and outflow resistances. Algebraic solutions demonstrate that P(i) and C(i) result from a ratio of the microvascular filtration coefficient (1/inflow resistance) and effective lymphatic resistance (outflow resistance), and P(i) is unaffected by interstitial compliance. These simple algebraic solutions predict P(i) and C(i) that are consistent with reported measurements. The present work therefore presents a simple, transparent, and general balance point characterization of interstitial fluid balance resulting from the interaction of microvascular, interstitial, and lymphatic function.

Edemagenic gain and interstitial fluid volume regulation.

Under physiological conditions, interstitial fluid volume is tightly regulated by balancing microvascular filtration and lymphatic return to the central venous circulation. Even though microvascular filtration and lymphatic return are governed by conservation of mass, their interaction can result in exceedingly complex behavior. Without making simplifying assumptions, investigators must solve the fluid balance equations numerically, which limits the generality of the results. We thus made critical simplifying assumptions to develop a simple solution to the standard fluid balance equations that is expressed as an algebraic formula. Using a classical approach to describe systems with negative feedback, we formulated our solution as a "gain" relating the change in interstitial fluid volume to a change in effective microvascular driving pressure. The resulting "edemagenic gain" is a function of microvascular filtration coefficient (K(f)), effective lymphatic resistance (R(L)), and interstitial compliance (C). This formulation suggests two types of gain: "multivariate" dependent on C, R(L), and K(f), and "compliance-dominated" approximately equal to C. The latter forms a basis of a novel method to estimate C without measuring interstitial fluid pressure. Data from ovine experiments illustrate how edemagenic gain is altered with pulmonary edema induced by venous hypertension, histamine, and endotoxin. Reformulation of the classical equations governing fluid balance in terms of edemagenic gain thus yields new insight into the factors affecting an organ's susceptibility to edema.

Application of local heat induces capillary recruitment in the Pallid bat wing.

Skin blood flow increases in response to local heat due to sensorineural and nitric oxide (NO)-mediated dilation. It has been previously demonstrated that arteriolar dilation is inhibited with NO synthase (NOS) blockade. Flow, nonetheless, increases with local heat. This implies that the previously unexamined nonarteriolar responses play a significant role in modulating flow. We thus hypothesized that local heating induces capillary recruitment. We heated a portion (3 cm2) of the Pallid bat wing from 25 degrees C to 37 degrees C for 20 min, and measured changes in terminal feed arteriole (approximately 25 microm) diameter and blood velocity to calculate blood flow (n = 8). Arteriolar dilation was reduced with NOS and sensorineural blockade using a 1% (wt/vol) NG-nitro-L-arginine methyl ester (L-NAME) and 2% (wt/vol) lidocaine solution (n = 8). We also measured changes in the number of perfused capillaries, and the time precapillary sphincters were open with (n = 8) and without (n = 8) NOS plus sensorineural blockade. With heat, the total number of perfused capillaries increased 92.7 +/- 17.9% (P = 0.011), and a similar increase occurred despite NOS plus sensorineural blockade 114.4 +/- 30.0% (P = 0.014). Blockade eliminated arteriolar dilation (-4.5 +/- 2.1%). With heat, the percent time precapillary sphincters remained open increased 32.3 +/- 6.0% (P = 0.0006), and this increase occurred despite NOS plus sensorineural blockade (34.1 +/- 5.8%, P = 0.0004). With heat, arteriolar blood flow increased (187.2 +/- 28.5%, P = 0.00003), which was significantly attenuated with NOS plus sensorineural blockade (88.6 +/- 37.2%, P = 0.04). Thus, capillary recruitment is a fundamental microvascular response to local heat, independent of arteriolar dilation and the well-documented sensorineural and NOS mechanisms mediating the response to local heat.

Inhibition of intestinal transit by resuscitation-induced gut edema is reversed by L-NIL.

BACKGROUND: Post-resuscitation gut edema and associated gut dysfunction is a common and significant clinical problem that occurs after traumatic injury and shock. We have shown previously that gut edema without ischemia/reperfusion injury delays intestinal transit [1]. We hypothesized that gut edema increases expression of inducible nitric oxide synthase (iNOS) protein, and that selective iNOS inhibition using L-NIL reverses the delayed intestinal transit associated with gut edema. MATERIALS AND METHODS: One hour prior to laparotomy, rats were pretreated with 10 mg/kg body weight of intraperitoneal L-NIL or saline vehicle and underwent 80 ml/kg body weight of 0.9% saline + superior mesenteric venous pressure elevation (Edema) or sham surgery (Sham). A duodenal catheter was placed to allow injection of a fluorescent dye for the measurement of intestinal transit. At 6 h, the small bowel was divided and the mean geometric center (MGC) of fluorescent dye was measured to determine transit. Ileum was harvested for histological assessment of mucosal injury, evaluation of iNOS protein expression by Western blotting, and MPO activity. Tissue water was determined using the wet-to-dry weight ratio to assess gut edema. Data are expressed as mean +/- SEM, n = 3-6 and * = P <0.05 using ANOVA. RESULTS: Gut edema, expressed as increased wet-to-dry ratio, was associated with decreased intestinal transit and elevated iNOS protein expression. Pretreatment with l-NIL improved intestinal transit and decreased expression of iNOS protein without decreasing intestinal tissue water compared to edema animals. There was no difference in mucosal injury or MPO activity among groups. CONCLUSION: Gut edema delays intestinal transit via an iNOS-mediated mechanism.

Optimal lymphatic vessel structure.

Lymphatic vessels transport excess interstitial fluid from the low-pressure tissues to the higher pressure veins. The basic structural unit of lymphatic vessels is the lymphangion, a segment of the vessel separated by two unidirectional valves. Lymphangions cyclically contract like ventricles and can actively pump lymph. Lymphangions, as conduit vessels, also can act as arteries, and resist lymph flow. Functional parameters such as pressures, flow, and efficiency are determined by structural parameters like length, radius, and wall thickness. Since these structural parameters are unalterable experimentally, we developed a computational model to study the effect of a particular structural parameter, lymphangion length, to a particular functional variable, lymph flow. The model predicts that flow is a bimodal function of length, exhibiting an optimal length in the same order of magnitude as that observed experimentally. In essence, when the length to radius ratio is small, lymphangions act more like ventricles, where longer lengths yield greater chamber volume and thus lymph pumped. When the length to radius ratio is large, lymphangions act more like arteries, where longer lengths yield greater resistances to flow. This approach provides the means to explore how lymphatic vessel structure is optimized in a variety of conditions.

Flow in lymphatic networks: interaction between hepatic and intestinal lymph vessels.

OBJECTIVE: Lymph from both the liver and intestine flows into the cisterna chyli. We hypothesized that increasing liver lymph flow would increase cisterna chyli pressure and, thereby, decrease intestinal lymph flow, potentiating intestinal edema formation. METHODS: Anesthetized dogs were instrumented to measure and manipulate portal vein pressure and cisterna chyli pressure. The effects of directly increasing portal pressure with and without directly increasing cisterna chyli pressure on intestinal wet-to-dry ratio and intestinal ascites formation rate were determined. Target values for portal and cisterna chyli pressures were determined following elevation of inferior vena caval pressure to levels seen in patients with obstructive caval disease. RESULTS: Direct elevation of portal pressure (P(port)) alone to 17.5 mm Hg caused a significant increase in intestinal wet-to-dry ratio (3.98 +/- 0.24 vs. 3.40 +/- 0.43) and the rate of ascites formation (0.36 +/- 0.12 vs. 0.05 +/- 0.03 mL/g dry wt/h). Simultaneous direct elevation of cisterna chyli pressure to 6.0 mm Hg and P(port) to 17.5 mm Hg caused further increases in intestinal wet-to-dry ratio (5.52 +/- 1.20) and ascites formation (0.57 +/- 0.11 mL/g dry wt./h). CONCLUSIONS: Inferior vena caval hypertension increases liver lymph flow that elevates cisterna chyli pressure, which inhibits intestinal lymph flow and augments intestinal edema formation.

Protein washdown as a defense mechanism against myocardial edema.

Myocardial edema occurs in many pathological conditions. We hypothesized that protein washdown at the myocardial microvascular exchange barrier would change the distribution of interstitial proteins from large to small molecules and diminish the effect of washdown on the colloid osmotic pressure (COP) of interstitial fluid and lymph. Dogs were instrumented with coronary sinus balloon-tipped catheters and myocardial lymphatic cannulas to manipulate myocardial lymph flow and to collect lymph. Myocardial venous pressure was elevated by balloon inflation to increase transmicrovascular fluid flux and myocardial lymph flow. COP of lymph was measured directly and was also calculated from protein concentration. Decreases occurred in both protein concentration and COP of lymph. The proportion of lymph protein accounted for by albumin increased significantly, whereas that accounted for by beta-lipoprotein decreased significantly. The change in the calculated plasma-to-lymph COP gradient was significantly greater than the change in the measured COP gradient. We conclude that the change in the distribution of interstitial fluid protein species decreases the effect of protein washdown on interstitial fluid COP and limits its effectiveness as a defense mechanism against myocardial edema formation.

Basic determinants of epicardial transudation.

Myocardial edema formation, which has been shown to compromise cardiac function, and increased epicardial transudation (pericardial effusion) have been shown to occur after elevation of myocardial venous and lymphatic outflow pressures. The purposes of this study were to estimate the hydraulic conductance and osmotic reflection coefficient for the epicardium and to determine the effect of coronary sinus hypertension and cardiac lymphatic obstruction on epicardial fluid flux (JV,e/Ae). A Plexiglas hemispheric capsule was attached to the left ventricular epicardial surface of anesthetized dogs. JV,e/Ae was determined over 30-min periods for three intracapsular pressures (-5, -15, and -25 mmHg) and two intracapsular solutions exerting colloid osmotic pressures of 7.0 and 2.0 mmHg. Hydraulic conductance was estimated to be 3.7 +/- 0.5 microliters.h-1.cm-2.mmHg-1. An osmotic reflection coefficient of 0.9 was calculated from the difference in JV,e/Ae of 16.5 +/- 8.4 microliters.h-1.cm-2 between the two solutions. Graded coronary sinus hypertension induced a linear increase in JV,e/Ae, which was significantly greater in dogs without cardiac lymphatic occlusion than in those with occlusion.

Regulation of microvascular filtration in the myocardium by interstitial fluid pressure.

We hypothesized that myocardial microvascular filtration rate (Jv) could be manipulated by varying end-diastolic myocardial interstitial hydrostatic (P(int)) pressure. Dogs under general anesthesia were instrumented with intramyocardial capsules to measure P(int) and with prenodal myocardial lymphatic trunk cannulas and superior vena caval balloon-tipped catheters to manipulate myocardial lymph flow. Because, for a given surface area, the lymph-to-plasma protein concentration ration (CL/CP) varies inversely with JV, CL/CP was utilized as an index of changes in JV. When lymphatic outflow pressure (P0) was elevated to abolish lymph flow and force myocardial interstitial fluid volume to expand, P(int) rose significantly from 15.0 +/- 0.8 to 27.6 +/- 1.0 mmHg and CL/CP increased significantly from 0.75 +/- 0.04 to 0.85 +/- 0.04, indicating a decrease in JV. When P0 was lowered and lymph flow resumed, P(int) and CL/CP decreased significantly to 15.3 +/- 0.9 mmHg and 0.75 +/- 0.04, respectively, indicating an increase in JV. We conclude that myocardial microvascular filtration rate may be modulated by changes in P(int) resulting from alterations in myocardial interstitial fluid volume secondary to variations in lymph flow from the heart.

Comparative evaluation of the short-term bactericidal potential of a steroid-antibiotic combination versus steroid in the treatment of chronic bacterial blepharitis and conjunctivitis.

The effects of four days' treatment with topical Maxitrol (neomycin sulphate 3500 IU/mL, polymyxin-B sulphate 6000 IU/mL with dexamethasone 0.1%) were compared with those of Maxidex (dexamethasone 0.1% alone) in a double-masked study in 111 patients with bacterial blepharitis or conjunctivitis, 95 of whom were evaluable for efficacy. The majority of patients (N = 80) had chronic blepharitis. Maxitrol treatment resulted in a significantly greater reduction (90%) in bacterial counts and bacterial eradication (50%) compared with Maxidex (34% and 17% respectively). Maxitrol treatment also produced a significantly greater reduction in conjunctival discharge than did Maxidex, while the treatments were equally effective in alleviating other ocular signs and symptoms. It was concluded that use of a fixed dose combination steroid-antibiotic product was more effective for bacterial control and therapeutic efficacy in the treatment of chronic blepharitis and conjunctivitis patients than treatment with steroid alone. However, in the long-term treatment of chronic blepharitis the well-known toxic problems of neomycin sulphate have to be taken into account.

A 90-day study of the efficacy and side effects of 0.25% and 0.5% apraclonidine vs 0.5% timolol. Apraclonidine Primary Therapy Study Group.

OBJECTIVE: To compare long-term intraocular pressure (IOP)-lowering efficacy of 0.25% and 0.5% apraclonidine hydrochloride with 0.5% timolol maleate. DESIGN: Multicenter, randomized, double-masked trial. Adult patients of either sex diagnosed as having open-angle glaucoma or ocular hypertension were enrolled following appropriate washout from all ocular hypotensive medications. Morning IOPs of 22 to 35 mm Hg were required for entry. Patients received 0.25% or 0.5% apraclonidine 3 times a day or 0.5% timolol twice a day for 90 days. Intraocular pressure was measured at 8 AM (before morning dosing) and at 4 PM (8 hours after dosing) on days 1, 30, and 90, and only at 8 AM on day 14. RESULTS: All 3 medications significantly reduced IOP from baseline at all observation times (P < .001): 0.5% apraclonidine reduced IOP more than 0.25% apraclonidine; no significant difference was observed between 0.5% apraclonidine and 0.5% timolol 8 hours after dosing on days 1, 30, and 90; and a significant difference (P < .05) in favour of 0.5% timolol over 0.25% apraclonidine was observed 8 hours after dosing on day 30. At all morning visits following evening dosing, 0.5% timolol significantly reduced IOP more than both concentrations of apraclonidine. CONCLUSIONS: Both 0.25% and 0.5% apraclonidine significantly reduce IOP when used as primary ocular hypotensive medication. Although 0.25% and 0.5% apraclonidine reduce IOP to a similar degree as 0.5% timolol 8 hours after morning dosing, neither concentration is as effective for reducing morning IOP after evening dosing.

Renal lymphatic function following venous pressure elevation.

The renal lymphatic system plays an important role in removing excess fluid from the kidneys. Unfortunately, the factors influencing lymphatic flow are difficult to measure. We used a simple model to represent renal lymphatics as a single pressure source (PL) pushing lymph through a single resistance (RL). In anesthetized dogs, we cannulated renal lymphatics and measured lymph flow rate (QL) as we varied pressure (PO) at the outflow end of the lymphatics. There was no significant change in QL as we increased PO from -5 to 0 cm H2O. In other words, there was a plateau in the QL vs. PO relationship. At higher PO's, QL decreased linearly with increases in PO. From this linear relationship, we calculated RL as -delta PO/ delta QL and we took PL as the PO at which QL = 0 microliter/min. At baseline, RL = 0.34 +/- 0.14 (SD) cm H2O.min/microliter and PL = 8.2 +/- 4.4 cm H2O. When we increased renal venous pressure (PV) from baseline (3.5 +/- 3.0 cm H2O), the plateau in the QL vs. PO relationship extended to higher PO's, RL decreased, and PL increased. Renal interstitial fluid volume and interstitial pressure increased following elevation of PV. The extension of the QL vs. PO plateau with increasing PV suggests that renal interstitial pressure may partially collapse intrarenal collecting lymphatics which may compromise lymph flow.

Periocular cutaneous pigmentary changes associated with topical betaxolol.

PURPOSE: We report two cases of periocular cutaneous hypopigmentation and one case of hyperpigmentation which appeared while the patients were on betaxolol. We propose several possible explanations for this phenomenon. METHODS: Charts of three patients with glaucoma who developed periocular cutaneous pigmentary changes while on betaxolol were reviewed retrospectively. RESULTS: Case #1 was a 47-year-old black man with primary open angle glaucoma, started on betaxolol 0.5% in both eyes in January 1981. Bilateral hypopigmentation of the eyelids was first documented in October 1987. Betaxolol was discontinued in November 1987. In December 1990 the pigmentation had returned to normal. Case #2 was a 4-month-old white boy with unilateral primary infantile glaucoma who was started in September 1992 on betaxolol 0.25% in the left eye. Left lower eyelid hypopigmentation was seen in April 1993. Betaxolol was discontinued in July 1993. Since that time the pigmentation has returned to normal. Case #3 was a 75-year-old black man with primary open angle glaucoma. He was placed on betaxolol 0.5% in both eyes in 1987 and in March 1988 hyperpigmentation of the eyelids was seen bilaterally. Betaxolol was discontinued, and by December 1990 the pigmentation had returned to normal. CONCLUSION: These three case histories suggest that the periocular cutaneous changes described herein are secondary to local instillation of betaxolol.