Co-regulation of primary mouse hepatocyte viability and function by oxygen and matrix.

Although oxygen and extracellular matrix cues both influence differentiation state and metabolic function of primary rat and human hepatocytes, relatively little is known about how these factors together regulate behaviors of primary mouse hepatocytes in culture. To determine the effects of pericellular oxygen tension on hepatocellular function, we employed two methods of altering oxygen concentration in the local cellular microenvironment of cells cultured in the presence or absence of an extracellular matrix (Matrigel) supplement. By systematically altering medium depth and gas phase oxygen tension, we created multiple oxygen regimes (hypoxic, normoxic, and hyperoxic) and measured the local oxygen concentrations in the pericellular environment using custom-designed oxygen microprobes. From these measurements of oxygen concentrations, we derived values of oxygen consumption rates under a spectrum of environmental contexts, thus providing the first reported estimates of these values for primary mouse hepatocytes. Oxygen tension and matrix microenvironment were found to synergistically regulate hepatocellular survival and function as assessed using quantitative image analysis for cells stained with vital dyes, and assessment of secretion of albumin. Hepatocellular viability was affected only at strongly hypoxic conditions. Surprisingly, albumin secretion rates were greatest at a moderately supra-physiological oxygen concentration, and this effect was mitigated at still greater supra-physiological concentrations. Matrigel enhanced the effects of oxygen on retention of function. This study underscores the importance of carefully controlling cell density, medium depth, and gas phase oxygen, as the effects of these parameters on local pericellular oxygen tension and subsequent hepatocellular function are profound.

A 3D Cell Culture Organ-on-a-Chip Platform With a Breathable Hemoglobin Analogue Augments and Extends Primary Human Hepatocyte Functions in vitro.

Remarkable advances in three-dimensional (3D) cell cultures and organ-on-a-chip technologies have opened the door to recapitulate complex aspects of human physiology, pathology, and drug responses in vitro. The challenges regarding oxygen delivery, throughput, assay multiplexing, and experimental complexity are addressed to ensure that perfused 3D cell culture organ-on-a-chip models become a routine research tool adopted by academic and industrial stakeholders. To move the field forward, we present a throughput-scalable organ-on-a-chip insert system that requires a single tube to operate 48 statistically independent 3D cell culture organ models. Then, we introduce in-well perfusion to circumvent the loss of cell signaling and drug metabolites in otherwise one-way flow of perfusate. Further, to augment the relevancy of 3D cell culture models in vitro, we tackle the problem of oxygen transport by blood using, for the first time, a breathable hemoglobin analog to improve delivery of respiratory gases to cells, because in vivo approximately 98% of oxygen delivery to cells takes place via reversible binding to hemoglobin. Next, we show that improved oxygenation shifts cellular metabolic pathways toward oxidative phosphorylation that contributes to the maintenance of differentiated liver phenotypes in vitro. Lastly, we demonstrate that the activity of cytochrome P450 family of drug metabolizing enzymes is increased and prolonged in primary human hepatocytes cultured in 3D compared to two-dimensional (2D) cell culture gold standard with important ramifications for drug metabolism, drug-drug interactions and pharmacokinetic studies in vitro.

Autologous attenuated T-cell vaccine (Tovaxin) dose escalation in multiple sclerosis relapsing-remitting and secondary progressive patients nonresponsive to approved immunomodulatory therapies.

An open-label dose escalation study of T-cell vaccination in multiple sclerosis patients was conducted using attenuated myelin reactive T-cells (MRTC) selected with six myelin peptides, two each from MBP, PLP and MOG. The dose range of subcutaneous injections given at weeks 0, 4, 12 and 20 was 6-9E6, 30-45E6 and 60-90E6 irradiated MRTC. Assessments were over 52 weeks for MRTC levels, EDSS, MSIS-29, brain MRI and relapses. The 30-45E6 dose was the most effective with reductions in MRTC ranging from 92.4% at week 5 to 64.8% at week 52. The reduction in relapses compared to baseline for the M-ITT and evaluable per-protocol analyses were 63.5%, and 85.0% at week 52. The MRI lesions were stable while there was an improvement trend in the EDSS and MSIS-29 physical subscore following the second injection. Adverse events were mild to moderate in intensity with mild injection site reactions occurring with increasing dosage. The mid-dose was selected for further clinical development studies because of the rapid depletion of peripheral blood MRTC and a trend for improvements in clinical outcomes following immunization.

Axial tensile fracture of microcrystalline cellulose compacts.

An adapted tensile stress methodology for the fracture of microcrystalline cellulose (MCC) tablets has been investigated and implemented. The application of the generally applied linear elastic fracture mechanic (LEFM) parameters used to describe the fracture behaviour of these porous systems has been discussed. The application of an effective crack length concept, comprising of the notch depth and a process zone length designated delta c, has enabled the localised non-linear response of the MCC tablets to be characterised in a quantified manner. The requirement of the composite value delta c is postulated to be a direct result of the internal properties of the tablet formed during the compaction process due to its strong dependence on porosity. The high compact relative density creates a greater possibility for both local small-scale plastic yielding at the crack tip, commonly found in polymer materials and microcracking ahead of the crack tip, typically observed in the fracture of ceramics. The extrapolated value of KIC0 of 0.72 MPa m0.5 found in this work lies within the range found in literature for this material indicating that the adopted procedure is acceptable for the determination of the resistance to fracture of MCC compacts.

An audio urine-glucose analyzer for blind diabetics.

At the instigation of one of the authors (J.M.)--a young man whose blindness is due to diabetic retinopathy--a urine-glucose analyzer was designed and constructed. Its purpose and function enable him to test his urine himself (free of dependence on thers for this service) and, thereby, he can then determine and administer his doses of insulin. He and other young blind diabetics may value the degree of freedom from dependence on others than the analyzer provides and feel it helps them to be able to work and care for themselves. A description of the instrument instructions for its use, and a summary of about 20 months' experience with it are submitted.

Maize yield response to a phosphorus-solubilizing microbial inoculant in field trials.

Findings from multi-year, multi-site field trial experiments measuring maize yield response to inoculation with the phosphorus-solubilizing fungus, Penicillium bilaiae Chalabuda are presented. The main objective was to evaluate representative data on crop response to the inoculant across a broad set of different soil, agronomic management and climate conditions. A statistical analysis of crop yield response and its variability was conducted to guide further implementation of a stratified trial and sampling plan. Field trials, analysed in the present study, were conducted across the major maize producing agricultural cropland of the United States (2005-11) comprising 92 small (with sampling replication) and 369 large (without replication) trials. The multi-plot design enabled both a determination of how sampling area affects the estimation of maize yield and yield variance and an estimation of the ability of inoculation with P. bilaiae to increase maize yield. Inoculation increased maize yield in 66 of the 92 small and 295 of the 369 large field trials (within the small plots, yield increased significantly at the 95% confidence level, by 0·17 ± 0·044 t/ha or 1·8%, while in the larger plots, yield increases were higher and less variable (i.e., 0·33 ± 0·026 t/ha or 3·5%). There was considerable inter-annual variability in maize yield response attributed to inoculation compared to the un-inoculated control, with yield increases varying from 0·7 ± 0·75 up to 3·7 ± 0·73%. No significant correlation between yield response and soil acidity (i.e., pH) was detected, and it appears that pH reduction (through organic acid or proton efflux) was unlikely to be the primary pathway for better phosphorus availability measured as increased yield. Seed treatment and granular or dribble band formulations of the inoculant were found to be equally effective. Inoculation was most effective at increasing maize yield in fields that had low or very low soil phosphorus status for both small and large plots. At higher levels of soil phosphorus, yield in the large plots increased more with inoculation than in the small plots, which could be explained by phosphorus fertilization histories for the different field locations, as well as transient (e.g., rainfall) and topographic effects.

Genetic differences in spatial learning between Dark Agouti and Sprague-Dawley strains: possible correlation with the CYP2D2 polymorphism in rats treated neonatally with methamphetamine.

Following neonatal exposure to d-methamphetamine, adult rats have previously been shown to exhibit augmented acoustic startle and spatial learning deficits. d-Methamphetamine is structurally similar to several phenylethylamines that are metabolized by CYP2D6. In humans, allelic differences in the CYP2D6 confer the extensive or poor metabolizer phenotype for the more than three dozen drugs that are members of the CYP2D6-mediated 'debrisoquine/sparteine panel.' An analogous genotype exists with the CYP2D2 gene in rats. Female Dark Agouti rats show the poor metabolizer phenotype, whereas Sprague-Dawley rats show the extensive metabolizer phenotype; male Dark Agouti rats are intermediate. We sought to test the possibility that these strains might exhibit altered d-methamphetamine-induced developmental neurotoxicity. Dark Agouti and Sprague-Dawley litters (11-20 days of age) were given d-methamphetamine or vehicle alone subcutaneously twice daily (15 mg/kg). Offspring were assessed as adults (beginning at 50 days of age) on acoustic startle, straight-channel swimming, and spatial learning and memory in a Morris hidden platform maze. Increases in d-methamphetamine-induced acoustic startle were found in both male and female Dark Agouti rats, but not Sprague-Dawley rats. In the Morris maze, d-methamphetamine-induced spatial navigation deficits were found in both strains among males, suggesting some mechanism other than the CYP2D2 polymorphism. In contrast, among females only the d-methamphetamine-treated Dark Agouti rats showed deficits in spatial navigation. The maze deficits in Dark Agouti females, and enhanced acoustic startle in Dark Agouti females and males, support the hypothesis that the CYP2D2 poor metabolizer phenotype confers increased vulnerability to d-methamphetamine-induced developmental neurotoxicity, indicating that the parent drug rather than a CYP2D2-mediated metabolite is responsible for this behavioural defect--which occurs in adults who had been exposed to d-methamphetamine during the neonatal period.

Increased urinary excretion of endothelin during hypothermic perfusion preservation in kidneys subjected to preretrieval warm ischemic injury.

The purpose of the study was two-fold: 1) to determine whether endothelin (ET) levels could be detected in the ureteral effluent during hypothermic perfusion preservation (HPP) and; 2) to determine whether preretrieval warm ischemic (WI) injury is associated with increased ureteral excretion of ET. In situ pre-WI injury was induced in Lewis rats (n=10) by a 30-min extrinsic occlusion of the suprarenal aorta. The left kidney underwent 16 hr of HPP, and ureteral effluent (UE) from ischemic and control kidneys (n=10) was collected over 16 hr of HPP. The UE ET concentration and total ET excretion over 16 hr of HPP were significantly higher in kidneys subjected to pre-WI injury compared with nonischemic controls. Kidneys subjected to pre-WI injury can be distinguished from nonischemic control kidneys during HPP by a significantly higher concentration of ET in the UE and a higher overall excretion of ET during HPP.

Identification of kidneys subjected to preretrieval warm ischemic injury by simultaneous monitoring of glomerular filtration and perfusate flow during hypothermic perfusion preservation.

BACKGROUND: Historically, ex vivo physiological evaluation of cadaveric renal allografts has been limited to assessing perfusate flow (PF) during hypothermic perfusion preservation (HPP). Using a small animal model, we have previously described a method for continuous monitoring of glomerular filtration rate (GFR) during HPP. Our study was undertaken to determine if monitoring GFR and PF during HPP distinguished kidneys subjected to preretrieval warm ischemic (WI) injury more reliably than PF alone. METHODS: In situ WI was induced in Lewis rats (n=10) by extrinsic occlusion of the suprarenal aorta for 30 min. After in situ cold perfusion and retrieval, the left kidney underwent 16 hr of HPP. Nonischemic (NI) control kidneys (n=10) were retrieved in the absence of suprarenal aortic occlusion. Longitudinal changes in PF, GFR, and filtration fraction (FF) during HPP were compared in WI versus NI kidneys (FF=GFR/PF x 100%). RESULTS: PF remained the same in both cohorts throughout HPP. GFR, however, increased to a significantly greater degree in WI versus NI kidneys during the first 4 hr of HPP (713+/-401 vs. 26+/-23%, respectively) (P<0.05). The increase in FF at 4 hr was 1203+/-696% in the WI kidneys versus 83+/-46% in the NI controls (P<0.05). CONCLUSIONS: In contrast to PF alone, measurement of both PF and GFR distinguished kidneys subjected to pre-WI from NI controls. The data provide a means to determine if monitoring of both GFR and PF during HPP will predict short- and long-term renal allograft function more reliably than PF alone.

Renal hemodynamic effects of lovastatin in a renal ablation model.

OBJECTIVES: Patients with renal mass reduction of more than 50% are at increased risk for progressive renal failure. Lipid-lowering agents have been shown to preserve renal function in various models of chronic renal failure. This study was performed to evaluate the hemodynamic effects of lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, in the remnant kidney model. METHODS: Two groups of animals were studied. Group 1 (n = 9) served as controls and group 2 (n = 14) received lovastatin, 15 mg/kg/day orally, for 2 weeks after renal ablation. Glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, ultrasonic flow probe), and 24-hour protein excretion were measured in anesthetized rats. RESULTS: Two weeks after renal ablation, GFR was 0.28 +/- 0.09 mL/min/gkw (gram kidney weight) in group 1, whereas in group 2, lovastatin preserved GFR at 0.58 +/- 0.3 mL/min/gkw (P < 0.05). RBF in group 1 was 1.2 +/- 0.2 mL/min/gkw and increased to 2.1 +/- 0.4 mL/min/gkw in group 2 (P < 0.05), representing a 43% increase. Protein excretion decreased significantly to 13 +/- 1.7 mg/24 hr in group 2. The lovastatin-treated group had a lower serum cholesterol (59 +/- 3 mg/dL versus 71 +/- 2 mg/dL, P < 0.05), but serum triglyceride levels were not different between the two groups. CONCLUSIONS: Lovastatin preserves renal function in a renal ablation model after 2 weeks of treatment. It specifically increased total RBF. Therefore, in addition to its known cholesterol lowering effect, lovastatin also has the direct renal hemodynamic effect of increasing RBF and maintaining GFR.

Role of endothelium-derived relaxing factor in the maintenance of renal blood flow in a rodent model of chronic hydronephrosis.

OBJECTIVES: To define the role of endothelium-derived relaxing factor (EDRF) in the regulation of renal hemodynamics in the hydronephrotic kidney. METHODS: Experiments were performed in control rats and in rats that had undergone unilateral ureteral ligation 6 weeks before. Renal blood flow was monitored before and after inhibition of EDRF synthesis in the control and hydronephrotic animals. Videomicroscopy was also performed in hydronephrotic animals to observe directly the effect of inhibition of EDRF synthesis on the renal microcirculation. RESULTS: Inhibition of EDRF synthesis resulted in a 61% decrease in renal blood flow in the control animals compared with only a 27% decrease for the hydronephrotic animals. The videomicroscopy studies demonstrated that inhibition of EDRF synthesis results in significant vasoconstriction of the preglomerular and postglomerular resistance vessels. CONCLUSIONS: Although EDRF continues to play a significant role in the maintenance of renal blood flow in the chronically obstructed kidney, EDRF synthesis by the renal vascular endothelium may be reduced in this setting, contributing to ischemic renal atrophy.

Renal microcirculatory effects of lovastatin in a rat model of reduced renal mass.

OBJECTIVES: Patients with reduced renal mass are at increased risk of developing renal failure. A remnant kidney model has been used to study the hemodynamic and structural changes that occur. We recently reported that the lipid-lowering agent lovastatin preserves renal function in this model. The purpose of the present study was to determine the specific effects of lovastation on the renal microcirculation of rats with reduced renal mass. METHODS: We used the rat hydronephrotic kidney preparation with a 5/6 partial nephrectomy. This model allows direct visualization of preglomerular and postglomerular vessels using videomicroscopy. The diameters and vascular responses to acetylcholine and angiotensin II of the interlobular, afferent, and efferent vessels were determined in two groups of animals with renal mass reduction: 15 rats with no lovastatin treatment and 18 rats treated with oral lovastatin (15 mg/kg body weight/day) for 2 weeks. RESULTS: In the lovastatin-treated rats, the baseline efferent vessel diameter was smaller by 21% (P < 0.05), but the interlobular and afferent vessel baseline diameters were not different from those in the untreated rats. Serum creatinine levels were lower in the treated rats (1.5 +/- 0.1 versus 2.0 +/- 0.2 mg/dL, P < 0.05), but serum lipids were not different. In the lovastatin-treated rats, vascular reactivity to acetylcholine was enhanced in the afferent and decreased in the efferent vessels. CONCLUSIONS: In this renal ablation model, lovastatin preserved renal function as measured by serum creatinine without lowering plasma lipid levels. Lovastatin treatment resulted in smaller efferent vessel diameters. Lovastatin also increased the vasodilatory response to acetylcholine in the afferent vessels. Together, these preglomerular and postglomerular changes would increase the single-nephron glomerular filtration rate. The renal protective effect of lovastatin may be due to these vasoactive effects on the renal microcirculation.

Diagnostic tunica vaginoscopy in a rodent model of testicular torsion.

OBJECTIVES: To evaluate the effectiveness of percutaneous endoscopy of the tunica vaginalis for identifying testicular torsion in a rodent model. METHODS: One testis was randomly selected in 10 Wistar rats weighing 500 to 600 g. Following 2 hours of 720 degree torsion, bilateral percutaneous endoscopy of the tunica vaginalis was performed by a blinded investigator utilizing a 70 degree cystoscope lens through a single midline 3 to 4 mm scrotal cutdown incision. RESULTS: Using this technique, the blinded investigator was able to identify the torsed testis rapidly in every case, which was distinguished by its cyanotic color and by the size and color of the testicular surface vessels. CONCLUSIONS: Tunica vaginoscopy is a simple, accurate, rapidly performed, minimally invasive, diagnostic technique in this experimental model of testicular torsion.

Prenatal phenytoin exposure and spatial navigation in offspring: effects on reference and working memory and on discrimination learning.

Previous research has shown that rats exposed to phenytoin (PHT) in utero demonstrate abnormal circling, decreased learning, hyperactivity, and delayed air righting reflex development. The effects of prenatal PHT on offspring learning have been found on multiple-T mazes (Biel and Cincinnati types) and on spatial navigation (Morris maze). However, the specificity of the latter effects is unknown. Herein, we tested the effects of prenatal PHT in a Morris maze using six different procedures: cued versus spatial reference memory-based learning, cued versus spatial working memory-based learning, and cued versus spatial discrimination learning. PHT-exposed offspring showed increased preweaning mortality, growth reduction, and abnormal circling as noted in previous studies. PHT offspring were separated into those exhibiting circling and those not. PHT noncircling offspring demonstrated impaired reference memory-based spatial learning (acquisition and reversal), but no other effects. By contrast, PHT circling offspring demonstrated not only impaired reference memory-based spatial learning, but also impaired cued platform learning, impaired spatial discrimination, and impaired working memory-based learning. These data confirm that prenatal PHT induces a specific reference memory-based spatial learning deficit even in asymptomatic (noncircling) offspring that is distinct from the impairment induced in littermates exhibiting the circling impairment.

Increased intra-abdominal pressure during pneumoperitoneum stimulates endothelin release in a canine model.

Prolonged pneumoperitoneum during laparoscopic surgery has been associated with oliguria in clinical experimental studies. Although the pathophysiology of this oliguria is thought to be renal parenchymal and venous compression, the role of the potent vasoconstrictor endothelin (ET) has not been studied. The purpose of this study was to investigate the effect of pneumoperitoneum on endothelin release and renal function in a canine model. Two groups of dogs were studied during pneumoperitoneum (Group 1, N = 7) or isolated left renal vein compression (Group 2, N = 6). Urine and plasma samples were collected for urine output, glomerular filtration rate (GFR), urine sodium, and plasma endothelin measurements. In Group 1, GFR fell significantly (p < 0.05) by 49% from a control of 0.88 +/- 0.12 mL/min per gram of kidney weight. Urine volume fell by 79% (p < 0.05) from a control value of 0.014 +/- 0.003 mL/min/gkw. Sodium excretion was decreased by 88%. Sodium reabsorption was significantly enhanced during pneumoperitoneum (99.56 +/- 0.15% v 98.44 +/- 0.25%). Arterial plasma ET concentrations were elevated by 8% during the first 20 minutes of pneumoperitoneum (30.8 +/- 3.6 v 33.3 +/- 3.4 pg/mL; p < 0.05). In Group 2, left renal vein compression resulted in a 31% decrease (p < 0.05) in GFR in the left kidney and a 25% decrease in the right kidney. Urine volume fell by 67% in the left kidney and 40% in the right. Renal venous ET concentrations also increased after renal vein compression. Although the mechanism by which oliguria occurs during pneumoperitoneum is not fully understood, the ET concentration was elevated. Because ET can decrease RBF, GFR, and sodium excretion, it may contribute to the oliguria observed during long periods of pneumoperitoneum.

Ventilatory muscle training in kyphoscoliosis.

Cardiorespiratory failure is the usual cause of death in severe kyphoscoliosis. The pathophysiology of this mechanism will be reviewed. Ventilatory muscle training (VMT), a relatively new respiratory technique, has been shown to improve the strength and endurance of the ventilatory muscles. It is known that stronger, endurance trained ventilatory muscles will guard against ventilatory muscle fatigue which may lead to respiratory failure. The actual technique is described with documentation of two representative cases. Case 1 showed a 63% increase in maximum inspiratory mouth pressure (PiMax) and an increased ability to walk and climb stairs with comfort. Case 2 used VMT as an adjunct to her weaning protocol from a portable ventilator. She progressed from full-time to nocturnal ventilator assistance in 1 month.

Lovastatin preserves renal function in experimental diabetes.

Although hyperlipidemia has been associated with the progression of glomerulosclerosis, little attention has been directed toward the use of lipid-lowering agents in altering diabetic nephropathy. We tested the hypothesis that lovastatin and the combination of lovastatin and enalapril would preserve renal function in streptozotocin-induced diabetic Wistar rats. Five groups of animals were studied: group 1, nondiabetic (n = 10); group 2, diabetic, insulin only (n = 12); group 3, lovastatin, (15 mg/kg/day, n = 13); group 4, enalapril, (50 mg/L drinking water, n = 10) and group 5, lovastatin plus enalapril, (n = 14). After 8 weeks of treatment, glomerular filtration rate (GFR, insulin clearance) was measured in anesthetized animals. The diabetic group was characterized by a GFR of 0.18 +/- 0.03 ml/min/g of kidney weight (gKW), a blood glucose level of 441 +/- 36 mg/dL, plasma cholesterol and triglyceride levels of 64 +/- 6.0 and 103 +/- 26.0 mg/dL. Lovastatin preserved GFR, 0.52 +/- 0.06 ml/min/gKW compared with the diabetic control subjects (P < 0.05). Enalapril also maintained GFR (0.42 +/- 0.06 ml/min/gKW, P < 0.05). In the lovastatin plus enalapril group, GFR (0.62 +/- 0.05 ml/min/gKW) was greater than in the enalapril group (P < 0.05), but was not different from the lovastatin group. Plasma lipid levels were not altered in any of the groups. Assessment of the kidneys by histology after treatment showed that the mesangial matrix injury score was better in the lovastatin, enalapril, and lovastatin plus enalapril groups compared with the diabetic group (P < 0.05). Lovastatin, enalapril, and lovastatin plus enalapril abrogated the decline in GFR and glomerular injury in diabetic rats. Lovastatin's direct renal protective effect seems to be independent of its lipid-lowering properties.

Preglomerular and postglomerular blood flow: relationship to kidney disease and treatment.

BACKGROUND: In the kidney, the afferent and efferent arterioles normally constrict or dilate in response to changes in systemic blood pressure to maintain glomerular filtration while protecting the glomerulus from excessive pressure. In diabetes mellitus and hypertension, the two most common causes of kidney failure, sustained hypertension within the glomerulus damages the glomerular membrane and eventually results in loss of kidney function. SUMMARY: Techniques developed in the last 10 years allow direct study of the glomerulus and the glomerular circulation. In both diabetes and hypertension, the afferent vessels may dilate, resulting in excessive pressure in the glomerulus. Calcium antagonists, angiotensin-converting enzyme inhibitors, and cyclosporine have direct effects on the preglomerular and postglomerular vessels, and the afferent and efferent arterioles may respond differently to the same agent. CONCLUSIONS: Techniques for studying afferent and efferent arteriolar changes and glomerular filtration rate may provide important insights into the actions of drugs and into renal diseases. Clinicians are beginning to be able to select drugs that have desired effects on the renal microcirculation.

Role of the renal microcirculation in antihypertensive therapy.

BACKGROUND: The renal circulation plays a central role in regulating blood pressure and glomerular filtration. OBJECTIVE: To examine the effects of the various classes of antihypertensive agents on the renal microcirculation. SUMMARY: Peripheral vascular resistance is generally increased in hypertension, and the microcirculation makes the major contribution to resistance. In the kidney, the preglomerular and postglomerular vessels constrict to protect the glomerular capillary from increased hydrostatic pressure, further increasing peripheral resistance. Because the renal microcirculation adjusts to maintain glomerular filtration and blood flow, antihypertensive agents that can normalize the pressure and blood flow in these vessels may help prevent the long-term consequences of hypertension. Angiotensin-converting enzyme inhibitors directly affect preglomerular and postglomerular resistance, but they further decrease postglomerular resistance. Calcium antagonists selectively decrease preglomerular resistance. The diuretics, vasodilators, alpha blockers, and beta blockers may also cause changes in preglomerular and postglomerular resistance; however, compensatory reflex responses may mitigate their direct effects. CONCLUSION: Some antihypertensive agents have unique actions on the renal microcirculation that better maintain renal function. A basic understanding of the physiologic action of these agents on the microcirculation may help in their selection.