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1.
J Appl Physiol (1985) ; 126(2): 494-501, 2019 02 01.
Article in English | MEDLINE | ID: mdl-30571293

ABSTRACT

Of the 300 billion capillaries in the human lung, a small fraction meet normal oxygen requirements at rest, with the remainder forming a large reserve. The maximum oxygen demands of the acute stress response require that the reserve capillaries are rapidly recruited. To remain primed for emergencies, the normal cardiac output must be parceled throughout the capillary bed to maintain low opening pressures. The flow-distributing system requires complex switching. Because the pulmonary microcirculation contains contractile machinery, one hypothesis posits an active switching system. The opposing hypothesis is based on passive switching that requires no regulation. Both hypotheses were tested ex vivo in canine lung lobes. The lobes were perfused first with autologous blood, and capillary switching patterns were recorded by videomicroscopy. Next, the vasculature of the lobes was saline flushed, fixed by glutaraldehyde perfusion, flushed again, and then reperfused with the original, unfixed blood. Flow patterns through the same capillaries were recorded again. The 16-min-long videos were divided into 4-s increments. Each capillary segment was recorded as being perfused if at least one red blood cell crossed the entire segment. Otherwise it was recorded as unperfused. These binary measurements were made manually for each segment during every 4 s throughout the 16-min recordings of the fresh and fixed capillaries (>60,000 measurements). Unexpectedly, the switching patterns did not change after fixation. We conclude that the pulmonary capillaries can remain primed for emergencies without requiring regulation: no detectors, no feedback loops, and no effectors-a rare system in biology. NEW & NOTEWORTHY The fluctuating flow patterns of red blood cells within the pulmonary capillary networks have been assumed to be actively controlled within the pulmonary microcirculation. Here we show that the capillary flow switching patterns in the same network are the same whether the lungs are fresh or fixed. This unexpected observation can be successfully explained by a new model of pulmonary capillary flow based on chaos theory and fractal mathematics.


Subject(s)
Capillaries/physiology , Erythrocytes/physiology , Hemodynamics , Lung/blood supply , Microcirculation , Models, Cardiovascular , Pulmonary Circulation , Animals , Blood Flow Velocity , Dogs , Fractals , Male , Microscopy, Video , Models, Animal , Nonlinear Dynamics , Time Factors , Tissue Fixation
2.
Exp Biol Med (Maywood) ; 230(1): 57-60, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15618126

ABSTRACT

Formation of multiple cysts in the kidneys occurs in several inherited diseases and often leads to terminal kidney failure. Because there is no definitive therapy to halt or slow the progression of renal cystic disease in people, numerous studies have examined possible therapies in animal models. Autosomal-dominant polycystic kidney disease (ADPKD) in the Han:SPRD rat is ameliorated when alkalinizing citrate salts are provided in drinking solutions. By contrast, pcy mice with cystic disease fare worse with the same treatment. We tested the hypothesis that pcy mice ingesting citrate salts in the feed would not be adversely affected by this treatment. Male homozygous pcy mice were given regular feed or 6% potassium citrate-supplemented feed and ad libitum access to water starting at 3 weeks of age. The survival curves of the treated and untreated mice were not significantly different. We conclude that treatment with potassium citrate in the feed does not affect the progression of renal cystic disease in the pcy mouse. This model closely resembles human adolescent nephronophthisis (NPHP3). Based on these findings, citrate treatment cannot be recommended for NPHP3. The fact that it did no harm, however, removes a significant barrier to its consideration as a therapy for ADPKD.


Subject(s)
Diet , Polycystic Kidney Diseases/genetics , Potassium Citrate/administration & dosage , Animals , Homozygote , Male , Mice
3.
Nephron Physiol ; 93(1): P14-20, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12411726

ABSTRACT

Progression of autosomal-dominant polycystic kidney disease (ADPKD) in the heterozygous male Han:SPRD rat is dramatically slowed by ingestion of potassium or sodium citrate. This study examined the efficacy of delayed therapy with sodium citrate, the effect of sodium citrate therapy on kidney cortex levels of transforming growth factor-beta (TGF-beta), and the response to calcium citrate ingestion. Rats were provided with citrate salts in their food, and renal clearance, blood pressure, blood chemistry, and survival determinations were made. Sodium citrate therapy was most effective when started at age 1 month, and delay of therapy until age 3 months produced no benefit. Kidney cortex TGF-beta levels were elevated in 3- and 8-month-old rats with ADPKD, but not in 6-week-old rats. Sodium citrate treatment, started at age 1 month, lowered TGF-beta levels to normal in 3-month-old rats, but this is probably not the primary mechanism of citrate's beneficial effect. Calcium citrate had only a modest effect in preserving glomerular filtration rate. Effective treatment of ADPKD in this rat model requires early administration of a readily absorbed alkalinizing citrate salt. Existing data on ADPKD patients on vegetarian diets or with kidney stones should be studied in light of these findings.


Subject(s)
Citrates/therapeutic use , Polycystic Kidney, Autosomal Dominant/diet therapy , Animals , Animals, Congenic , Calcium/blood , Calcium/urine , Calcium Citrate/blood , Calcium Citrate/therapeutic use , Calcium Citrate/urine , Citrates/blood , Citrates/urine , Creatinine/blood , Disease Models, Animal , Glomerular Filtration Rate/drug effects , Hydrogen-Ion Concentration , Kidney Cortex/chemistry , Kidney Cortex/pathology , Kidney Cortex/physiology , Male , Polycystic Kidney, Autosomal Dominant/blood , Polycystic Kidney, Autosomal Dominant/urine , Rats , Rats, Sprague-Dawley , Sodium Citrate , Transforming Growth Factor beta/metabolism , Urea/blood , Urine/chemistry
4.
Kidney Int ; 62(6): 1947-57, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12427119

ABSTRACT

BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is associated with a progressive decline in glomerular filtration rate (GFR) that often leads to end-stage renal disease. The basis for this decline in GFR is poorly understood. METHODS: Glomeruli in heterozygous Han:SPRD rats with ADPKD and their normal litter mates were studied by light microscopy, using serial sectioning techniques. The connections of the renal corpuscles to proximal tubules were classified as normal, atrophied, or absent (atubular glomerulus). Renal corpuscles also were examined by scanning electron microscopy. Single nephron glomerular blood flows were determined using microspheres. RESULTS: In the kidneys of six-month-old rats with ADPKD, 50% of the glomeruli were atubular and another 26% were associated with atrophied neck segments; these glomeruli were most often smaller in size than normal. About 16% of the glomeruli were hypertrophied and had normal connections to proximal tubules. Sclerotic changes in cystic kidney glomeruli were usually mild or moderate, and belied the failure of glomerular function. Glomerular blood flow in the cystic kidneys averaged half of normal and was markedly heterogeneous; the majority of small glomeruli displayed very low blood flows and a few showed relatively high blood flows. Fewer glomerular abnormalities were found in rats treated for five months with potassium citrate in their drinking water. CONCLUSIONS: The diminished GFR in the rat with ADPKD can be accounted for largely by the formation of atubular glomeruli. Compensatory glomerular hypertrophy also is present and may contribute to the progression of the renal disease.


Subject(s)
Kidney Glomerulus/pathology , Kidney Tubules, Proximal/pathology , Polycystic Kidney Diseases/pathology , Animals , Disease Models, Animal , Glomerular Filtration Rate , Kidney Glomerulus/ultrastructure , Kidney Tubules, Proximal/ultrastructure , Male , Microscopy, Electron, Scanning , Rats , Rats, Mutant Strains , Rats, Sprague-Dawley
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