Structural evidence for counter-current flow in proximal tubules versus pertitubular capillaries in the rat kidney. Evaluation of the counter-current mechanism between the proximal convoluted tubules and the peritubular capillaries in the rat nephron

BACKGROUND: In spite of the very high exchange of water and solutes between the proximal tubules and the peritubular capillaries, very little is known about flow directions in these two interrelated structures. We therefore developed a morphological technique suitable for the quantitative evaluation of a counter-current system between the proximal convoluted tubules and the peritubular capillaries in rat renal cortex. METHODS: In male pentothal-anesthetized Wistar rats (body weight 200-250 g), India ink was injected into the aorta above the renal arteries, followed by instant freezing of the right kidney in isopentane at -165 degrees C, and subsequent freeze-substitution in alcohol. In microscopic slides from kidneys in which only 20-55% of the cortical peritubular capillary loops was filled with ink--representing the arterial end of the capillaries--and in which the proximal tubular segmentation could be identified in PAS-stained sections, the segments of the convoluted proximal tubules were quantitatively compared with regard to the presence of ink-stained and unstained peritubular capillaries in nephrons from the whole renal cortex. RESULTS: In the microscopic specimens of the five animals used both the loops from the first segment (P1) of the proximal convoluted tubule and those of the second segment (P2) were systematically packed closely together, the transitional segment (P1-2) being interposed between the groups. Around the loops of P1, 8%+/-2% of the capillaries was stained with India ink. In contrast, surrounding the P2 loops 67%+/-5% of the capillaries contained ink, significantly exceeding that for P1 (p<0.01). CONCLUSION: Throughout the rat renal cortex, the most proximal fraction of the peritubular capillaries surrounds the second segments of the proximal convoluted tubules, while the first tubular segments are surrounded by the more distal fraction of the peritubular capillaries. Consequently, the flows in the peritubular capillaries and in the proximal convoluted tubules in the rat renal cortex are systematically arranged as a counter-current system. This feature was previously identified only in superficial nephrons.     

Compact and accurate linear and nonlinear autoregressive moving average model parameter estimation using Laguerre functions

A linear and nonlinear autoregressive moving average (ARMA) identification algorithm is developed for modeling time series data. The algorithm uses Laguerre expansion of kernals (LEK) to estimate Volterra-Wiener kernals. However, instead of estimating linear and nonlinear system dynamics via moving average models, as is the case for the Volterra-Wiener analysis, we propose an ARMA model-based approach. The proposed algorithm is essentially the same as LEK, but this algorithm is extended to include past values of the ouput as well. Thus, all of the advantages associated with using the Laguerre function remain with our algorithm; but, by extending the algorithm to the linear and nonlinear ARMA model, a significant reduction in the number of Laguerre functions can be made, compared with the Volterra-Wiener approach. This translates into a more compact system representation and makes the physiological interpretation of higher order kernels easier. Furthermore, simulation results show better performance of the proposed approach in estimating the system dynamics than LEK in certain cases, and it remains effective in the presence of significant additive measurement noise.     

A one year health economic model comparing transdermal fentanyl with sustained-release morphine in the treatment of chronic noncancer pain

A Markov model was constructed to simulate the resource use and health outcomes of one year of treatment comparing the fentanyl transdermal therapeutic system (fentanyl-TTS) with oral sustained-release (SR) morphine in outpatients with noncancer pain in Denmark. Effectiveness was assessed in terms of days of good pain control and days on initial treatment. Costs included those of baseline pain management, including breakthrough pain; co-medication costs; and control of adverse events. Fentanyl-TTS was more effective than SR-morphine in achieving good pain control (99 vs. 64 days, respectively) and the incremental cost-effectiveness of fentanyl-TTS was US dollars 10.26 per extra day of good pain control. Patients treated with fentanyl-TTS remained considerably longer on initial treatment compared with those treated with SR-morphine (166 days vs. 117 days, respectively). The results of this study suggest that fentanyl-TTS is a competitive therapeutic and economic choice for the treatment of chronic noncancer pain.     

Effect of renal nerve activity on tubular sodium and water reabsorption in dog kidneys as determined by the lithium clearance method

The reliability of the lithium clearance method in studies of the effect of renal nerve activity upon tubular sodium and water handling in the dog kidney was investigated. Following unilateral acute surgical denervation of the kidney a significant increase in urinary flow rate (40 +/- 7%), sodium clearance (26 +/- 4%), lithium clearance (9 +/- 2%) and fractional lithium clearance (8 +/- 2%) was seen, as compared to the contralateral kidney with preserved innervation. Calculated absolute proximal reabsorption rate decreased significantly by 7 +/- 2%, while calculated absolute rates of distal reabsorption of sodium and water increased significantly by 9 +/- 2% and 8 +/- 2%. Low-frequency electrical stimulation of the distal nerve bundle of the denervated kidney caused a significant decrease in urine flow rate (37 +/- 6%), sodium clearance (31 +/- 4%), lithium clearance (17 +/- 5%) and in fractional lithium clearance (18 +/- 5%). Calculated absolute proximal reabsorption rate increased significantly by 17 +/- 3%, while calculated absolute rates of distal sodium and water reabsorption decreased significantly by 16 +/- 5% and 16 +/- 5%. These changes in tubular sodium and water reabsorption during alterations in renal nerve activity occurred without measurable changes in renal blood flow (RBF) and glomerular filtration rate (GFR). Administration of amiloride had no significant effect either on the lithium clearance, RBF or GFR, while the sodium excretion rate increased and potassium excretion rate decreased, supporting that significant distal lithium reabsorption did not occur under the present experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

TGF-mediated oscillations in the proximal intratubular pressure: differences between spontaneously hypertensive rats and Wistar-Kyoto rats

A highly sensitive oscillatory tubulo-glomerular feedback (TGF) response has previously been demonstrated in normotensive Sprague-Dawley rats. The purpose of the present study was to examine whether such as oscillating TGF-response could be elicited in Wistar-Kyoto rats (WKY) and genetically hypertensive rats (SHR) and furthermore if any differences in the TGF-response characteristics between SHR and WKY rats could be detected. The closed loop function of the TGF-system was studied. In 12-18-week-old WKY rats regular oscillations in the intratubular pressure occurred spontaneously. The median frequency were 29.7 mHz (range 20-46.7 mHz). In SHR rats, spontaneous oscillations also occurred, but these were highly irregular. Spontaneous oscillations were more frequent in WKY than in SHR (88% vs. 54%). In both strains, oscillations could be elicited by free flow microperfusion with artificial tubular fluid (ATF). When furosemide was added to the ATF in a concentration of 0.1 mM, the oscillations were abolished in both strains of rats. It is concluded that, in both strains of rats the oscillatory phenomena depend upon TGF activity. It is suggested that the irregular pattern of the oscillations observed only in SHR rats may represent a chaotic process.     

Lithium clearance in chronic nephropathy

1. Lithium clearance measurements were made in 72 patients with chronic nephropathy of different aetiology and moderate to severely reduced renal function. 2. Lithium clearance was strictly correlated with glomerular filtration rate, and there was no suggestion of distal tubular reabsorption of lithium or influence of osmotic diuresis. 3. Fractional reabsorption of lithium was reduced in most patients with glomerular filtration rates below 25 ml/min. 4. Calculated fractional distal reabsorption of sodium was reduced in most patients with glomerular filtration rates below 50 ml/min. 5. Lithium clearance data were independent of whether renal disease was of primarily glomerular or tubular origin and, further, were not influenced by long-term conventional antihypertensive treatment. 6. It is concluded that, even with a reduced kidney function, the data are compatible with the suggestion that lithium clearance may be a measure of the delivery of sodium and water from the renal proximal tubule. With this assumption it was found that adjustment of the sodium excretion in chronic nephropathy initially takes place in the distal parts of the nephron (loop of Henle, distal tubule and collecting duct). With more severe impairment the proximal tubule also becomes involved in the adjustment.     

A life under pressure: circumferential stress in the microvascular wall

Microvessels live 'a life under pressure' in several ways. In a literal sense, vessels of the microcirculation are exposed to high levels of stress caused primarily by the intravascular pressure head. In a figurative sense, the individual vessel and the microvascular network as a whole must continuously strive to meet the changing demands of the surrounding tissue. The 'principle of optimal operation' as formulated by Y. C. Fung states that living tissues adapts structurally through remodelling and growth until a level of tensile and compressive stresses is reached at which tissue performance is optimal. This behaviour is characteristic for the microvascular wall. It is highly plastic by nature and meets sustained changes by structural adaptation so as to maintain functional optimality. Owing to the orientation of the vascular smooth muscle cell in the media, in particular, the circumferential stress component has a huge impact on the state of the vascular wall. It is involved as a unifying factor on vastly different timescales in processes as diverse as acute regulation of vessel diameter, structural vessel remodelling and growth or atrophy of the vascular wall. The aim of this MiniReview was to outline in brief this integrative role of circumferential wall stress in the microcirculation.     

Atrial natriuretic peptide and renal adaptation to contralateral nephrectomy in healthy man.

Atrial natriuretic peptide (ANP), angiotensin II (AII), aldosterone (Aldo) and arginine vasopressin (AVP) in plasma were determined in 12 healthy renal transplant donors before and 5, 12, 26, 54 days after uninephrectomy (Nx) in order to study the possible role of these hormones in functional adaptation to acute reduction in renal mass. Glomerular and tubular function was studied by measurements of the clearances of 51Cr-EDTA, lithium, sodium, potassium, and albumin. ANP was 7.4 +/- 3.1 pmol l-1 (mean +/- SD) before Nx and 8.7 +/- 6.1 pmol l-1 at 5 days after Nx and remained at this level through the observation period. Aldo showed a non-significant transient fall at 5 days after Nx. AII and AVP remained normal after Nx. At 5 days after Nx glomerular filtration rate (GFR) of the remaining kidney had risen from 45 +/- 7 ml min-1 before Nx to 57 +/- 8 ml min-1 (p less than 0.01), lithium clearance had risen from 13 +/- 2 ml min-1 before Nx to 20 +/- 7 ml min-1 (p less than 0.01), and sodium and water balance was normal. To conclude, plasma ANP, AII, Aldo and AVP do not appear to be responsible for the hyperfiltration and depression of fractional proximal sodium and water reabsorption observed in recently uninephrectomized man with normal sodium and water balance.     

The renal handling of sodium and water is not affected by the standard-dose cisplatin treatment for testicular cancer

Renal clearances of 51Cr-EDTA, lithium, sodium and potassium were measured before and after each of four consecutive treatment series with cisplatin in 15 men with testicular cancer. Since lithium is reabsorbed like sodium and water in the proximal tubules, but not reabsorbed to any measurable degree in the remainder of the nephron, lithium clearance equals the amount of fluid delivered from the end of the proximal straight segment to the thin descending limb of the loop of Henle. From the clearances of lithium and sodium, distal tubular reabsorption can be calculated. Lithium clearance and all other parameters of glomerular filtration and renal sodium handling remained normal throughout the study (with the exception of a fall in fractional sodium excretion after the first treatment series). Plasma magnesium declined during all four treatment periods, signifying renal magnesium wasting.     

Angiotensin II modulates conducted vasoconstriction to norepinephrine and local electrical stimulation in rat mesenteric arterioles

OBJECTIVE: Localized application of a vasoconstricting agent onto the wall of an arteriole results not only in a local constriction of the vessel, but also in a conducted vasoconstriction which is detectable more than a millimeter upstream and downstream from the application site. We investigated the effect of intravenous infusion of angiotensin II (ANG II), losartan or methoxamine on conducted vasoconstriction to local application of norepinephrine (NE) or local electrical stimulation onto the surface of rat mesenteric arterioles in vivo. METHODS: In anesthetized male Wistar rats (n = 43) NE (0.1 mM) or a local depolarizing current was continuously applied onto mesenteric arterioles using micropipettes. Local and conducted vasoconstriction was measured using videomicroscopy. Conducted responses were measured 200-1000 microns upstream from the application site. RESULTS: Systemic infusion of ANG II (4 ng/min) raised mean arterial blood pressure by 6 +/- 2 mm Hg and increased the conducted but not the local vasoconstrictor response to NE (P < 0.02). Infusion of the alpha 1-agonist methoxamine raised blood pressure to the same extent, but did not change conducted vasoconstriction significantly. Blockade of endogenous ANG II by infusion of the AT1-receptor blocker losartan decreased conducted vasoconstriction to NE (P < 0.03). In parallel with the findings using NE, ANG II increased (P < 0.05) and losartan decreased (P < 0.01) conducted vasoconstriction when local electrical stimulation was used to initiate the conducted vascular response. CONCLUSION: The findings suggest that conducted vasoconstriction to NE and local electrical stimulation in rat mesenteric arterioles are modulated by ANG II, an increase in the plasma levels of ANG II increasing conducted vasoconstriction.