Role of angiotensin in the renal vasoconstriction observed during the development of genetic hypertension.

Studies have examined renal function to determine the role of the kidney in the pathogenesis and maintenance phases of hypertension in the Okamoto-Aoki strain of spontaneously hypertensive rat (SHR). As compared to age-matched Wistar-Kyoto rats (WKY), 4- to 6-week old SHR are moderately hypertensive and have a reduced glomerular filtration rate (GFR) and renal blood flow (RBF), and an increased renal vascular resistance. Cross-breeding studies indicate the reduction in RBF and GFR in young SHR is genetically linked to the hypertension and thus may be of primary pathogenetic importance. The combination of an elevated vascular resistance and reduced RBF and GFR in young SHR implicates increased activity of a vasoconstrictor system(s), decreased activity of a vasodilator system(s), or both. Observations from several laboratories support the notion that endogenous angiotensin II contributes to the renal vasoconstriction in young SHR during the developmental phase of hypertension. Acute and chronic inhibition of angiotensin converting enzyme reduce arterial pressure, reduce renal vascular resistance and increase renal blood flow in young and adult SHR. Renal vascular tone in SHR is more dependent on angiotensin converting enzyme activity than that in WKY. The ability of angiotensin converting enzyme inhibitors to produce renal vasodilation may be responsible, at least in part, for its antihypertensive effects. Other studies indicate that renal vascular reactivity to angiotensin II is exaggerated in young SHR. The strain differences in renal reactivity to angiotensin II can be abolished by cyclooxygenase inhibition with indomethacin, indicating that endogenous prostanoids counteract some of the constrictor action of angiotensin II, with more pronounced buffering activity in WKY.(ABSTRACT TRUNCATED AT 250 WORDS)

Tubuloglomerular feedback kinetics in spontaneously hypertensive and Wistar-Kyoto rats.

The steady-state behavior of the tubuloglomerular feedback system has been studied in detail, but little is known about its dynamics. However, kinetic data can provide insight regarding the contribution of feedback to autoregulatory responses. Accordingly, experiments were conducted in anesthetized, euvolemic, spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats to characterize the time course of changes in proximal tubular stop-flow pressure after step changes in the rate of orthograde perfusion of Henle's loop. We studied the responses both to increase in perfusion rate, which produced preglomerular vasoconstriction, and decreases in perfusion rate, which produced preglomerular vasodilation. In both strains, the pattern of induced stop-flow pressure transients consisted of a pure delay followed by a monoexponential decay to a new steady state. In SHR rats, delay times were shorter than in WKY rats, but response time constants were not significantly different in the two strains. However, response time constants for dilation were longer than for constriction in both strains. The delay times and relatively large response time constants observed indicate that tubuloglomerular feedback cannot mediate rapid autoregulatory responses to fluctuations in renal perfusion pressure. The response time of tubuloglomerular feedback is probably limited by both the time lag associated with fluid transit through the loop of Henle and a relatively slow rate-limiting step in the signal transduction process at the macula densa.

Exaggerated renal vascular reactivity to angiotensin and thromboxane in young genetically hypertensive rats.

The objective of this study was to test the hypothesis that angiotensin II and thromboxane A2 (TxA2) contribute to the elevated renal vascular resistance observed during the development of genetic hypertension. In 6-wk-old anesthetized spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats, renal blood flow (electromagnetic flowmetry) and carotid arterial pressure were measured during bolus injections of different doses of angiotensin II and U46619 (stable receptor agonist of TxA2) into the renal artery before and during inhibition of prostaglandin synthesis by indomethacin. In all cases, arterial pressure remained unchanged at the pre-injection levels. Under control conditions, angiotensin II reduced renal blood flow in SHR almost twice as much as in WKY. This strain difference was abolished by inhibition of prostaglandin synthesis, suggesting that a deficiency in the action of endogenous vasodilator prostaglandins is responsible for the enhanced response to angiotensin II in SHR. Under control conditions, the TxA2-receptor agonist produced similar reductions of renal blood flow in SHR and WKY. However, after indomethacin, the agonist-induced vasoconstriction was twice as large in SHR as in WKY, suggesting that SHR kidneys have an increased vascular reactivity to TxA2, which is unmasked when indomethacin reduces elevated levels of endogenous TxA2. These findings indicate important strain differences between young SHR and WKY in the renal vascular response to angiotensin II and TxA2 that may contribute to the renal vasoconstriction observed during the development of genetic hypertension.

Errors in estimates of peritoneal fluid volume.

Inherent limitations in the suitability of drainage volumes for monitoring intraperitoneal fluid volume have resulted in the frequent use of indicator dilution techniques, but little attention has been given to confirming the adequacy of the estimates that volume markers provide. In a series of experimental exchanges in rats, volume estimates were compared based on the dilution of blue dextran and hemoglobin with direct collections of surgically exposed intraperitoneal fluid. Significant systematic and random errors in the indicator dilution volume estimates were observed. The systematic errors appeared to be due to the rapid removal of a fixed amount of marker from peritoneal fluid, while the random errors were caused by the rapid appearance of a variable amount of endogenous chromogen. The behavior of the markers observed in this study was not consistent with the assumptions commonly used to analyze volume transport in peritoneal dialysis.

Tubuloglomerular feedback and autoregulation in spontaneously hypertensive rats.

Experiments were conducted in 8-wk-old spontaneously hypertensive rats to determine whether tubuloglomerular feedback is essential for the autoregulation of renal blood flow. Autoregulation curves were obtained by measuring mean renal arterial blood pressure and flow during graded aortic occlusion. Renal vascular admittance was calculated from recordings of pulsatile renal arterial blood pressure and flow during induced atrial fibrillation. After a control period, acute ureteral obstruction was used to suppress tubuloglomerular feedback, as confirmed by measuring stop-flow pressure responses to rapid perfusion of Henle's loop. Ureteral obstruction did not impair steady-state autoregulation. During both the control and obstruction periods, the admittance gain was less than 1 at frequencies below 0.2 Hz, indicating dynamic autoregulatory activity. The control admittance contained two gain shoulders and two phase maxima, suggesting the presence of two control systems with response half-times of 1 and 10 s. During ureteral obstruction, the low-frequency shoulder and maximum disappeared, indicating that the slower system was no longer active. However, the high-frequency shoulder and maximum persisted, suggesting continued activity of the faster system. Collectively, these observations indicate the existence of a rapidly acting intrarenal control mechanism, in young spontaneously hypertensive rats, that may provide efficient autoregulation without assistance from tubuloglomerular feedback.

The use of polyelectrolytes as osmotic agents for peritoneal dialysis.

Various small and large molecules have been studied as osmotic agents to replace dextrose in peritoneal dialysis. Macromolecules are attractive because of their slow absorption from intraperitoneal solutions; however, it has been assumed that they are only marginally effective as osmotic agents unless they function as polyelectrolytes at physiological pH. In experimental exchanges conducted in rats we measured volume changes induced by Gelifundol (5.5% oxypolygelatin) and Ringers lactate to which was added either nothing, 4.25% dextrose, or 5% albumin. In the control exchanges using Ringers lactate, intraperitoneal fluid volume remained unchanged for eight hours. The volume changes induced by 4.25% dextrose were complete within two hours and resulted in a two-thirds increase over the amount of fluid administered. In both series in which polyelectrolytes were used volume transport was sustained throughout an eight hour dwell. With 5% albumin the total increase in fluid volume was about 40% of that installed, while Gelifundol caused fluid volume to double. Qualitatively similar results were obtained in transport studies conducted in vitro. Physical studies of the oxypolygelatin solutions indicated that the fixed charges per liter were comparable to those in the albumin solutions. Thus the different volume transport the two proteins induced could not be attributed to Donnan effects. However, since the molecular weight of albumin is triple that of Gelifundol the van't Hoff pressures of the two macromolecules can explain the observed differences in volume transport. These results suggest that neutral macromolecules deserve further study as potential osmotic agents for peritoneal dialysis.

Formulating and evaluating quantitative models of control of sodium stores.

Numerous factors that influence sodium handling have been identified, and many have been studied in minute detail; however, relatively little information is available regarding either the steady-state relationship between dietary sodium intake and sodium stores or the transient response of intact animals to challenges to sodium homeostasis. In this paper the principles of elementary feedback control theory have been used both to obtain and analyze quantitative models of the feedback control of sodium stores. It has been assumed that the sodium content of the body determines the rate of urinary sodium excretion, and a mass balance has been used to obtain differential equations that describe the dynamics of sodium stores. Both first- and second-order models are considered, and their predictions for both steady states and transients are compared critically with observations from the literature, using data from human studies whenever possible. The results indicate that a relatively simple proportional feedback controller describes most available data well; however, gaps in the available information are identified, and opportunities for future experimental investigation are described.

Effect of variations in dietary sodium intake on sodium excretion in mature rats.

Sprague-Dawley rats weighing 400 g or more were studied to determine whether their continued weight gain affects renal sodium handling. Rats maintained on a wide range of sodium intakes gained 3.9 +/- 0.4 g/day. The intercept of a linear regression of intake against urinary excretion provided an estimate of the minimum daily requirement for sodium intake of 247 +/- 33 microEq/day. When more than this required amount was ingested, the animals excreted the excess quantitatively in the urine. When less was ingested they continued to gain weight at a slower rate, 1.6 +/- 0.6 g/day, and remained in positive sodium balance. Nonetheless, they developed a sodium deficit manifested as retention of a sodium challenge. Thus, on an adequate dietary intake the normal physiological state of Sprague-Dawley rats of this size is one of chronic sodium retention rather than neutral sodium balance. In contrast, when inadequate sodium is ingested a deficit develops in the absence of external losses. These observations have important implications for the interpretation of studies of renal sodium handling in these animals.

A graph theory model of the glomerular capillary network and its development.

Graph theory methods were used to analyze the topology of the renal glomerular capillary network using data both from a serial reconstruction of a rat glomerulus and from the literature. The graphs obtained were tested for planarity, and all but one were found to be nonplanar. This result indicated that the development of the glomerular capillary network must include a nonplanar growth process, and new growth models were proposed. In addition, the statistical properties of capillary branching patterns were analyzed, and a node degree distribution function estimate was obtained.

Glucose and glycerol compared as osmotic agents for peritoneal dialysis.

The potential utility of glycerol as an osmotic agent for peritoneal dialysis was evaluated by conducting both isosmotic and hyperosmotic exchanges in anesthetized rats. Similar exchanges were conducted using glucose, and the results with the two agents were compared. During hyperosmotic exchanges both agents produced significant osmotic flow of water, but at initial molar concentrations that were equal the flow observed with glycerol was nearly 40% less than that observed with glucose. The lower volume transport generated by glycerol was found to be due to its surprisingly rapid removal from peritoneal fluid when it was present at hyperosmotic concentrations, but paradoxically during isosmotic exchanges, when its concentration was low, glycerol was absorbed only slightly faster than glucose. The observed increase in peritoneal permeability when glycerol was used resulted in a twofold increase in the caloric load imposed per unit of water removed in comparison with glucose.

The use of hemoglobin solutions in kidney perfusions.

Solutions of hemoglobin have often been considered for both hypothermic and normothermic perfusion of isolated kidneys. This paper considers basic issues, preparative techniques, and the viscosity of hemoglobin solutions, as well as the demands made by the kidney on a perfusate. The natural system of oxygen transport in higher animals is complex, and its perturbation to produce convenient hemoglobin-based renal perfusates produces numerous problems. The desirable effect of 2,3-diphosphoglycerate is not easily maintained in a perfusate, but its inclusion can be avoided by appropriate choice of species donating hemoglobin. Hemoglobin tetramer in free solution may dissociate and be lost by glomerular filtration. Ferric hemoglobin, the dominant form at redox equilibrium, is useless for oxygen transport; the ferrous form is maintained in the erythrocyte by reducing metabolites and, under normothermic conditions, the ferrous to ferric conversion is slow but significant. Methods for lysis of erythrocytes and removal of their stroma are discussed; reduction of ferric hemoglobin by chemical agents and electrolysis are considered in detail; and means for adjusting concentration and solute background are presented. The need for carbonic anhydrase in hemoglobin solutions used as perfusates is shown and methods for its provision are discussed. A review of viscometric data for hemoglobin solutions is provided to which original data are added. Hemoglobin solutions show a temperature-independent intrinsic viscosity, according to Einstein's theory for a molecule of 23 A radius. The O2 and CO2 transport requirements of renal perfusates are analyzed comprehensively. The normothermic kidney has an unusual respiration pattern, requiring an amount of oxygen that is not fixed but, rather, proportional to the total blood flow rate. In canines the average arterio-venous O2 content difference found by many investigators is 2.14 vol%; the corresponding CO2 value is 2.47 vol%; and the respiratory quotient is greater than unity. Wide limits of PO2, but not P CO2 in perfusate, appear allowable. A final section evaluates hemoglobin solutions as both normothermic and hypothermic renal perfusates from the viewpoints of blood gas chemistry, urinary loss, oncotic pressure, fatty acid carrying capacity, viscosity, and the need for functions usually attributed to platelets. It is concluded, overall, that perfusates containing free hemoglobin have only a limited role to play in renal perfusion.