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Biomedical subjects

I Ichikawa

Publications and source records attributed to I Ichikawa.

At least 163 records · Page 9Linked to original sources
PubMed1982

Direct analysis of the effector mechanism of the tubuloglomerular feedback system.

The determinants of single nephron glomerular filtration rate (SNGFR) were examined in Munich-Wistar rats by direct glomerular micropuncture during orthograde perfusion of the same nephron's loop of Henle with isotonic Ringer solution at O and 40 nl/min. At the higher loop flow rate, SNGFR decreased significantly by approximately 35% relative to the nonperfused condition. Whereas indirect stop-flow estimates of mean glomerular capillary hydraulic pressure (PGC) also decreased significantly by approximately 8 mmHg, directly measured PGC values were found to be unaffected by the change in loop flow rate. Instead, both glomerular plasma flow rate (QA) and the ultrafiltration coefficient were found to decrease significantly at the higher loop flow rate, thereby accounting for the measured reduction in SNGFR. Given the observed near constancy of directly measured PGC and significant reduction in QA, both afferent and effect arteriolar resistances were calculated to increase in response to the higher loop perfusion rate. In a separate set of experiments, it was demonstrated that cessation of glomerular filtration increased directly measured PGC in the condition of zero loop perfusion but not when the loop was perfused at a high flow rate. These results indicate 1) that tubuloglomerular feedback-induced changes in SNGFR are not accompanied by changes in PGC; and 2) that tubuloglomerular feedback regulation of GFR is mediated by alterations in vasomotor tone of preglomerular, glomerular, and postglomerular microvessels. 3) Based on the close anatomical contact between mesangial cells and these vessels, a single effector mechanism channeled through mesangial contractility is suggested.

Animals↗
PubMed1982

Mechanism of glomerulotubular balance in the setting of heterogeneous glomerular injury. Preservation of a close functional linkage between individual nephrons and surrounding microvasculature.

Autologous immune complex nephropathy (AICN), an experimental model for human membranous glomerulopathy, is characterized by marked heterogeneity in function from glomerulus to glomerulus. However, the fraction of the filtered load of fluid reabsorbed by the proximal tubule remains nearly constant from nephron to nephron, despite wide variation in single nephron glomerular filtration rate (SNGFR). To define the physiological mechanisms responsible for this marked variation in SNGFR values within a given kidney and for the remarkable preservation of glomerulotubular balance, the various determinants of fluid exchange across glomerular and peritubular capillary networks were evaluated in Munich-Wistar rats with AICN. For comparison, similar measurements were obtained in rats with the functionally more homogeneous lesion of heterologous immune complex nephropathy. In AICN rats studied approximately 5 mo after injection of renal tubule epithelial antigen (Fx1A), a high degree of glomerulus-proximal tubule balance was found, despite marked variations in SNGFR values within a single kidney. These changes were associated with marked heterogeneity in immunoglobulin and complement deposition within and among glomeruli. Although mean capillary hydraulic pressure and Bowman's space hydraulic pressure ranged widely from glomerulus to glomerulus, the mean glomerular transcapillary hydraulic pressure difference was remarkably uniform among these functionally diverse glomeruli and could not, therefore, be implicated as the cause of the dispersion in SNGFR values. The two remaining determinants of SNGFR, namely, glomerular plasma flow rate (Q(A)) and ultrafiltration coefficient (K(f)), varied markedly from glomerulus to glomerulus, but always in direct proportion to SNGFR, and proved to be responsible for the marked variation in SNGFR. The mean net peritubular capillary reabsorptive force ( P(r)) correlated closely with the absolute rate of fluid reabsorption in adjacent proximal tubules (APR) in AICN. Of the factors determining P(r), peritubular capillary hydraulic pressure was essentially constant in a given AICN kidney, whereas peritubular capillary plasma protein concentration and oncotic pressure varied directly with APR and largely accounted for the observed tight correlation between P(r) and APR. ON THE BASIS OF THESE OBSERVED CORRELATIONS, WE SUGGEST THAT THE CLOSE QUANTITATIVE COUPLING BETWEEN SNGFR AND APR IN INDIVIDUAL NEPHRONS IN AICN IS DUE TO THE FUNCTIONAL RESPONSE OF INDIVIDUAL GLOMERULI: those with the most pronounced declines in SNGFR are characterized by the most pronounced declines in Q(A) and K(f). The resultant low peritubular capillary oncotic pressure favors a decline in APR, thus favoring nearly perfect glomerulotubular balance. In glomeruli with higher SNGFR values, Q(A) and K(f) values are also higher. These changes in K(f) once again are capable of establishing the conditions in downstream peritubular capillaries, this time favoring augmented APR (i.e., high intracapillary oncotic pressure), again leading to nearly perfect glomerulotubular balance.

Animals↗
PubMed1982

Hemodynamic influence of altered distal salt delivery on glomerular microcirculation.

The current notion that tubuloglomerular feedback-mediated regulation of GFR involves selective changes in afferent arteriolar vasomotor tone stems from the familiar finding that manipulation of distal salt delivery alters glomerular capillary hydraulic pressure (PGC). Stop-flow technique, which has been used for this PGC measurement, however, has recently been shown to fail to provide a reliable estimate of true PGC. In the present study, glomerular dynamics were examined by direct glomerular puncture during loop perfusion with Ringer solution at rates of 0 and 40 nl/min. With the increased loop flow, single nephron GFR (SNGFR) decreased by approximately 35%. Because directly measured PGC remained unchanged, this reduction in SNGFR was due to the falls in glomerular plasma flow rate and ultrafiltration coefficient, the former a consequence of increases in both afferent and efferent arteriolar resistances. By contrast, PGC values estimated by the stop-flow technique declined substantially with increased loop flow. These results indicate that tubuloglomerular feedback-induced regulation of GFR is mediated by changes in the vasomotor tone of preglomerular, glomerular, and postglomerular vessels. In view of the close anatomical contact between mesangial cells and these vessels, mesangial contractility may play a role as the single effector mechanism regulating the vasomotor tone of these vessels.

Animals↗
PubMed1981

Mechanisms of action of various hormones and vasoactive substances on glomerular ultrafiltration in the rat.

Angiotensin II (AII) and arginine vasopressin are capable of triggering glomerular mesangial cell contraction in vitro. A similar mechanism acting in vivo to reduce glomerular capillary surface area could account for the decline in the ultrafiltration coefficient (Kf)( that occurs in single glomeruli in response to infusion of these substances. Less clear is the mechanism whereby similar declines in Kf are induced with infusions of dibutyryl cyclic AMP (DBcAMP), parathyroid hormone (PTH), and prostaglandins, because PTH and PGE2, at least, are incapable of eliciting mesangial cell contraction in vitro. To further explore the factors that regulate Kf in vivo, we performed micropuncture experiments in 47 euvolemic Munich-Wistar rats. Infusions of DBcAMP, PTH, prostaglandins I2 and E2 led to lower mean values for plasma flow rate (QA) and Kf in superficial glomeruli than were found in animals given vehicle alone (control group), whereas average values for glomerular transcapillary hydraulic pressure difference (delta P) and total renal arteriolar resistance (RTA) tended to be higher. These increases in delta P and RTA, and decreases in QA and Kf, with DBcAMP, PTH, PGI2, and PGE2 are typical of changes induced by AII. Indeed, when saralasin, a competitive AII antagonist, was infused together with these various vasoactive substances, the effects on delta P, QA, RTA, and Kf were largely abolished. Therefore, the actions of DBcAMP, PTH, PGI2, and PGE2 on the glomerular microcirculation appear to depend on an intermediate action of AII. By contrast, although pitressin (ADH) infusion also led to a significant decline in Kf, saralasin administration did not reverse this change, suggesting that the action of ADH on the glomerular microcirculation is independent of a pathway involving AII. Based on these studies, it seems reasonable to propose that AII and ADH are both potentially important regulators of mesangial cell contraction, and thereby, glomerular capillary filtering surface area and Kf.

Animals↗
PubMed1981

Pathophysiology of altered glomerular function in aminoglycoside-treated rats.

To evaluate the relative influences of gentamicin and tobramycin on glomerular function, we studied three groups of normal hydropenic rats. Group 1 had 8 rats that served as control. Group 2 had 9 rats that were given gentamicin (40 mg/kg of body wt per day for 10 days). Group 3 had 10 rats that received tobramycin instead of gentamicin. In addition, we attempted to suppress angiotensin II (AII) generation in two additional groups of rats and then study the glomerular response to gentamicin: in 6 rats, isotonic sodium chloride was substituted for tap water for drinking throughout the period of study (group 4), and in 7 other gentamicin-treated rats, captopril was given orally (group 5). A sixth group received captopril alone (group 6). Following gentamicin treatment in group 2, values for single nephron GFR (SNGFR) were markedly lower (21.7 +/- 2.1 nl/min) than they were in groups 1(35.7 +/- 1.4) or 3(34.1 +/- 2.9). Declines in whole kidney GFR in group 2 paralleled the fall in SNGFR. Reduction in SNGFR with gentamicin was due both to a marked decline in the glomerular capillary ultrafiltration coefficient, Kf, and in the initial glomerular plasma flow rate, QA. With saline administration (group 4), the decline in SNGFR was partially blunted, whereas with captopril (group 5) the effects of gentamicin on SNGFR, QA, and Kf were largely abolished. Morphologic studies revealed no discernible glomerular defects in any groups, whereas proximal tubule damage was evident with both aminoglycosides, irrespective of the state of the renin-angiotensin system. Thus, in the dosage used, gentamicin elicits greater impairment in glomerular function than does tobramycin, and by mechanism(s) that are at least partially responsive to suppression of AII generation.

Animals↗
PubMed1980

Glomerular adaptations to chronic dietary salt restriction or excess.

Micropuncture studies were performed in 33 Munich-Wistar rats maintained chronically either on dietary NaCl restriction (group 1) or excess (group 2). Values for single nephron (SN) and total kidney glomerular filtration rate (GFR) were identical in both groups. Nevertheless, because of preferential efferent vasoconstriction, glomerular capillary hydraulic pressure (PGC) was higher in group 1, offsetting the lower initial glomerular plasma flow rate (QA) also found in group 1. The pressor response to infusion of exogenous angiotensin II (AII) was less in group 1 than in group 2, suggesting that vascular receptors for AII may have been occupied by endogenous hormone, the latter leading to the efferent arteriolar vasoconstriction. In addition to AII, prostaglandins also appear to be involved in the adaptations of the glomerular microcirculation to chronic variations in salt intake. In group 1, indomethacin or meclofenamate infusion mimicked exogenous AII, causing declines in QA and SNGFR. These changes were lacking in group 2. Because of relative contraction of plasma volume, the vasodilatory effects of prostaglandins appear to be needed in low salt animals to sustain SNGFR and QA. In the high salt group, however, since plasma volume is not contracted, maintenance of SNGFR and QA appears to be less critically dependent on endogenous prostaglandins.

Angiotensin II↗
PubMed1980

Effects of parathyroid hormone on glomerular function.

Acute thyroparathyroidectomy (TPTX) in rats results in a marked increase in the glomerular capillary ultrafiltration coefficient, Kf. Infusion of a submaximal dose of bovine PTH (1 U/kg/min) returns Kf to non-TPTX levels. Infusion of 10 U/kg/min of bovine PTH further reduces Kf and leads to a net reduction in single nephron GFR. These findings suggest that PTH may play an important role in modulating Kf and, consequently, GFR.

Animals↗
PubMed1980

Importance of efferent arteriolar vascular tone in regulation of proximal tubule fluid reabsorption and glomerulotubular balance in the rat.

Micropuncture study was performed in 21 mildly volume-expanded Munich-Wistar rats before and during partial aortic constriction to examine the effects of endogenous prostaglandins (PG) and angiotensin II (AII) on single nephron glomerular filtration rate (SNGFR) and absolute proximal reabsorption rate (APR). Animals received either vehicle (group 1), indomethacin (group 2), or indomethacin plus saralasin (group 3). Before aortic constriction, these inhibitors were without effect on values of SNGFR and APR. In group 1 rats, reduction in mean renal arterial perfusion pressure (RAP) to approximately 65 mm Hg resulted in marked and proportional declines in SNGFR and APR. With equivalent reduction in RAP in group 2 rats, however, SNGFR fell to a lesser extent and APR tended to increase slightly above preconstriction values. Indomethacin administration was therefore associated with disruption of glomerulotubular balance. In view of the roughly equivalent declines in afferent arteriolar resistance measured in groups 1 and 2, the magnitude of increase in efferent arteriolar resistance (R(E)) appeared to be of major importance in determining the observed presence or absence of glomerulotubular balance. Thus, the lesser fall in SNGFR in group 2 than in group 1 was a result of the higher value for glomerular capillary hydraulic pressure in group 2, a consequence of the higher value of R(E). The higher average value for APR during reduced RAP in group 2 than in group 1 is also attributable to this pronounced rise in R(E), the effect of which was to augment the net reabsorptive pressure both by favoring higher postglomerular oncotic pressure and lower downstream (peritubular capillary) hydraulic pressure. Since intrarenal release of AII is enhanced when RAP declines, and because AII is known to raise R(E) selectively, it is likely that endogenous AII brought about the marked increase in R(E) in group 2, which was readily demonstrable only in indomethacin-treated rats, presumably because endogenous PG synthesis was suppressed. In keeping with this conclusion, when the action of endogenous AII was inhibited by saralasin in group 3 rats, reduction in RAP failed to induce a rise in R(E), so that net filtration and reabsorption pressures again declined proportionally, as did SNGFR and APR. The present evidence therefore suggests that glomerulotubular balance is influenced to an important extent by the prevailing vasomotor tone of the efferent arteriole.

Animals↗
PubMed1980

Mechanism of reduced glomerular filtration rate in chronic malnutrition.

To determine the physiological basis for the low glomerular filtration rate in chronic malnutrition, micropuncture studies were performed in Munich-Wistar rats chronically pair-fed isocaloric diets of either low (group 1, nine rats) or high protein content (group 2, nine rats). Despite the absence of hypoalbuminemia, average values for single nephron and total kidney glomerular filtration rate were nearly 35% lower in group 1 than in group 2. Mean values for glomerular capillary and Bowman's space hydraulic pressures were essentially identical in the two groups, thereby excluding glomerular transcapillary hydraulic pressure difference as the cause for the low filtration rates in group 1 animals. On the other hand, average glomerular capillary plasma flow rate and glomerular capillary ultrafiltration coefficient were significantly lower (by approximately 25 and approximately 50%, respectively) in group 1 than in group 2. The fall in glomerular capillary plasma flow rate was the consequence of increased afferent and efferent arteriolar resistances. Plasma and erythrocyte volumes were found to be equal in five additional pairs of group 1 and group 2 rats. Thus, the substantial alterations in the ultrafiltration coefficient, glomerular capillary plasma flow rate, and renal arteriolar resistances responsible for the low filtration rate in group 1 animals were not merely a consequence of decreased circulating blood or plasma volumes. Mean values for glomerular cross sectional area were significantly lower in group 1 than in group 2 despite similar values for kidney weight in the two groups. This reduction in glomerular cross sectional area in group 1 rats is presumed to reflect a decrease in effective filtration surface area and therefore likely accounts, at least in part, for the decline in ultrafiltration coefficient observed in this group.Finally, since the daily caloric intake of group 2 animals was restricted because of pair feeding requirements tied to the group 1 rats, we studied a third group of seven rats (group 3) allowed an ad lib. intake of the same high protein diet as given to group 2 rats. Average values for single nephron glomerular filtration rate and its determinants were found to be indistinguishable between groups 2 and 3. These results suggest that low protein intake, rather than calorie deficiency per se, is primarily responsible for the reduction in filtration rate seen in this experimental model of chronic malnutrition.

Animals↗
PubMed1979

Reversal of renal cortical actions of angiotensin II by verapamil and manganese.

Experiments were performed on 19 euvolemic Munich Wistar rats to examine the role of calcium in the action of angiotensin II(AII) on the glomerular microcirculation. Intravenous infusion of a mildly pressor dose of AII(N = 7 rats) led to a significant rise in mean glomerular capillary hydraulic pressure (PGC) and significant decines in glomerular plasma flow rate (QA) and the ultrafiltration coefficient (Kf). Because of these offsetting effects, single nephron GFR (SNGFR) and total kidney GFR failed to change significantly. Both afferent and efferent arteriolar resistances (RA and RE) increased during AII infusion, on average by approximately 40% and 75%, respectively. Despite continued AII infusion, addition of verapamil led to return of values for PGC, QA, Kf, RA, and RE essentially to pre-AII levels. In 7 other rats, verapamil infusion alone failed to exert significant influences on these indices. Likewise, no significant changes in these measures were observed when this same dose of AII was infused into verapamil-pretreated animals. Moreover, intrarenal arterial injection of a nonpressor dose of AII into 6 other rats also resulted in changes in PGC, QA, Kf, and RE similar to those seen during intravenous infusion, and addition of manganese abolished these effects. Since verapamil and manganese are both known to interfere with excitation-contraction coupling of smooth muscle, perhaps by inhibiting transcellular calcium transport, the present results suggest that the calcium ion may be an important cofactor required for the expression of AII action on the glomerular microcirculation, by affecting mesangial and efferent arteriolar smooth muscle contractility.

Angiotensin II↗
PubMed1979

Local intrarenal vasoconstrictor-vasodilator interactions in mild partial ureteral obstruction.

Micropuncture studies were performed in Munich-Wistar rats with surgically created chronic partial unilateral ureteral obstruction (UUO). Mean values for superficial single nephron (SN)GFR, total GFR, and initial glomerular plasma flow rate (QA) in obstructed kidneys were essentially identical to values in nonobstructed kidneys. Nevertheless, glomerular capillary hydraulic pressure (PGC) was significantly higher in obstructed than in nonobstructed kidneys. This increase in PGC served to offset the markedly reduced glomerular capillary ultrafiltration coefficient that was also confined to the kidneys ipsilateral to the ureteral obstruction. During infusion of indomethacin or meclofenamate, SNGFR and QA decreased significantly, in association with elevations in arteriolar resistances in obstructed kidneys, whereas such changes were not observed in nonobstructed kidneys. The results suggest that local intrarenal factors, rather than circulating or systemic factor(s), bring about functional adaptations to partial ureteral obstruction. In particular, an indomethacin- and meclofenamate-sensitive vasodilator (presumably prostaglandin) plays a role in antagonizing the effects of a simultaneously acting vasoconstrictor which, although not identified, displayed the functional properties of angiotensin II.

Animals↗
PubMed1979

Maturational development of glomerular ultrafiltration in the rat.

To ascertain the cause of low glomerular filtration rate in newborn and immature mammals, we measured glomerular pressures and flows directly in immature (30- to 45-day-old) euvolemic Munich-Wistar rats with surface glomeruli. As with total kidney GFR, single nephron (SN)GFR was found to be significantly lower than in adult rats, on average by 40% when corrected for kidney weight. Equality between efferent oncotic pressure and transglomeruler hydraulic pressure difference (deltaP) was usually achieved in immature rats, indicating that the glomerular capillary ultrafiltration coefficient is not a factor limiting SNGFR and GFR in immature rats. Although the average values for deltaP in immature rats were slightly, albeit significantly, lower than in adults, markedly lower values (79 +/- 5 vs. 136 +/- 10 nl/min per g kidney wt) for glomerular plasma flow rate (QA) proved to be the primary factor responsible for the lower SNGFR and GFR values in immature rats. Considerably higher values for afferent and efferent arteriolar resistances contributed to this low QA state in immature rats.

Aging↗
PubMed1979

Mechanism of inhibition of proximal tubule fluid reabsorption after exposure of the rat kidney to the physical effects of expansion of extracellular fluid volume.

The natriuresis and concomitant decline in absolute proximal reabsorption (APR) that occur in rats in response to saline loading are blunted markedly when renal perfusion pressure is reduced immediately before, but not after, the volume load. To ascertain the mechanism responsible for these differences between early clamp (EC) vs. late clamp (LC), intracapillary and interstitial determinants of peritubular capillary uptake of APR were measured in seven LC and seven EC Munich-Wistar rats before and after isotonic saline loading (80% body wt). With volume expansion in LC animals, we observed a marked decline in APR (averaging 11+/-1 nl/min), associated with large increases in urinary sodium excretion rate, which averaged 8+/-2 mueq/min. In EC, the changes in urinary sodium excretion rate (+1+/-0 mueq/min) and APR (-3+/-1 nl/min) with volume expansion were smaller in magnitude. Since peritubular capillary reabsorption coefficient and mean peritubular transcapillary hydraulic pressure difference did not change with saline loading in LC, the marked fall in APR was attributed primarily to a measured large decline in mean peritubular transcapillary oncotic pressure difference (deltapi). Despite an equivalent mean fall in deltapi with volume expansion in EC, near-constancy of APR was found to be associated with a simultaneous and equivalent decline in mean peritubular transcapillary hydraulic pressure difference (a consequence of decreased mean peritubular capillary hydraulic pressure), which effectively offset the fall in deltapi. These results demonstrate the importance of hydraulic pressure patterns of the peritubular capillaries in modulating APR and are consistent with the view that Starling forces across the postglomerular microcirculation play a fundamental role in determining APR.

Absorption↗
PubMed1978

Influence of parathyroid hormone on glomerular ultrafiltration in the rat.

Experiments were performed on 22 plasma-expanded Munich-Wistar rats to investigated the effects of parathyroid hormone (PTH) on the determinants of glomerular ultrafiltration. Mean values for single nephron filtration rate (SNGFR), glomerular plasma flow rate (QA), systemic oncotic pressure, and transglomerular hydraulic pressure difference (deltaP) were similar in acutely thyroparathyroidectomized (TPTX) rats and non-TPTX rats. Nevertheless, the glomerular capillary ultrafiltration coefficient (Kf) was uniformly higher in TPTX rats (greater than 0.113 +/- 0.005 (SE) nl/(s.mmHg)] than in non-TPTX controls (0.088 +/- 0.005). In TPTX rats, infusion of a submaximal dose (1 U/kg per min) of PTH resulted in significant decreases in SNGFR at constant QA and deltaP, due primarily to return of Kf to non-TPTX levels. Infusion of 10 U/kg per min of PTH to non-TPTX rats further reduced Kf, on average to 0.042 +/- 0.001 nl/(s.mmHg), leading to further reduction in SNGFR, whereas QA and deltaP again remained constant. These findings suggest that PTH may play an important role in modulating Kf, and consequently, SNGFR.

Animals↗
PubMed1978

Evidence for a parathyroid hormone-dependent influence of calcium on the glomerular ultrafiltration coefficient.

Experiments were performed on 36 plasma-expanded Munich-Wistar rats to examine the effects of acute hypercalcemia on the determinants of glomerular ultrafiltration. Elevation of total plasma calcium concentration to an average value of 13.2 +/- 0.5 mg/dl, by acute infusion of calcium chloride into nonthyroparathyroidectomized (non-TPTX) rats, resulted in significant declines in single nephron and whole kidney glomerular filtration rate. These declines were due primarily to a fall in the glomerular capillary ultrafiltration coefficient (Kf), to a mean value approximately 60% below that determined in the pre-infusion period. These changes were not seen in a separate group of sham-treated non-TPTX rats. It is of interest that these effects of acute hypercalcemia were largely abolished in rats that underwent acute TPTX before hypercalcemia. Infusion of a submaximally phosphaturic dose of parathyroid hormone, together with calcium chloride, into a second group of acute TPTX rats, however, had the effect of reproducing the striking declines in filtration rate and Kf noted in non-TPTX rats given calcium chloride alone. These findings suggest that the decline in filtration rate associated with hypercalcemia is due largely to the reduction in Kf, the latter dependent upon the presence of parathyroid hormone.

Animals↗