A B S T R A CT The effects of both synthetic and biologically produced angiotensin II (AII) upon the process of glomerular filtration were examined in the plasma-expanded (2.5% body wt) Munich-Wistar rat, by micropuncture evaluation of pressures, nephron plasma flow (rpf) and filtration rate (sngfr). Plasma expansion was chosen as a control condition because (a) response to AII was uniform and predictable, (b) endogenous generation of AII was presumably suppressed, and (c) the high control values for rpf permitted accurate determination of values for the glomerular permeability coefficient (LPA) before and during AII infusion. With subpressor quantities of synthetic Asn-1, Val-5 AII (< 5 ng/100 g body wt/min), sngfr fell from 47.7 in the control group to 39.8 nl/min/g kidney (P < 0.005). The rpf fell to 60% of control values (P < 0.001). Measurement of glomerular capillary (Pa) and Bowman's space (P.) hydrostatic pressures in surface glomeruli with a servo-nulling device permitted evaluation of the hydrostatic pressure gradient (AP = Pa-P0). AP increased from 38.1+±1.2 in control to 45.9±1.3 mm Hg after Asn-1, Val-5 AII and essentially neutralized the effect of decreased rpf in sngfr. The sngfr then fell as a result of a decrease in LPA from 0.063+0.008 in control to 0.028±0.004 nl/s/g kidney/mm Hg after Asn-1, Val-5 AII (P < 0.02).Lower doses of Asp-1, Ile-5 AII (< 3 ng/100 g body wt/min) had no effect on sngfr, rpf, AP, and afferent and efferent vascular resistance, but significantly elevated systemic blood pressure, suggesting peripheral ef- fects on smooth muscle at this low dose. LPA was 0.044+ 0.007 nl/s/g kidney/mm Hg after low-dose Asp-1, Ile-5 AII, and 0.063±0.008 in the control group (0.2 > P > 0.1). Higher, equally pressor doses of native AII (5 ng/ 100 g body wt/min) produced effects almost identical to similar quantites of synthetic Asn-1, Val-5 AII upon rpf, AP, sngfr, and renal vascular resistance. LPA again fell to 0.026±0.004 nl/s/g kidney/mm Hg, a value almost identical to that after the synthetic AI. Paired studies with Asp-1, Ile-5 AII also demonstrated a consistent reduction in LPA.Both synthetic (Asn-1, Val-5 AII) and native AII (Asp-1, Ile-5 AII) produce a reduction in LpA, presumably by direct action on the glomerular capillary or mesangium, where no smooth muscle cells are present. Although quantitative differences in peripheral vascular effects of the two forms of AII are demonstrated, the effects on LPA occur at similar doses of both agents in the plasma-expanded rat. A third major physiologic action for AII is postulated that requires an effector cell in the glomerulus that differs from those previously demonstrated for vascular smooth muscle and the adrenal glomerulosa.

This study was undertaken to investigate the mechanisms by which an infusion of recombinant human insulin-like growth factor I (rhIGF-I) increases GFR and renal plasma flow (RPF) in rats. Glomerular micropuncture studies were carried out in 14 nonstarved Munich Wistar rats and in 12 rats deprived of food for 60-72 h. Animals were given an intravenous injection and infusion of either rhIGF-I or vehicle. In both nonstarved and starved animals, the IGF-I injection and infusion increased the serum IGF-I levels, left kidney GFR, single nephron glomerular filtration rate (SNGFR), single nephron blood flow rate (SNBF), and single nephron plasma flow rate (SNPF). The increase in SNPF and SNGFR was in part due to a fall in efferent arteriolar resistance (RE); there was a tendency, not significant, for afferent arteriolar resistance (RA) to fall in comparison to controls. The increase in SNGFR was partly caused by a rise in SNPF but was primarily due to an increase in glomerular ultrafiltration coefficient (LpA) to twice the control values. The increase in LpA resulted in an increase in SNGFR because the rats operated at ultrafiltration pressure disequilibrium. Control starved as compared with nonstarved rats had lower SNGFR, SNBF, and SNPF. This reduction was due to a tendency, not significant, for both RA and RE to be higher. Decreased SNGFR in food-depri'ved rats resulted from a reduced SNPF, a lower glomerular transcapillary hydrostatic pressure difference (AP), and possibly a somewhat reduced LpA. These data indicate that IGF-I increases SNGFR, SNPF, and SNBF primarily by increasing LpA and also by decreasing RE without affecting AP. Short-term starvation lowers SNGFR, SNPF, and SNBF primarily by decreasing AP and possibly by lowering LpA and increasing RA and RE. IGF-I reverses some of the glomerular hemodynamic effects of short-term food deprivation. (J. Clin. Invest. 1991. 87:1200-1206

To understand the mechanism, magnitude, and time course of facial puffiness that occurs in microgravity, seven male subjects were tilted 6 degrees head-down for 8 h, and all four Starling transcapillary pressures were directly measured before, during, and after tilt. Head-down tilt (HDT) caused facial edema and a significant elevation of microvascular pressures measured in the lower lip: capillary pressures increased from 27.7 +/- 1.5 mmHg (mean +/- SE) pre-HDT to 33.9 +/- 1.7 mmHg by the end of tilt. Subcutaneous and intramuscular interstitial fluid pressures in the neck also increased as a result of HDT, whereas interstitial fluid colloid osmotic pressures remained unchanged. Plasma colloid osmotic pressure dropped significantly by 4 h of HDT (21.5 +/- 1.5 mmHg pre-HDT to 18.2 +/- 1.9 mmHg), suggesting a transition from fluid filtration to absorption in capillary beds between the heart and feet during HDT. After 4 h of seated recovery from HDT, microvascular pressures in the lip (capillary and venule pressures) remained significantly elevated by 5-8 mmHg above baseline values. During HDT, urine output was 126.5 ml/h compared with 46.7 ml/h during the control baseline period. These results suggest that facial edema resulting from HDT is caused primarily by elevated capillary pressures and decreased plasma colloid osmotic pressures. The negativity of interstitial fluid pressures above heart level also has implications for maintenance of tissue fluid balance in upright posture.

Head-down tilt is considered an effective experimental model to simulate weightlessness. To determine the acute effects of simulated weightlessness on transcapillary fluid balance, tissue fluid shifts, muscle function, and triceps surae reflex time, eight supine subjects were tilted 5 degrees head down for 8 h. A cephalic fluid shift from the legs was indicated by facial edema, nasal congestion, increased urine flow, decreased creatinine excretion, reduced calf girth, and decreased lower leg volume. As measured by wick catheters inserted under local anesthesia, interstitial fluid pressure in the tibialis anterior muscle (4.6 +/- 0.6 mmHg) and subcutaneous tissue (0.6 +/- 0.5 mmHg) of the lower leg fell significantly to -2.8 +/- 0.5 and -3.8 +/- 0.4 mmHg, respectively. Other transcapillary pressures (capillary and interstitial fluid colloid osmotic pressures) were relatively unchanged. Needle-biopsy specimens, obtained just before and after tilt, indicated that total water content of soleus muscle was unchanged during 8 h of head-down tilt. After head-down tilt, isometric strength and isokinetic strength of the plantar flexors were unchanged. Triceps surae reflex time associated with plantar flexion movement slowed slightly after the tilt maneuver. Collectively these results demonstrated a dehydration effect of head-down tilt on muscle and subcutaneous tissues of the lower leg that may affect muscle function.

The specific mechanism whereby superficial nephron glomerular filtration rate (sngfr) is reduced after the administration of benzolamide, a carbonic anhydrase inhibitor with a primary inhibitory effect in the proximal tubule, have been examined by measuring pertinent pressures, flows, and glomerular permeabilities in the hydropenic Munich-Wistar rat, a strain with surface glomeruli. Because benzolamide decreases absolute proximal reabsorptive rate, the rate of delivery of tubular fluid to the distal nephron should be at least transiently increased and may reduce sngfr by activating the tubulo-glomerular feedback system. Sngfr fell from 29.2+/2.0 to 2.1+/3.1 nl/min (P less than 0.01) after benzolamide (group 1), a percentage reduction equal to kidney glomerular filtration rate and similar to sngfr obtained in collections from distal tubules. Separate studies (group 2) revealed that if transient increases in distal nephron delivery were prevented by insertion of a long oil block in proximal tubules before control, the decrease in sngfr was prevented (30.3+/1.0 vs. 30.3+/1.8 nl/min, P greater than 0.9). In paired "unblocked" nephrons in the same rats, sngfr fell in group 2 (33.0+/1.0 vs. 25.2+/2.3 nl/min, P less than 0.01). In "blocked" nephrons in which sngfr reduction was prevented, the rate of fluid leaving the proximal tubule increased from 16.9+/ to 23.1+/1.0 nl/min (P less than 0.01). In group 1 studies in which sngfr fell and transient increases in flow out of the last segment of the proximal tubule (distal delivery) (approximately equal to 8 nl/min) were not prevented, steady-state distal delivery was unchanged by benzolamide (13.9+/1.1 vs. 14.2+/2.2 nl/min). Also, sngfr returned toward control, pre-benzolamide values, when a proximal oil block was placed for 15 min and the rate of distal delivery reduced after benzolamide administration, which suggests that this activation was reversible. These data suggest that activation of tubulo-glomerular feedback by transient increases in distal delivery was responsible for decreases in sngfr. Analysis of all determinants of glomerular ultra-filtration revealed that the efferent mechanism leading to reduced sngfr after benzolamide was decreased nephron plasma flow (101+/13 vs. 66+/13 nl/min, P less than 0.01). Hydrostatic pressure and the glomerular permeability coefficient did not contribute to reductions in sngfr with benzolamide. Because the rate of distal delivery remained constant in spite of large changes in both sngfr and absolute proximal reabsorptive rate, it is suggested that the rate of distal delivery may be the physiologic entity that is regulated by the tubulo-glomerular feedback system via alterations in sngfr.

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A B S T R A C T Recent studies from this laboratory have revealed that single nephron filtration rate (sngfr) decreases significantly within 1 h of the administration of large doses of complement-fixing antiglomerular basement membrane antibody ( the result of an 86% reduction in rpf and a decrease in LpA from 0.092+0.020 to 0.007+0.004 nl/s per g kw mm Hg (P < 0.001). Therefore, at lower doses sngfr fell primarily as a result of a 40% reduction in LpA and a 10% decrease in rpf; however, at the high dose massive reductions in both rpf and LPA led to the large decrease in sngfr.In complement-depleted rats, receiving identical doses, low-dose AGBM Ab no longer reduced the sngfr, but a reduction in LpA persisted (other factors compensating to maintain sngfr). At the high dose, complement depletion ameliorated the reduction in sngfr (55.1+2.4 to 37.2+3.4 nl/min per g kw mm Hg) by nearly eliminating the vasoconstriction but only partially diminished the reduction in LpA (0.097+0.020 to 0.032+0.004 nl/s per g kw mm Hg, P < 0.05).Complement depletion prevented the migration of polymorphonuclear leukocytes (present

Microalbuminuria (26-250 mg/d) is considered to be an indicator of incipient diabetic nephropathy in humans in insulin-dependent diabetes (IDD). However, before microalbuminuria is observed, glomerular alterations, such as glycosylation of the glomerular basement membrane and glomerular hyperfiltration, in IDD may result in increased filtration of albumin before any observed increase in albumin excretion. Glomerular and tubular albumin kinetics were examined in streptozotocin (65 mg/kg body wt, i.v.) diabetic, Munich-Wistar rats at 7-10 (untreated) and 50-70 d (poorly controlled with small doses of insulin) after the onset of diabetes and compared with nondiabetic controls. Additional rats in each condition received acute lysine treatment to prevent tubular protein reabsorption. Urinary albumin excretion and nonvascular albumin distribution volumes were measured in the renal cortex and compared with morphometric measurements of interstitial space and the proximal tubule to assess intracellular uptake of albumin in the proximal tubule. Urinary albumin excretion under anesthesia was not different in 7-10-d IDD versus controls (19±3 vs.