B. J. Tucker

Functional effects on glomerular hemodynamics of short-term chronic cyclosporine in male rats.

We evaluated the effects of chronic cyclosporine (CsA) administration on the determinants of nephron filtration rate (SNGFR) using micropuncture techniques (mp) in male Munich-Wistar rats. Animals received CsA (30 mg/kg SQ) in olive oil daily for 8 d before mp. Controls (PFC) were pair fed. SNGFR, glomerular capillary hydrostatic pressure gradient (delta P), nephron plasma flow (SNPF), plasma protein oncotic pressure (pi A), and glomerular ultrafiltration coefficient (LpA) were quantitated in each experiment. CsA was associated with a lower SNGFR due to decreases in SNPF and a major reduction in delta P but no decrease in LpA. Plasma volume expansion (PVE) caused SNGFR, delta P, and SNPF to increase in both CsA and PFC without eliminating the differences between CsA and PFC. CsA/PVE rats responded normally to angiotensin II (AII) infusion indicating that the low delta P associated with CsA is not due to unresponsiveness to AII. Prior renal denervation caused SNGFR and SNPF to increase in CsA-treated animals but failed to alter the reduction in glomerular capillary pressure after CsA or to eliminate the glomerular hemodynamic differences between treated animals and pair-fed controls. This constellation of glomerular hemodynamic abnormalities suggests that the renal effect of short-term chronic CsA administration is mediated primarily by a reduction in the afferent effective filtration pressure resulting from an imbalance between pre- and postglomerular vascular resistances.

The acute effects of antiglomerular basement membrane antibody upon glomerular filtration in the rat. The influence of dose and complement depletion.

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 (AGBM Ab) in plasma-expanded Munich-Wistar rats. This reduction in sngfr was due to decreases in nephron plasma flow (rf) and the glomerular permeability coefficient (LpA) utilizing direct evaluation of all pertinent pressures, flows, and permeabilities. With identical micropuncture techniques, we have determined (a) the respective influences of rpf and LpA upon sngfr by examining the effects of differing doses of AGBM Ab, and (b) the specific effect of complement fixation upon the reduction in sngfr. In normal rats, low dose (1.4 microgram/g body wt) AGBM Ab decreased sngfr from 57.9 +/- 3.4 to 50.8+/- 3.9 nl/min per g kidney wt (kw) (P less than 0.001), and this was due to a 10% reduction in rpf and a decrease in LpA FROM 0.069 +/- 0.014 in control to 0.041 +/- 0.007 nl/s per g kw per mm Hg (P less than 0.02). At the high dose (2.3 microgram/g body wt), sngfr fell dramatically from 58.4 +/- 4.0 to 7.6 +/- 3.8 nl/min per g kw (P less than 0.001), and this effect upon filtration was 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 less than 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 rps 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 less than 0.05). Complement depletion prevented the migration of polymorphonuclear leukocytes (present in larger numbers after the high dose of AGBM Ab) into the capillary and eliminated vasoconstriction. Complement depletion resulted in a lesser effect of high-dose AGBM Ab upon LpA than in normal rats, and this is likely due to lesser polymorphonuclear leukocyte effects upon capillary surface area. The persistent reduction in LpA observed in complement-depleted rats correlated with separation of the endothelial cell from the glomerular basement membrane after AGBM Ab, AGBM Ab diminished glomerular ultrafiltration by decreasing LpA and altering the endothelial surface of the glomerular membrane, and this effect is not totally dependent upon the fixation of complement.

Measurements of Glomerular Dynamics

The rate of glomerular ultrafiltration is high in mammals and defines the filtered load to each nephron unit. The major focus in renal physiology has been upon the varied mechanisms involved in the process of tubular reabsorption of solute and water. However, it has long been apparent that equally exacting mechanisms are required in maintaining the load of solute and water to the tubule for volume homeostasis to be maintained (Smith, 1951). Analysis of the specific factors determining and controlling glomerular filtration has awaited the development of micro methods capable of providing the necessary measurements of all the pertinent pressures, flows, and permeabilities. During the past few years such systems of measurement have been developed (Brenner et al., 1971; Blantz et al., 1972) and knowledge of the specific factors contributing to glomerular ultrafiltration has advanced rapidly during this recent period (Brenner et al., 1972; Deen et al., 1972; Blantz, 1974; Maddox et al., 1975; Blantz et al., 1976). In this section, we will summarize the specifics of current methods used in the analysis of glomerular dynamics.

Interaction between alpha 2-adrenergic and angiotensin II systems in the control of glomerular hemodynamics as assessed by renal micropuncture in the rat.

The hypothesis that renal alpha 2 adrenoceptors influence nephron filtration rate (SNGFR) via interaction with angiotensin II (AII) was tested by renal micropuncture. The physical determinants of SNGFR were assessed in adult male Munich Wistar rats 5-7 d after ipsilateral surgical renal denervation (DNX). DNX was performed to isolate inhibitory central and presynaptic alpha 2 adrenoceptors from end-organ receptors within the kidney. Two experimental protocols were employed: one to test whether prior AII receptor blockade with saralasin would alter the glomerular hemodynamic response to alpha 2 adrenoceptor stimulation with the selective agonist B-HT 933 under euvolemic conditions, and the other to test whether B-HT 933 would alter the response to exogenous AII under conditions of plasma volume expansion. In euvolemic rats, B-HT 933 caused SNGFR to decline as the result of a decrease in glomerular ultrafiltration coefficient (LpA), an effect that was blocked by saralasin. After plasma volume expansion, B-HT 933 showed no primary effect on LpA but heightened the response of arterial blood pressure, glomerular transcapillary pressure gradient, and LpA to AII. The parallel results of these converse experiments suggest a complementary interaction between renal alpha 2-adrenergic and AII systems in the control of LpA.