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Biomedical subjects

S C Thomson

Publications and source records attributed to S C Thomson.

At least 37 records · Page 2Linked to original sources
PubMed1996

Increased tubular flow induces resetting of tubuloglomerular feedback in euvolemic rats.

As single-nephron glomerular filtration rate (SNGFR) and late proximal flow (VLP) increase during growth or following volume expansion, the tubuloglomerular feedback (TGF) function (defined as the decrement in SNGFR due to the process of TGF) shifts rightward in the plane defined by VLP and SNGFR as required to maintain the homeostatic efficiency of TGF. It is not known whether this resetting of TGF requires changes in the systemic hormonal milieu or results from prolonged activation of TGF itself. We employed micropuncture and videometric flow velocitometry (an optical technique for measuring flow in unobstructed nephrons) to address this issue in Inactin-anesthetized euvolemic rats. The fractional compensation (C) of TGF for perturbations [late proximal flow perturbation (VH) = +/- 5 nl/min] in VLP was assessed repeatedly before and during a sustained increase in flow imposed by adding 20 nl/min to early proximal flow (VEP). Augmenting VEP initially saturated TGF, thus suppressing C. Over the next 30 min, C recovered to 70% of its original value, suggesting a rightward resetting of the TGF function to match the increase imposed on VLP. Resetting was confirmed by documenting an evolving asymmetry of C about VH = 0 by testing C vs. VH for -12 < or = VH < or = 12 in increments of 4 nl/min. Beyond 30 min of augmented VEP, C gradually declined due to desensitization of TGF. A sustained increase in VLP is sufficient to include TGF resetting, independent of any change in the systemic neurohumoral milieu.

Animals↗
PubMed1996

Renal response to blood pressure elevation in normal and glomerulonephritic rats.

Concurrent renal disease appears to augment greatly the adverse effects of systemic hypertension on renal function and the development of glomerulosclerosis. This study examined the effects of systemic hypertension and treatment of hypertension in groups of normal non-nephritic rats and rats submitted to 16 wk of glomerulonephritis induced by the administration of anti-glomerular basement membrane antibody. Hypertension was produced by application of a clip to the right renal artery and blood pressure was treated with an angiotensin-converting enzyme (ACE) inhibitor, quinapril. Glomerulosclerosis of two types developed: a diffuse type that is characteristic of anti-glomerular basement membrane glomerulonephritis, and a focal segmental glomerulosclerosis that is characteristic of systemic hypertension. Glomerulonephritis significantly reduced the capacity of ACE inhibitors to decrease systolic blood pressure in awake animals. In addition, glomerulonephritis produced significant effects on plasma angiotensin II concentrations, whereby ACE inhibition no longer lowered plasma angiotensin II levels and in fact produced an increase. Glomerular capillary hydrostatic pressure and hydrostatic pressure gradient correlated with systolic blood pressure and with the incidence of focal glomerulosclerosis in non-nephritic rats. However, in glomerulonephritis, systolic blood pressure no longer correlated with glomerular capillary pressure, and glomerular capillary pressure no longer correlated with the development of glomerulosclerosis, although systolic blood pressure did correlate with the degree of focal segmental glomerulosclerosis. Concurrent glomerulonephritis strongly conditions the effects of superimposed hypertension by altering the relationship between systemic blood pressure and glomerular capillary hydrostatic pressure and by decreasing the response of hypertension to therapy.

Angiotensin II↗
PubMed1995

Interactive control of renal function by alpha 2-adrenergic system and nitric oxide: role of angiotensin II.

We studied the role of angiotensin II (AII) in the interactive control of renal function by the alpha 2-adrenergic system and nitric oxide (NO) in adult male Munich Wistar rats 5-7 days after ipsilateral renal denervation (DNX). Renal micropuncture was used under euvolemic conditions before (period 1) and during (period 2) systemic inhibition of NO synthase (NOS) with NG-monomethyl-L-arginine (L-NMMA) in three groups. Group 1 served as a DNX control. In group 2, the alpha 2-adrenergic agonist B-HT 933 (BHT) was infused systemically throughout the experiment. In group 3, the AII-receptor blocker, Iosartan (LOS), was infused before period 2 as well as throughout infusion of BHT. L-NMMA increased blood pressure (BP) to a similar degree in all three groups. In group 1, infusion of L-NMMA did not affect glomerular hemodynamics or tubular function. With BHT in group 2, L-NMMA reduced absolute proximal tubular reabsorption (APR) and by reducing nephron plasma flow (SNPF) and glomerular ultrafiltration coefficient (LpA) caused nephron filtration rate (SNGFR) to decrease, a response described in innervated kidneys. LOS in group 3 abrogated the BHT-facilitated reduction of LpA and SNGFR but not of SNPF and APR in response to L-NMMA. In group 1, urinary sodium excretion (UNaV) did not change and urinary flow rate (UV) increased slightly in period 2. L-NMMA combined with BHT, however, exerted a profound diuresis and natriuresis in group 2. These effects were further exaggerated with LOS. In a fourth group of DNX rats. LOS given alone before period 2 did not affect SNGFR, SNPF, LpA, APR, UV, or UNaV. We conclude that after subacute renal denervation alpha 2-adrenergic activation sensitizes (a) LpA to reduction by NOS inhibition through an AII-dependent mechanism, and (b) SNPF and proximal tubular reabsorption to reduction by L-NMMA regardless of the AII activity. Furthermore, our results suggest a potential role for the alpha 2-adrenergic system and AII in the diuretic and natriuretic effect of systemic NOS inhibition.

Angiotensin II↗
PubMed1995

Glomerular and tubular interactions between renal adrenergic activity and nitric oxide.

Endothelium-dependent nitric oxide (EDNO) exerts control over the processes of glomerular filtration and tubular reabsorption. The importance of the renal nerves to the tonic influence of EDNO in the glomerular microcirculation and proximal tubule was tested by renal micropuncture in euvolemic adult male Munich-Wistar rats. The physical determinants of glomerular filtration and proximal reabsorption were assessed before and during administration of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), in control animals and in animals 5-9 days after either ipsilateral surgical renal denervation (DNX) or after either sham surgery (SHX). L-NMMA caused single-nephron glomerular filtration rate to decline in control and SHX animals but not in DNX rats. L-NMMA caused a reduction in proximal reabsorption in control and SHX rats, which was prevented by prior DNX. DNX did not alter urinary guanosine 3',5'-cyclic monophosphate excretion, and, although DNX upregulates glomerular angiotensin II (ANG II) receptors, prior DNX did not alter intrarenal ANG II content as evaluated by radioimmunoassay. Some component of renal adrenergic activity is required for the full expression of the glomerular and tubular effects of blockade of nitric oxide synthase.

Analysis of Variance↗
PubMed1995

Alpha 2-adrenoceptors determine the response to nitric oxide inhibition in the rat glomerulus and proximal tubule.

Arginine-derived nitric oxide exerts control over the processes of glomerular filtration and tubular reabsorption. The tonic influence of nitric oxide over both of these is eliminated by renal denervation. The hypothesis that the renal nerves function, in this regard, via the activation of alpha 2-adrenoceptors was tested by renal micropuncture. The physical determinants of glomerular filtration and proximal tubular reabsorption were assessed in Munich-Wistar rats before and during the administration of the nitric oxide synthase inhibitor NG-monomethyl L-arginine (L-NMMA). In one set of studies, the systemic infusion of the alpha 2-agonist B-HT 933 rendered nephron GFR, nephron plasma flow, and proximal reabsorption sensitive to reduction by L-NMMA after renal denervation. In a second set of studies, the infusion of the alpha 2 receptor antagonist, yohimbine, to rats with renal nerves intact was found to suppress the effects of L-NMMA on nephron plasma flow and proximal reabsorption. The effects of L-NMMA on nephron GFR and nephron plasma flow, afferent and efferent arteriolar resistances, and proximal reabsorption correlated with the level of underlying alpha 2-adrenergic activity. The activation of renal alpha 2-adrenoceptors increases the influence of arginine-derived nitric oxide in the glomerulus and proximal tubule.

Adrenergic alpha-Agonists↗
PubMed1993

Homeostatic efficiency of tubuloglomerular feedback in hydropenia, euvolemia, and acute volume expansion.

We assessed the homeostatic efficiency of the tubuloglomerular feedback (TGF) system in Inactin-anesthetized Munich-Wistar rats by use of perturbation analysis in closed-loop micropuncture studies. Nephrons were studied in vivo under conditions of hydropenia (HYD, n = 17), euvolemia (EUV, n = 23), and acute isoncotic extracellular volume expansion (EXP, n = 15). Proximal tubular flow was perturbed in free-flowing nephrons with a microperfusion apparatus. Flow rate (VM) was measured upstream from the perturbation (VH) by a noninvasive optical technique. The dependence of VM on VH was estimated by polynomial regression. By using fractional compensation (C = -dVM/dVH), as an index of homeostatic efficiency, we constructed efficiency profiles (C vs. VH). At VH = 0, C tended toward higher values with decreasing volume status, although the effect did not achieve significance. The maximum value of C did not differ between groups. The efficiency profiles shifted leftward with each increment in volume (P < 0.03, HYD vs. EXP), suggesting that the TGF system adapts to acute increments in volume by shifting the efficiency profile in favor of a vasodilatory role.

Animals↗
PubMed1993

Arginine feeding modifies cyclosporine nephrotoxicity in rats.

Glycine (G) infusion causes renal vasodilation mediated by nitric oxide (NO). Cyclosporine A (CsA) nephrotoxicity is characterized by preglomerular vasoconstriction and decreased efferent arteriolar tone probably related to reduced NO and angiotensin II, respectively. L-Arginine (ARG) is a precursor to NO. To test the hypothesis that chronic CsA decreases renal NO activity, we compared the glomerular hemodynamic response to glycine infusion in rats after 8 d of CsA (30 mg/kg per d s.c.), CsA and ARG (1.6 g/kg per d p.o.) (A/CsA), and in two groups of pair-fed controls (CON, A/CON). Single nephron GFR (SNGFR), single nephron plasma flow (SNPF), glomerular capillary hydrostatic pressure gradient (delta P), proximal tubular reabsorption (APR), and kidney tissue angiotensin II (AIIk) were measured before and during G. CsA was associated with baseline decrements in SNGFR, SNPF, delta P, and AIIk, and with a blunted hemodynamic response to G. In CON, ARG did not affect baseline hemodynamics or modify the response to G. In CsA, ARG decreased baseline preglomerular resistance and restored the glomerular hemodynamic response to G. G was associated with a significant increase in AIIk in both CON and CsA. These findings suggest that (a) CsA is associated with decreased AIIk, and (b) CsA may diminish NO activity within the kidney, and that this capacity may be partially restored by arginine feeding.

Administration, Oral↗
PubMed1992

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.

Adrenergic alpha-Antagonists↗
PubMed1991

Effects of beta-adrenergic blockade on the glomerular and tubular response to acute renal denervation.

Using micropuncture techniques in euvolemic adult male Munich-Wistar rats, we assessed the functional role of renal beta-adrenoceptors in mediating neural control of glomerular filtration and proximal tubular reabsorption. The determinants of nephron filtration and rate of proximal tubular reabsorption were measured in two groups of animals before and after acute surgical renal denervation (DNX). Group A animals (n = 6) were pretreated with the beta-adrenoceptor antagonist propranolol (25 mg/kg body weight per day for 4-6 days). Group B animals (n = 7) served as non-beta-blocked controls. Acute renal DNX resulted in no significant change in nephron filtration rate or any of its determinants in either group. Acute DNX caused similar decrements in the rate of fluid reabsorption from the proximal convoluted tubule of beta-blocked and control rats. Loop of Henle fluid reabsorption did not appear to be affected by DNX in either group. Because the effect of denervation on proximal tubular reabsorption was not conditioned by prior beta-blockade, the beta-adrenoceptors present within the proximal convoluted tubule do not appear to be the primary mediators of the adrenergic influence on fluid transport in that segment of the nephron.

Absorption↗
PubMed1991

Tubuloglomerular feedback responses to acute contralateral nephrectomy.

After unilateral nephrectomy adaptive events must occur in the remaining kidney within the first 12-14 h in anticipation of an increase in glomerular filtration rate (GFR) and eventual renal hypertrophy. Utilizing micropuncture and microperfusion techniques in the rat, we have examined tubuloglomerular feedback (TGF) and single-nephron GFR (SNGFR) responses while the late proximal tubule was microperfused [late proximal tubule flow (VLP)] from 0 to 40 nl/min in 10 nl/min intervals at 2-4 and 12 h after contralateral nephrectomy. Urinary excretion increased, but SNGFR derived from distal collections was reduced, and early distal flow rate remained constant 2-4 h after nephrectomy. The operating point was shifted, suggesting activation of TGF. The turning point half-maximal activity (V1/2) and slope were not statistically different when all nephron data were submitted to a curve-fitting procedure, but group mean data suggested a quantitatively lower V1/2 and steeper slope of the TGF profile. Twelve to fourteen hours after contralateral nephrectomy, values for SNGFR at all microperfusion rates were increased, as were late proximal and early distal flow rates. The values for V1/2 and slope of TGF were not statistically different from control values. We conclude that TGF activity and sensitivity are not suppressed at 2 and 12 h after nephrectomy. Increased urinary excretion does not require TGF alterations. Changes in TGF may be adaptive to increases in SNGFR and may not be causal to the increase in filtration rate after nephrectomy.

Animals↗
PubMed1991

Tubuloglomerular feedback activity after acute reductions in renal mass.

Removal of one kidney results in prompt increases in urinary excretion of NaCl and water from the remaining kidney, followed rather soon thereafter by increases in glomerular filtration rate (GFR). At 12-15 h and 24 h after contralateral nephrectomy, the single nephron filtration rate (SNGFR) is increased, accompanied by parallel increases in absolute proximal tubular reabsorption, late proximal tubular and early distal tubular flow rates, suggesting that these events might be critical to the increased urinary excretion. However, micropuncture studies 2-4 h after contralateral nephrectomy demonstrate that increased SNGFR and even increased distal tubular flow rates are not requirements for augmented urinary excretion, suggesting that decreased tubular reabsorption in the most distal nephron segments causes the increase in urinary excretion. Analysis of TGF profiles by stop-flow pressure response at 2-4 h after contralateral nephrectomy have suggested suppression of TGF as assessed by a rightward shift in the turning point with increasing late proximal tubular perfusion. However, our studies have examined SNGFR responses and shown no suppression of TGF profiles but a downward shift in the operating point, suggesting activation of TGF and a modest reduction in SNGFR, determined from distal tubular collections. Although SNGFR was increased at all late proximal perfusion rates 12 h after nephrectomy, the turning point (V 1/2) was not altered. TGF profiles are not suppressed within 12 h after nephrectomy while SNGFR is increased. Suppression of TGF does not cause the increase in SNGFR after nephrectomy and TGF activity is maintained and adapts to increases in SNGFR caused by TGF-independent mechanisms.

Animals↗
PubMed1990

Physiologic adaptations of the tubuloglomerular feedback system.

Knowledge of the existence of a tubuloglomerular feedback system has been available for many years. Only recently, however, have tenable hypotheses and supporting experimental data become available which have served to provide details regarding the complex inner workings of this system. The facility for examining this integrated physiologic network has derived, in large part, from the routine ability to perform in vivo micropuncture. We anticipate that further advances in this field will hinge on the development of additional experimental techniques to allow cellular biologic aspects of the system to be closely monitored in situ.

Adaptation, Physiological↗
PubMed1990

Glomerular hemodynamics and alpha 2-adrenoreceptor stimulation: the role of renal nerves.

We evaluated the effects of alpha 2-adrenoceptor stimulation on the determinants of nephron filtration rate (SNGFR) using micropuncture in Munich-Wistar rats. Micropuncture was performed in animals 5-7 days after sham surgery (group 1) or renal denervation (DNX) (groups 2, 3, and 4). Glomerular hemodynamic measurements were made before and during a systemic infusion of the alpha 2-agonist, B-HT 933 (1.0 mg.kg-1.h-1) (groups 1, 2, and 3). Group 3 rats were pretreated with the alpha 2-antagonist, yohimbine (3 mg.kg-1.h-1). In group 4, hydralazine was substituted for B-HT 933 to dissociate specific alpha 2-effects from nonspecific effects on blood pressure. Arterial pressure declined by similar amounts between experimental periods in groups 1, 2, and 4. In group 1, B-HT 933 caused SNGFR to increase due to an increment in nephron plasma flow. In group 2, B-HT 933 caused SNGFR to decrease due to a decrement in glomerular ultrafiltration coefficient (LpA). In groups 3 and 4, SNGFR was unaffected by B-HT 933 or hydralazine. Ligand-binding studies in glomerular membranes documented the presence of alpha 2-adrenoreceptors (275 +/- 22 fmol/mg protein). Receptor density was not altered by DNX. These observations could be explained by an alpha 2-mediated inhibition of renal nerve activity combined with intrinsic sympathomimetic effects not dependent on renal nerves, with the latter effects unmasked by DNX and manifested by a decrease in LpA.

Adrenergic alpha-Agonists↗
PubMed1990

Adrenergic influences and interactions with angiotensin II.

Increasing evidence indicates the existence of a complex interplay between the angiotensin and adrenergic nervous systems within the kidney. Since both of these vasoconstrictor systems are integrally involved in the maintenance of systemic blood pressure and fluid and electrolyte homeostasis, it is not surprising that each might influence the other vis-a-vis their mutual capacity to alter the physiologic determinants of glomerular filtration.

Angiotensin II↗
PubMed1989

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.

Angiotensin II↗
PubMed1988

Tubuloglomerular feedback.

Increasing evidence is accumulating that the tubuloglomerular feedback system exercises significant control over the glomerular filtration rate. We present our current understanding of the mechanisms underlying the operation of the TGF system and discuss several situations applicable to clinical medicine where altered TGF responses are likely to be manifested as perceivable changes in overall renal function.

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