Renin-angiotensin system inhibition reduces glycine-induced glomerular hyperfiltration in conscious rats.

It has been reported that high protein intake or amino acid infusion-induced glomerular hyperfiltration are accompanied by an elevation of plasma renin activity and renal renin mRNA. We therefore investigated the effect of inhibition of the renin-angiotensin system by SK&F 108566, a novel, nonpeptide angiotensin II (AII) receptor antagonist, or by enalapril, an angiotensin converting enzyme inhibitor, on glycine-induced hyperfiltration. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by inulin and p-aminohippurate clearances in conscious chronically instrumented rats. Glycine infusion (3.7 mg/min i.v.; n = 8) significantly increased GFR by 27% (from 1.09 +/- 0.53 to 1.38 +/- 0.08 ml/min.100 g), ERPF by 22% (2.96 +/- 0.30 to 3.61 +/- 0.32 ml/min.100 g) and significantly decreased effective renal vascular resistance by 22% [from 25.4 +/- 2.9 to 20.8 +/- 2.5 mm Hg/(ml/min.100 g)]. SK&F 108566 (30 micrograms/kg.min) or enalapril (1 mg/kg), at doses which inhibited the pressor effects of AII or AI, respectively, but had no significant influence on base-line GFR and ERPF, significantly attenuated the glycine-induced glomerular hyperfiltration and hyperemia. In the presence of SK&F 108566 or enalapril, glycine resulted in only small, statistically insignificant changes in GFR (from 1.07 +/- 0.03 to 1.10 +/- 0.04 and from 1.19 +/- 0.03 to 1.21 +/- 0.08 ml/min.100 g, respectively), ERPF (from 3.27 +/- 0.21 to 3.53 +/- 0.26 and from 3.57 +/- 0.11 to 3.41 +/- 0.38 ml/min.100 g, respectively) and effective renal vascular resistance [from 21.2 +/- 1.9 to 19.2 +/- 1.6 and from 18.4 +/- 0.9 to 20.2 +/- 2.2 mm Hg/(ml/min.100 g], respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of adenosine receptor antagonists on the responses to contrast media in the isolated rat kidney

Contrast media can induce both a decrease in renal blood flow and a reduction in glomerular filtration rate (GFR) when administered to both experimental animals and humans. In the present study we have examined the role of adenosine in mediating these effects using the isolated perfused rat kidney. Kidneys were perfused with a 6. 7%-(w/v)-albumin-based perfusate supplemented with glucose and amino acids (n=6 per group). They were exposed to diatrizoate [20 mg of iodine (mgI)/ml; osmolality 1650 mOsm/kg of water] or iotrolan (20 mgI/ml; osmolality 320 mOsm/kg of water) in the presence or absence of theophylline (10.8 microg/ml), or to diatrizoate in the presence or absence of a specific adenosine A(1) receptor antagonist (KW-3902; 2 microg/ml) or a specific A(2) receptor antagonist (KF17837; 6 microg/ml). Diatrizoate (n=6) produced a fall in GFR from 0.65+/-0.04 to 0.42+/-0.03 ml.min(-1).g(-1) (P<0.05); renal perfusate flow (RPF) also declined, from 36.5+/-3.8 to 22.0+/-3.2 ml. min(-1).g(-1) (P<0.05). Iotrolan (n=6) produced a fall in GFR from 0. 64+/-0.02 to 0.48+/-0.04 ml.min(-1).g(-1) (P<0.05) and in RPF from 33.3+/-3.8 to 24.0+/-3.0 ml.min(-1).g(-1) (P<0.05). Theophylline (10.8 microg/ml) prevented the fall in GFR caused by either diatrizoate (baseline, 0.63+/-0.05 ml.min(-1).g(-1); diatrizoate+theophylline, 0. 60+/-0.04 ml.min(-1).g(-1)) or iotrolan (baseline, 0.64+/-0.04 ml. min(-1).g(-1); iotrolan+theophylline, 0.67+/-0.05 ml.min(-1).g(-1)), but did not affect the decreases in RPF caused by either agent. KW-3902 (2 microg/ml) also prevented the fall in GFR produced by diatrizoate (baseline, 0.66+/-0.05 ml.min(-1).g(-1); diatrizoate+KW-3902, 0.61+/-0.05 ml.min(-1).g(-1)), while the fall in RPF remained unaffected. KF17837 (6 microg/ml) had no effect on the decreases in either GFR or RPF induced by diatrizoate (n=6 per group). The results suggest a role for adenosine acting at the A(1) receptor in mediating the decrease in GFR induced by contrast media. This effect is independent of a change in renal vascular resistance, and possibly secondary to mesangial cell contraction causing a decrease in the ultrafiltration coefficient.     

Effect of a somatostatin analogue, octreotide, on renal haemodynamics and albuminuria in acromegalic patients

Although insulin-like growth factor I increases renal function, the renal haemodynamic abnormality underlying the glomerular hyperfiltration in acromegaly is unknown. In normal subjects, amino acids and low doses of dopamine increase the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), presumably by a predominant vasodilation of the afferent and efferent glomerular arterioles, respectively. We studied baseline GFR and ERPF (determined with 125I-iothalamate and 131I-hippuran, respectively), the renal stimulatory effects of amino acid and dopamine infusion, and albuminuria before and after 3 months octreotide treatment in seven acromegalic patients with metabolically active disease. Octreotide reduced growth hormone concentrations from 14.7 +/- 3.0 to 5.5 +/- 1.0 micrograms l-1 (mean +/- SEM, n = 7; P less than 0.001) and insulin-like growth factor I levels from 4.12 +/- 1.31 to 2.44 +/- 0.68 kU l-1 (P less than 0.02). Glucagon concentrations did not change. Baseline GFR and ERPF declined from 132 +/- 5 to 117 +/- 6 and from 547 +/- 32 to 478 +/- 31 ml min-1 1.73 m-2, respectively (P less than 0.05 for both). Initially the response to amino acids was impaired (increment in GFR: 4.8 +/- 6.0%, NS; ERPF: -1.5 +/- 6.8%, NS), whereas the response to dopamine was normal (GFR: 10.6 +/- 1.1%, P less than 0.05: ERPF: 33.2 +/- 3.1%, P less than 0.01). After octreotide, amino acid infusion increased GFR by 15.0 +/- 6.8% (P less than 0.02) and ERPF by 11.3 +/- 5.6% (P less than 0.02), while the dopamine response was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of adenosine in the gastric blood flow response to pentagastrin in the rat

We tested the hypothesis that the increase in gastric mucosal blood flow during pentagastrin-stimulated acid secretion in the rat is mediated partly by endogenously generated adenosine. In in vivo microscopic studies, topical 10(-5) to 10(-3) M adenosine dose-dependently dilated the submucosal arterioles, the vessels that control mucosal blood flow. The adenosine receptor antagonist 8-phenyltheophylline, significantly reduced adenosine's vasodilatory response. An adenosine analog with a high A2 receptor affinity was 100 times more potent as a vasodilator than one with a high A1 receptor affinity but lower A2 receptor affinity. We then examined the effect of i.v. 8-phenyltheophylline, 10 mg/kg, on the pentagastrin-stimulated increase in gastric blood flow and gastric acid secretion. Mucosal blood flow was estimated by the hydrogen clearance technique. Pentagastrin increased mucosal blood flow from 26.6 +/- 2.6 to 42.7 +/- 4.9 ml/min/100 g and this was reduced to 31.9 +/- 3.1 ml/min/100 g upon the addition of 8-phenyltheophylline. Gastric acid secretion upon the addition of 8-phenyltheophylline. Gastric acid secretion was stimulated by pentagastrin and stimulated further by the addition of 8-phenyltheophylline from 2.06 +/- 0.34 mEq of H+ per min to 2.84 +/- 0.49 mEq/min. 8-Phenyltheophylline had no effect on basal mucosal blood flow or gastric acid secretion. In contrast, the nonmethylxanthine phosphodiesterase inhibitor RO 20-1724 stimulated acid secretion and increased gastric mucosal blood flow during pentagastrin administration. The data suggest that gastric submucosal arterioles contain adenosine receptors of the A2 subtype that vasodilate when activated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beneficial effect of the atrial natriuretic factor analog A68828 in postischemic acute renal failure

Short-term administration of atrial peptides has been reported to improve renal function in several animal models of acute renal failure. We designed experiments that determined the effect of a 13-amino acid analog of atrial natriuretic factor (ANF), A68828, on renal function in the postischemic model of acute renal failure. Experiments were conducted using euvolemic, male Sprague-Dawley rats (200-250 g) under Inactin anesthesia. Acute renal failure was induced by complete occlusion of both renal arteries for 30 min. After release of the clamp, vehicle (0.1% bovine serum albumin in saline), A68828 (3, 10 or 30 micrograms/kg/min), dopamine (10 micrograms/kg/min), A68828 (10 micrograms/kg/min) plus dopamine (10 micrograms/kg/min) or ANF (1-28) (0.5 micrograms/kg/min) were infused i.v. for a 2-h period. A68828 at 10 micrograms/kg/min produced a significant increase in glomerular filtration rate (GFR) compared with vehicle controls (0.39 +/- 0.08 vs. 0.19 +/- 0.04 ml/min/100 g; P less than .05) despite a lower arterial pressure (87 +/- 5 vs. 101 +/- 5 mm Hg; P less than .05). A subpressor dose of dopamine had no effect on GFR during the postischemic period (0.25 +/- 0.11 ml/min/100 g). Dopamine in combination with A68828 prevented the decrease in arterial pressure seen with A68828 alone but did not potentiate the beneficial effects on GFR (0.28 +/- 0.05 ml/min/100 g). ANF (1-28) at 0.5 micrograms/kg/min increased GFR to levels nearly identical to those induced by A68828 (0.40 +/- 0.04 ml/min/100 g). These results indicate that infusion of a reduced-size analog of ANF improves renal function in the immediate postischemic period. Furthermore, prevention of the hypotensive effects of the analog with dopamine provides no additional beneficial effect.     

Mechanisms of glucagon-induced renal vasodilation: role of prostaglandins and endothelium-derived relaxing factor.

The mechanisms underlying the renal hemodynamic responses (vasodilation and hyperfiltration) to an amino acid or protein load are currently unknown and are relevant to understanding the effect of dietary protein on the progression of chronic renal failure. Glucagon (GLC) has been suggested to be important in these renal hemodynamic responses, although the mechanism is again unclear. Thus we investigated potential mediators of the renal hemodynamic response to GLC in the anesthetized rat, including prostanoids and endothelium-derived relaxing factor (EDRF). The effects of glucagon alone and after pretreatment were tested as follows: (1) after baseline renal hemodynamic measurements done with clearance techniques, rats were given GLC alone (n = 5; 200 ng/min IV continuous infusion); (2) glucagon was given after pretreatment with the EDRF synthesis inhibitor nitro-arginine-methyl-ester (NAME; n = 6; 125 micrograms/kg/min intrarenal artery by continuous infusion); (3) glucagon was given after pretreatment with indomethacin (INDO; n = 6; 5 mg/kg IV bolus). Repeat clearances demonstrated that GLC infusion increased glomerular filtration rate (GFR; basal vs GLC, 0.87 +/- 0.04 ml/min vs 1.14 +/- 0.09 ml/min, p < 0.05); renal plasma flow (RPF; 4.10 +/- 0.18 ml/min vs 5.56 +/- 0.32 ml/min, p < 0.05) and decreased renal vascular resistance (RVR; 15.82 +/- 1.17 mm Hg/[ml/min] vs 10.72 +/- 0.65 mm Hg/[ml/min], p < 0.05). Intrarenal N-nitro-L-arginine-methyl-ester (NAME) infusion significantly reduced basal GFR (-20% +/- 8%, p < 0.05) and RPF (-43% +/- 2%, p < 0.05), while increasing RVR (+108% +/- 9%, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevated plasma atrial natriuretic peptide levels in diabetic rats. Potential mediator of hyperfiltration.

Infusion of atrial natriuretic peptide (ANP) increases the glomerular filtration rate (GFR), and ANP is released from cardiac myocytes in response to extracellular fluid volume expansion. Since diabetes mellitus is associated with glomerular hyperfiltration and volume expansion, we investigated the relationship between ANP and GFR in diabetic rats given insulin to achieve stable moderate hyperglycemia or normoglycemia. At 2 wk after induction of diabetes, moderately hyperglycemic diabetic rats exhibited elevations of plasma ANP levels averaging 281 +/- 28 pg/ml vs. 158 +/- 15 pg/ml in normoglycemic diabetic rats. In hyperglycemic rats, the GFR was also elevated on average to 2.24 +/- 0.28 ml/min as compared with 1.71 +/- 0.13 ml/min in normoglycemic diabetic rats. To test further the relationship between ANP and GFR in diabetes, moderately hyperglycemic diabetic rats were infused either with a specific ANP antiserum or with nonimmune serum. The infusion of specific ANP antiserum uniformly reduced the GFR on average from 2.38 +/- 0.1 ml/min to 1.60 +/- 0.1 ml/min, whereas the infusion of nonimmune serum was without effect. It is concluded that elevated endogenous ANP levels contribute to the hyperfiltration observed in early diabetes in the rat.     

Renal response to pentobarbital anesthesia in rats: effect of interrupting the renin-angiotensin system

The influence of interrupting the renin-angiotensin system on the renal hemodynamic response to barbiturate anesthesia was assessed in conscious, trained, chronically catheterized rats. Anesthesia induced by pentobarbital caused a marked reduction in mean arterial pressure, heart rate, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Pretreatment of rats with captopril, an inhibitor of angiotensin I converting enzyme, prevented the impairment of renal hemodynamics by pentobarbital without restoring blood pressure. GFR remained at 100 to 110% of control values in captopril-pretreated rats receiving pentobarbital, but was reduced by pentobarbital (90-120 min after induction) to 75 +/- 5% in rats which did not receive captopril. ERPF showed similar changes. An antagonist of angiotensin II receptors, 1-sarcosine-8-isoleucine-angiotensin II, did not prevent the anesthesia-induced decrements in GFR and ERPF (GFR was reduced to 78 +/- 6% and ERPF to 68 +/- 4% at 90-120 min after pentobarbital). This failure of the antagonist of angiotensin II receptors to protect renal hemodynamics may have been due to its intrinsic agonist activity on the renal vasculature. This is suggested by the fact that, in captopril-pretreated rats, which maintained renal hemodynamics in response to pentobarbital, addition of 1-sarcosine-8-isoleucine-angiotensin II caused a reduction in GFR and ERPF and an elevated blood pressure. At 100 min after administration of pentobarbital, plasma renin activity was elevated compared to a conscious control group (3.57 +/- 0.42 vs. 1.94 +/- 0.34 ng angiotensin l/ml X hr, P less than .05). It is concluded that the renin-angiotensin system mediates an impairment of renal hemodynamics during pentobarbital anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Early glomerular hyperfiltration in insulin-dependent diabetics and late nephropathy

The aim of this study was to clarify whether early glomerular hyperfiltration, a characteristic feature of insulin-dependent diabetes, is associated with late diabetic nephropathy. In 1984 we re-examined 12 patients previously investigated in our laboratory around 1970; entrance criteria were as follows: male diabetics, clearly insulin-dependent, and age at onset of diabetes less than or equal to 20 years; glomerular filtration rate (GFR) and renal plasma flow (RPF) measured at least 7 years before follow-up study; duration of diabetes at initial examination 3-7 years. All patients fulfilling these criteria accepted a re-examination. The end-point at follow-up (final criterium) was the level of urinary albumin excretion (UAE), either elevated (greater than or equal to 15 micrograms/min) or normal (less than 15 micrograms/min). A clear discrimination was seen, patients being either grossly abnormal (95-4117 micrograms/min) or normal (2.6-7.4 micrograms/min). A marked difference in initial GFR was seen: 166 ml/min +/- 15.4 in those with high UAE at follow-up versus 138 +/- 8.6 in patients with normal UAE at follow-up (2p = 0.2%). The GFR at follow-up was significantly decreased in diabetics with high follow-up UAE (mean values 166----80 ml/min) but stable in patients with low UAE (138----132 ml/min). Initial blood pressure, plasma glucose and RPF were not different between groups. Marked glomerular hyperfiltration, whatever its cause, may contribute to late glomerular damage in diabetic nephropathy. Early measurements of GFR and UAE can be used to identify patients at risk of subsequently developing nephropathy.     

Effects of acute protein loads of different sources on renal function of patients with diabetic nephropathy

To evaluate effects of acute loading of different proteins on renal function, glomerular filtration rate (GFR), albumin excretion rate (AER), and concentrations of plasma amino acids, 11 normal volunteers and 20 diabetic patients were studied before and after eating 1.0 g/kg body weight of either tuna fish meal or bean curd on separate days. In normal subjects, the mean baseline GFR was 115.8 +/- 9.5 ml/min/1.73 m2, and the mean GFRs after ingestion of tuna fish meal were 134.1 +/- 15.5 (1 hr), 146.2 +/- 18.8 (2 hr), and 157.8 +/- 21.2 (3 hr), respectively. GFR did not significantly increase in normal subjects after ingestion of bean curd. GFR in diabetic patients with normoalbuminuria after ingestion of each protein was similar to the response in normal subjects. In diabetic patients with microalbuminuria, GFR did not significantly increase after ingestion of each protein. In diabetes with macroalbuminuria, GFR decreased after ingestion of tuna fish meal and did not significantly change after intake of bean curd. In both normal subjects and diabetic patients, urinary AER did not increase after each kind of protein loading. Plasma concentrations of alanine, glycine, and arginine, known to induce glomerular hyperfiltration, increased to a greater degree after ingestion of tuna fish meal than after administration of bean curd. These findings suggest that responses of GFR to acute protein loading may differ according to the amino acid composition of the protein ingested and to the stage of diabetic nephropathy.     

Enhanced GFR response to oral versus intravenous arginine administration in normal adults.

Both oral protein ingestion and intravenous amino acid infusions have been shown to increase glomerular filtration rate (GFR) and renal plasma flow (RPF) in normal subjects. Although the mechanism of this effect is not known, the renal responses to these loads have been associated with increases in peripheral glucagon concentrations. Conflicting data exist concerning the role of glucagon in the hyperfiltration response after an oral protein meal or administration of an intravenous amino acid mixture. Using a single amino acid as the stimulus for hyperfiltration, we compared the renal responses in six normal subjects to 30 gm oral arginine-HCl, intravenous arginine-HCl, and intravenous glucagon infused at the rate of 10 ng/kg/min. GFR, RPF, and glucagon concentration, as well as levels of plasma amino acids and selected gastrointestinal hormones, were measured for six 30-minute clearance periods after each load. Significant rises in mean peak GFR were noted after both oral arginine (104 +/- 5 ml/min x 1.73 m2 to 145 +/- 9 ml/min x 1.73 m2, p less than 0.02) and intravenous arginine (118 +/- 10 ml/min x 1.73 m2 to 134 +/- 11 ml/min x 1.73 m2, p = 0.02) administration. Mean peak RPF rose significantly after oral arginine (510 +/- 26 ml/min x 1.73 m2 to 710 +/- 32 ml/min x 1.73 m2, p less than 0.01) but not after intravenous arginine (616 +/- 60 ml/min x 1.73 m2 to 687 +/- 64 ml/min x 1.73 m2, p = 0.18). Intravenous glucagon infusion also increased both mean peak GFR (99 +/- 9 ml/min x 1.73 m2 to 149 +/- 10 ml/min x 1.73 m2, p less than 0.01) and RPF (514 +/- 48 ml/min x 1.73 m2 to 771 +/- 38 ml/min x 1.73 m2, p less than 0.01) significantly. We found the mean peak percent rise in GFR (43% +/- 13%) and RPF (42% +/- 12%) after oral arginine to be notably greater than that after intravenous arginine (14% +/- 5% and 13% +/- 9%, respectively). However, the mean peak percent rise in glucagon concentration after oral arginine was significantly lower than that after intravenous arginine (62% +/- 25% versus 479% +/- 176%, respectively, p = 0.04). Infusion of glucagon increased GFR (54% +/- 13%) and RPF (55% +/- 12%) to a degree similar to that seen after oral arginine, but again with a significantly higher mean peak percent rise in peripheral glucagon concentrations when compared with the rise after oral arginine (798% +/- 348% vs 62% +/- 25%, p less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)     

Atrial natriuretic peptide protects against acute ischemic renal failure in the rat.

Because of its ability to increase glomerular filtration, antagonize the actions of vasoconstrictors, and produce vasodilation, alpha human atrial natriuretic peptide (alpha-hANP) was evaluated for its potentially beneficial effects in experimental ischemic renal failure induced by 45-60 min of renal artery occlusion in bilaterally or unilaterally renally intact Sprague-Dawley rats. After ischemia, a 4-h intrarenal infusion of alpha-hANP restored 14C-inulin clearances in bilaterally and unilaterally intact animals from 0.05 +/- 0.006 and 0.05 +/- 0.01 ml/min per 100 g to 0.314 +/- 0.04 and 0.25 +/- 0.01 ml/min per 100 g, respectively (P less than 0.001, n = 8), compared with normal values of 0.49 +/- 0.023 ml/min per 100 g. Histologically, there was a progressive decrease in medullary hyperemia and prevention of intratubular cell shedding and granulocyte margination as a result of the 4-h alpha-hANP infusion such that after 24 and 48 h the histological appearance of the tissue was essentially normal. The results show that a 4-h intrarenal infusion of alpha-hANP after renal ischemia can preserve glomerular filtration rate and reduce renal tissue damage.     

Tertatolol ameliorates renal function in rats with chronic renal failure

Tertatolol is a new beta-blocking agent which induces renal vasodilation in experimental animals and humans and increases glomerular filtration rate (GFR), diuresis and natriuresis. The mechanisms underlying renal effects of tertatolol are not known. Our aims were to establish whether tertatolol influences renal function by a systemic or by an intrarenal effect and to assess whether tertatolol could maintain GFR in chronic renal failure. Tertatolol but not propranolol when given as i.v. bolus injection at the dose of 25 and 50 micrograms/kg. b.w. induces a significant increase in GFR and perfusate flow rate (PFR) in an isolated perfused kidney model [GFR: tertatolol, 25 micrograms/kg; preinjection: 0.477 +/- 0.077 ml/min/g of kidney; 30 min postinjection: 0.996 +/- 0.114 ml/min/g of kidney. Tertatolol (50 micrograms/kg) preinjection: 0.517 +/- 0.040 ml/min/g of kidney; 30 min postinjection: 0.879 +/- 0.035 ml/min/g of kidney. Propranolol (500 micrograms/kg) preinjection: 0.574 +/- 0.045 ml/min/g of kidney; 30 min postinjection: 0.538 +/- 0.029 ml/min/g of kidney. PFR: tertatolol, 25 micrograms/kg, preinjection: 30.00 +/- 0.79 ml/min; 30 min postinjection: 36.20 +/- 2.58 ml/min. Tertatolol (50 micrograms/kg) preinjection: 29.30 +/- 1.44 ml/min; 30 min postinjection: 38.01 +/- 1.87 ml/min. Propranolol (500 micrograms/kg) preinjection: 28.70 +/- 1.04 ml/min; 30 min postinjection: 28.30 +/- 0.91 ml/min]. In the same preparation tertatolol significantly increases urine flow rate and Na+ excretion [urine flow rate: tertatolol (25 micrograms/kg) preinjection: 28.28 +/- 4.10 microliter/min; 60 min postinjection: 38.23 +/- 6.74 microliter/min. Tertatolol (50 micrograms/kg) preinjection: 24.02 +/- 0.63 microliter/min; 60 min postinjection: 33.18 +/- 2.07 microliter/min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glomerular prostaglandin and thromboxane synthesis in rat nephrotoxic serum nephritis. Effects on renal hemodynamics.

Glomerular arachidonate cyclooxygenation by isolated rat glomeruli was assessed in vitro in antiglomerular basement membrane (anti-GBM) antibody-induced glomerulonephritis by radioimmunoassay for prostaglandins (PG) and thromboxane. After a single intravenous injection of rabbit anti-rat GBM serum, we observed enhancement of glomerular thromboxane B2 (TxB2) synthesis as early as 2 to 3 h with smaller increments in PGF2 alpha, PGE2 and 6-keto-PGF1 alpha synthetic rates. On day 2 of the disease, the glomerular synthesis of TxB2 and, to a lesser extent, PGF2 alpha and PGE2 remained enhanced, whereas on days 8, 11, and 14, TxB2 was the only prostanoid synthesized at increased rates. Glomerular TxB2 synthesis correlated with the presacrifice 24-h protein excretion. 60 min after intravenous infusion of anti-GMB serum, glomerular filtration rate (GFR) decreased (0.66 +/- 0.04 to 0.44 +/- 0.03 ml/min per 100 g, P less than 0.05), without a significant change in renal plasma flow (RPF): 1.97 +/- 0.23 to 1.80 +/- 0.23 ml/min per 100 g) and without a change in glomerular PG synthetic rates. At 2 h, GFR and RPF reached a nadir (0.25 +/- 0.04 and 1.3 +/- 0.1 ml/min per 100 g, respectively) coinciding with a fivefold increment in glomerular TxB2. By 3 h GFR and RPF partially recovered to 0.43 +/- 0.07 and 1.77 +/- 0.20 ml/min per 100 g, respectively, P less than 0.05, despite further increments in TxB2 synthesis. This recovery of GFR and RPF coincided with increments in vasodilatory PG, (PGE2 and PGI2). The thromboxane synthetase inhibitor OKY-1581 markedly inhibited platelet and glomerular TxB2 synthesis and preserved GFR at 1, 2, and 3 h. Another thromboxane synthetase inhibitor, UK-38485, also completely inhibited platelet and glomerular TxB2 synthesis and prevented decrements of GFR at 2 and 3 h. A cyclooxygenase inhibitor, ibuprofen, inhibited platelet TxB2 and PGE2 synthesis and significantly reduced glomerular PGE2 but not TxB2 synthesis. In the ibuprofen-treated rats, the partial recoveries of GFR and RPF at 3 h were attenuated. The in vitro glomerular TxB2 synthesis correlated inversely with the presacrifice GFR and filtration fraction. These observations indicate that in anti-GBM nephritis there is enhanced synthesis of TxA2 and PG in the glomerulus that mediate changes in renal hemodynamics.     

Theophylline improves early allograft function in rat kidney transplantation

Several previous studies have demonstrated a beneficial effect of the adenosine receptor (AdoR) antagonist theophylline in different forms of acute renal failure in laboratory animals and in humans. Therefore, we wanted to test whether theophylline can also improve impaired allograft function following ischemia reperfusion injury in experimental kidney transplantation (KT). Orthotopic transplantation of the left kidney was performed from Fisher 344 into Lewis rats. All transplanted rats received daily cyclosporine (5 mg/kg). The effect of theophylline treatment (10 mg/kg) on graft function was compared with appropriate controls on day 5 after KT by assessment of glomerular filtration rate (GFR) (inulin clearance). On day 5, GFR of allografts in control rats was 0.23 +/- 0.05 ml/min/g kidney weight (n = 10) compared with 0.50 +/- 0.09 ml/min/g in rats receiving theophylline (n = 9, p < 0.01), representing a 2-fold increase in GFR. Renal AdoR A(1) mRNA content was significantly increased in both KT groups compared with their respective control groups, whereas mRNA of AdoR A(2a), A(2b), and A(3) were found to be unchanged. Theophylline did not affect significantly interstitial infiltration of the graft by monocytes/macrophages and T-cells. Likewise, serum cytokines [interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor-alpha] and erythropoietin plasma levels were not different among the allograft groups. The present study demonstrates that theophylline remarkably improved early renal allograft function in rats undergoing KT without influencing cytokine serum patterns or tissue inflammation. Since theophylline is a commonly used medication in humans, clinical studies in patients undergoing KT are warranted.     

Caffeine and theophylline attenuate adenosine-induced vasodilation in humans

In this study the local vasoactive effects of adenosine were explored in the human forearm. Adenosine (15 micrograms/100 ml forearm/min) infused into the brachial artery (n = 6) increased forearm blood flow by 572% +/- 140%, versus - 0.5% +/- 5.8% during placebo infusion (p less than 0.01). Lower adenosine infusion rates (5 micrograms/100 ml forearm/min, three times) induced forearm blood flow increments to 330% +/- 94%, 339% +/- 67% and 330% +/- 79%, respectively (n = 8). These forearm blood flow responses were reduced (p = 0.02) during concomitant intra-arterial infusion of two doses of caffeine (30 and 90 micrograms/100 ml forearm/min) to 150% +/- 45% and 98% +/- 28%, respectively. Theophylline (30 micrograms/100 ml forearm/min; n = 6) also significantly attenuated the adenosine-induced increase in forearm blood flow. Enprofylline (30 micrograms/100 ml forearm/min), a related xanthine with a low affinity to adenosine receptors in vitro, did not change the response to adenosine. Nonspecific vasodilation by sodium nitroprusside infusion (50 ng/100 ml forearm/min) was not inhibited by caffeine compared with placebo (forearm blood flow responses were 202% +/- 21% versus 216% +/- 40%; n = 6). This study demonstrated that caffeine and theophylline specifically reduce adenosine-induced vasodilation in humans, supporting the existence of functional human vascular adenosine receptors.     

Mechanisms of amphotericin B-induced decrease in glomerular filtration rate in rats.

Mechanisms responsible for the reductions in renal blood flow (RBF) and glomerular filtration rate (GFR) in response to acute infusions of amphotericin B were investigated in vivo in rats. The influence of salt status and the roles of adenosine, cyclic AMP, and calcium influx were examined. Amphotericin B was infused into the renal artery in seven groups of rats at 0.025 mg/kg of body weight per min for 15 min. RBF and GFR were measured over 15 min before, during, and after the infusion. Control rats were maintained on a normal salt diet; a second group of rats received a salt-depleted diet, and a third group received a high-salt intake. Four other groups were kept on a normal diet and received theophylline (0.5 mumol/kg/min into the renal artery, intra-arterially [i.a.]), dibutyryl cyclic AMP (85 micrograms/min, i.a.), the 5'-nucleotidase inhibitor adenosine alpha,beta-methylene diphosphate (4 mg/kg, intramuscularly), or diltiazem (20 micrograms/kg/min, i.a.). Control rats had a prompt 50% decrease in RBF in response to amphotericin B. This was sustained over the 15-min infusion period and was accompanied by a decrease in creatinine clearance (CLCR) (from 0.83 +/- 0.08 to 0.40 +/- 0.09 ml/min; P less than 0.05). On stopping the infusion, RBF returned quickly to baseline but CLCR continued to decrease further (to 0.35 +/- 0.07 ml/min; P less than 0.05). Salt loading, theophylline, and diltiazem administration prevented the decreases in both RBF and CLCR. Both RBF and CLCR responses in the remaining groups were not significantly different from those in controls. The results of this study reveal a protective effect of salt loading and theophylline against amphotericin B nephrotoxicity in the rat but deny a role for adenosine in mediating these effects. They further suggest that theophylline inhibits the acute responses by a mechanism unrelated to either adenosine receptor blockade or phosphodiesterase inhibition and that calcium influx into the cells is probably responsible for the acute changes in RBF and GFR in response to amphotericin B.     

Relationship between glomerular hyperfiltration and ACE insertion/deletion polymorphism in type 1 diabetic children and adolescents

OBJECTIVE: Glomerular hyperfiltration may predict diabetic nephropathy in type 1 diabetes, and some studies suggest that the ACE D allele is associated with diabetic nephropathy. The aim of this study was to examine a possible relationship between glomerular hyperfiltration and ACE insertion/deletion (I/D) polymorphism in type 1 diabetic children and adolescents. RESEARCH DESIGN AND METHODS: A cross-sectional study was conducted to examine the relationship between glomerular hyperfiltration and ACE (I/D) polymorphism in 76 type 1 diabetic children and adolescents without diabetic nephropathy (mean +/- SD: age 16 +/- 3 years; diabetes duration 7 +/- 4 years; age at diabetes onset 9 +/- 4 years; HbA1c 9.5 +/- 1.9%). Glomerular hyperfiltration (defined as a glomerular filtration rate [GFR] > or = 135 ml.min-1. 1.73 m-2 and by 51Cr-labeled EDTA plasma disappearance technique) and ACE I/D genotypes and plasma levels (enzyme-linked immunosorbent assay [ELISA] method) were determined. RESULTS: Of the patients, 29 (38%) displayed glomerular hyperfiltration. An association between glomerular hyperfiltration and ACE (I/D) polymorphism was observed (chi 2 = 7.09, P = 0.029) because of a reduced proportion of DD genotypes among patients with glomerular hyperfiltration (4 vs. 19; chi 2 = 6.03, P = 0.014) and not because of an excess of the II genotype (5 vs. 9; chi 2 = 0.04, P = 0.83). Age, diabetes duration, age at diabetes onset, and HbA1c were not different according to genotype. Patients with glomerular hyperfiltration had low plasma ACE levels, compared with those with normal glomerular filtration (457 +/- 157 vs. 553 +/- 186 micrograms/l; P = 0.027). CONCLUSIONS: These results suggest an unexpected association between glomerular hyperfiltration and ACE (I/D) polymorphism, characterized by a defect of the DD genotype among type 1 diabetic children and adolescents with glomerular hyperfiltration.     

Glomerular filtration rate and kidney volume in normoalbuminuric non-insulin-dependent diabetics--lack of glomerular hyperfiltration and renal hypertrophy in uncomplicated NIDDM

Glomerular filtration rate (GFR) and kidney volume were evaluated in 18 healthy normoalbuminuric non-insulin-dependent diabetic patients and compared to 12 healthy controls matched for sex, age and body mass index (BMI). The patients (12 males, six females) were 61.6 +/- 3.4 (mean +/- SD) years old, the known diabetes duration was 5 +/- 4.8 years, fasting plasma glucose 8.6 +/- 2.3 mmol/l, urinary albumin excretion rate 7.9 x/divided by 2.0 micrograms/min, BMI 26.8 +/- 2.8 kg/m2 and blood pressure systolic/diastolic 145 +/- 19/82 +/- 7 mmHg. The GFR was measured by the plasma clearance of [51Cr]EDTA, using a single shot procedure. The kidney volume was measured by ultrasonic scanning. The GFR was not increased in diabetics: 100.4 +/- 16.7 ml/min/1.73 m2 as compared to controls: 93.8 +/- 11.4 ml/min/1.73 m2. The kidney volume was similar in the two groups. Diabetics: 231.1 +/- 33.4 ml/1.73 m2. Controls: 236.3 +/- 45.7 ml/1.73 m2. There was a borderline significant correlation between kidney volume and GFR (r = 0.40, p = 0.10) in diabetics. No correlation between glycosylated haemoglobin and GFR was found in diabetics. In contrast to the findings in insulin-dependent diabetes renal hypertrophy and hyperfunction were not characteristic features in this series of non-insulin-dependent diabetics. It is suggested that diabetic glomerulopathy is not always a consequence of long-standing hyperfiltration.