Cyclosporine-induced hypertension and decline in renal function in healthy volunteers

OBJECTIVE: To investigate the effect of cyclosporine A (CsA; Sandimmun Neoral) on systemic and renal hemodynamics, tubular function, and sodium excretion in healthy volunteers. Furthermore, we studied whether CsA enhances the systemic and renal hemodynamic sensitivity to norepinephrine. METHODS: Eighteen healthy volunteers were administered 10 mg/kg CsA or placebo capsules in a double-blind fashion. The mean arterial blood pressure (MAP), renal vascular resistance (RVR), glomerular filtration rate (GFR), and renal clearances of lithium (CLi) and sodium (CNa) were measured for 8 h after ingestion of the capsules. Norepinephrine (2 microg/kg per h) was infused intravenously for 1.5 h into nine subjects. RESULTS: CsA increased the MAP by 17+/-2 mmHg. The GFR decreased by 18+/-2% (P < 0.001) and the RVR increased by 37+/-4% (P< 0.001) after ingestion of CsA. The CsA-induced increase in MAP preceded the CsA-induced fall in GFR. The rise in MAP was followed by an early 35+/-8/0 increase in CNa (P < 0.001). At the end of the 8 h study period, CNa decreased by 25+/-7% (P < 0.001). Using CLi, it was found that the initial natriuresis had been caused by a relative decrease both in proximal and in distal tubular reabsorption of sodium, whereas the late sodium retention was secondary to the CsA-induced fall in GFR. Infusion of norepinephrine increased the MAP, RVR, and filtration fraction, and decreased the renal plasma flow, without CsA having any additional effect. CONCLUSION: It was demonstrated that a single oral dose of CsA caused a rise in blood pressure and transient natriuresis, followed by a fall in GFR and antinatriuresis. Thus, the present study confirms and extends earlier observations that renal dysfunction and sodium retention are not the initiating events in CsA-induced hypertension. The study also affords evidence suggesting that such rises in blood pressure are not mediated by an increased sensitivity to norepinephrine.     

Prevention of hypoxemia-induced renal dysfunction by perindoprilat in the rabbit

The role of angiotensin II, a potent postglomerular vasoconstrictor, in the hypoxemia-induced renal changes is still controversial. The ability of perindoprilat, an angiotensin converting-enzyme inhibitor, to prevent the acute renal effects of hypoxemia was assessed in 22 anesthetized-ventilated rabbits. In 8 untreated rabbits, hypoxemia induced a significant drop in mean blood pressure (MBP) (-12 +/- 2%), glomerular filtration rate (GFR) (-16 +/- 3%) and renal blood flow (RBF) (-12 +/- 3%) with a concomittant increase in renal vascular resistance (RVR) (+18 +/- 5%) and urine flow rate (+33 +/- 14%), and without any changes in filtration fraction (FF) (-4 +/- 2%). This suggests the occurrence of glomerular vasoconstriction during the hypoxemic stress. In 7 normoxemic rabbits, intravenous perindoprilat (20 microg/kg) induced an increase in urine flow rate (+17 +/- 4%) and RBF (+17 +/- 4%), and a decrease in MBP (-6 +/- 1%), RVR (-14 +/- 3%) and FF (-11 +/- 2%) without a significant change in GFR. The drop in FF and the increase in RBF suggests preferential postglomerular vasodilatation. In 7 rabbits, perindoprilat prevented the occurence of the hypoxemia-induced changes in RBF and RVR without improving MBP. FF decreased significantly (-18 +/- 2%), while the drop in GFR (-7 +/- 2%) was partially blunted and the increase in urine flow rate (+25 +/- 9%) was confirmed. These results could be explained by the inhibition of the angiotensin-mediated efferent vasoconstriction and by the inhibition of bradykinin degradation by perindoprilat. These data confirm the ability of converting-enzyme inhibitors to prevent the renal hypoperfusion induced by acute hypoxemia.     

The effect of felodipine on renal function and blood pressure in cyclosporin-treated renal transplant recipients during the first three months after transplantation

BACKGROUND: Due to their vasodilatory effect, calcium antagonist may have a renoprotective against cyclosporin (CsA)-induced nephrotoxicity and rise in blood pressure (BP) seen in renal transplantation. METHODS: In order to evaluate the effect of the calcium antagonist felodipine on renal function and BP during cyclosporin treatment, 79 CsA-treated renal transplant recipients were investigated during the first 3 months after transplantation in a randomized, double-blind, placebo-controlled study with two parallel groups. Felodipine (ER tablets, 10 mg) or placebo was given prior to transplantation and each day during the study period. The patients were assessed twice, i.e. at 4-6 weeks and at 10-12 weeks after transplantation. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured by constant infusion technique. Tubular function was estimated from clearance of lithium. RESULTS: At 6 weeks after transplantation, felodipine caused a significantly higher RPF [felodipine: 219 +/- 70 ml/min; placebo: 182+/-56 ml/min (mean+/-1 SD); P=0.03]. No differences were found in GFR, filtration fraction (FF), tubular sodium handling, or sodium excretion. Felodipine lowered BP significantly. At 12 weeks after transplantation, felodipine caused a significantly higher GFR (felodipine: 49+/-18 ml/min; placebo: 40+/-16 ml/min; P=0.05) and RPF (felodipine: 225+/-77 ml/min; placebo: 175+/-48 ml/min; P<0.01). No difference was found in FF. Felodipine lowered BP significantly. No differences were found with regard to duration of primary anuria, hospitalization time, number of rejection episodes, plasma creatinine day 7 post-transplant, or treatment doses of CsA. CONCLUSIONS: It is concluded that in renal transplant recipients treated with CsA, felodipine significantly increased both GFR and RPF 3 months after transplantation when compared with placebo, despite a concomitant lowering of BP. A possible antagonizing affect of felodipine against CsA-induced nephrotoxicity in these patients is suggested.     

Effects of natriuretic peptide receptor inhibition on remnant kidney function in rats

To identify the contribution of natriuretic peptide (NP) activity to the adaptative increases in glomerular filtration rate (GFR), effective renal plasma flow rate (ERPF) and fractional sodium excretion (FENa) observed in the remnant kidney, we investigated the acute effects of administering HS-142-1 (HS), a potent NP receptor antagonist, in 5/6th nephrectomized (NPX) rats. In addition to normal sodium intake, high or low sodium intakes were used to stimulate or suppress, respectively, endogenous NP activity in NPX rats. In rats three days after NPX on high sodium, HS (20 mg/kg bolus i.v.) reduced GFR from 0.55 +/- 0.05 to 0.35 +/- 0.04 ml/min; ERPF from 1.83 +/- 0.19 to 1.53 +/- 0.16 ml/min; and FENa from 7.1 +/- 1.1 to 1.6 +/- 0.4%, without affecting MAP. Similar changes of lesser magnitude were observed in NPX rats on normal sodium intake. By contrast, GFR, ERPF, FENa and MAP were unchanged following HS in NPX rats on low sodium intake, suggesting that the magnitude of responses to HS is dependent upon the expected levels of activity of NP. We conclude that in anesthetized rats, natriuretic peptides contribute to the compensatory increases in GFR, ERPF and FENa observed in the remnant kidney under normal and salt-replete conditions.     

Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. "Gruppo Italiano di Studi Epidemiologici in Nefrologia" (GISEN)

We investigated the predictors of the rate of glomerular filtration rate decline (delta GFR) and progression to end-stage renal failure (ESRF) in the 352 patients with proteinuric non-diabetic chronic nephropathies [urinary protein excretion rate (UProt) > or = 1 g/24 hr, creatinine clearance 20 to 70 ml/min/1.73 m2] enrolled in the Ramipril Efficacy In Nephropathy (REIN) study. Overall the GFR declined linearly by 0.46 +/- 0.05 ml/min/1.73 m2/month (mean rate +/- SEM) over a median follow-up of 23 months (range 3 to 64 months), and progression to ESRF was 17.3%. Using multivariate analysis, higher UProt and mean arterial pressure (MAP) independently correlated with a faster delta GFR (P = 0.0001 and P = 0.0002, respectively) and progression to ESRF (P = 0.0001 and P = 0.003, respectively). Mean UProt and systolic blood pressure during follow-up were the only time-dependent covariates that significantly correlated with delta GFR (P = 0.005 and P = 0.003, respectively) and ESRF (P = 0.006 and P = 0.0001, respectively). After stratification for baseline UProt, patients in the lowest tertile (UProt < 1.9 g/24 hr) had the slowest delta GFR (0.16 +/- 0.07 ml/min/1.73 m2/month) and progression to ESRF (4.3%) as compared with patients in the middle tertile (UProt 2.0 to 3.8 g/24hr; delta GFR, 0.55 +/- 0.09 ml/min/1.73 m2/month, P = 0.0002; ESRF, 15.3%, P = 0.0001) and in the highest tertile (UProt 3.9 to 18.8 g/24 hr; delta GFR, 0.70 +/- 0.11 ml/min/1.73 m2/month, P = 0.0001; ESRF, 32.5%, P = 0.0001). Both delta GFR (P = 0.01) and progression to ESRF (P = 0.01) significantly differed even between the middle and the highest tertiles. On the contrary, stratification in tertiles of baseline MAP failed to segregate subgroups of patients into different risk levels. Patients with the highest proteinuria and blood pressure were those with the fastest progression (delta GFR, 0.91 +/- 0.23; ESRF 34.7%). Of interest, at each level of baseline MAP, a higher proteinuria was associated with a faster delta GFR and progression to ESRF. On the other hand, at each level of proteinuria, a faster delta GFR was associated with MAP only in the highest tertile (> 112 mm Hg) and the risk of ESRF was independent of the MAP. Thus, in chronic nephropathies proteinuria is the best independent predictor of both disease progression and ESRF. Arterial hypertension may contribute to the acceleration of renal injury associated with enhanced traffic of plasma proteins. Antihypertensive drugs that most effectively limit protein traffic at comparable levels of blood pressure are those that most effectively slow disease progression and delay or prevent ESRF in proteinuric chronic nephropathies.     

Renal reserve filtration capacity in growth hormone deficient subjects

In normal subjects, the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) acutely increase in response to infusion of amino acids and to low doses of dopamine. It is uncertain whether circulatory growth hormone (GH) is a permissive factor for these stimulatory effects. GFR and ERPF (constant infusion technique using 125I-iothalamate and 131I-hippuran, respectively) were measured before and during the infusion of dopamine and amino acids in 8 GH deficient subjects. The clearance study was repeated during concomitant administration of octreotide to investigate whether this somatostatin analogue would modify the amino acid and dopamine-induced renal haemodynamic changes. Dopamine increased baseline GFR from 89 +/- 3 (mean +/- SEM, n = 8) to 102 +/- 4 ml min-1 1.73 m-2 and ERPF from 352 +/- 19 to 476 +/- 26 ml min-1 1.73 m-2, P less than 0.001 for both. During amino acid infusion GFR and ERPF increased to 108 +/- 3 and 415 +/- 23 ml min-1 1.73 m-2, respectively, P less than 0.001 for both. Octreotide did not significantly decrease baseline and dopamine-stimulated renal haemodynamics but lowered the amino acid-stimulated GFR (98 +/- 4 ml min-1 1.73 m-2, P less than 0.05) and ERPF (381 +/- 18 ml min-1 1.73 m-2, P less than 0.05). Basal plasma glucagon concentrations were not suppressed by octreotide, whereas the amino acid-induced increments in plasma glucagon were partially inhibited. It is concluded that GH is not a necessary factor for the stimulatory effects of amino acids and dopamine on renal haemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of prostaglandins and nitric oxide on the renal effects of angiotensin II in the anaesthetized rat

1. The potential influences of nitric oxide (NO) and prostaglandins on the renal effects of angiotensin II (Ang II) have been investigated in the captopril-treated anaesthetized rat by examining the effect of indomethacin or the NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), on the renal responses obtained during infusion of Ang II directly into the renal circulation. 2. Intrarenal artery (i.r.a.) infusion of Ang II (1-30 ng kg(-1) min(-1)) elicited a dose-dependent decrease in renal vascular conductance (RVC; -38+/-3% at 30 ng kg(-1) min(-1); P < 0.01) and increase in filtration fraction (FF; +49+/-8%; P < 0.05) in the absence of any change in carotid mean arterial blood pressure (MBP). Urine output (Uv), absolute (UNaV) and fractional sodium excretion (FENa), and glomerular filtration rate (GFR) were unchanged during infusion of Ang II 1-30 ng kg(-1) min(-1) (+6+/-17%, +11+/-17%, +22+/-23%, and -5+/-9%, respectively, at 30 ng kg(-1) min(-1)). At higher doses, Ang II (100 and 300 ng kg(-1) min(-1)) induced further decreases in RVC, but with associated increases in MBP, Uv and UNaV. 3. Pretreatment with indomethacin (10 mg kg(-1) i.v.) had no significant effect on basal renal function, or on the Ang II-induced reduction in RVC (-25+/-7% vs -38+/-3% at Ang II 30 ng kg(-1) min(-1)). In the presence of indomethacin, Ang II tended to cause a dose-dependent decrease in GFR (-38+/-10% at 30 ng kg(-1) min(-1)); however, this effect was not statistically significant (P=0.078) when evaluated over the dose range of 1-30 ng kg(-1) min(-1), and was not accompanied by any significant changes in Uv, UNaV or FENa (-21+/-12%, -18+/-16% and +36+/-38%, respectively). 4. Pretreatment with L-NAME (10 microg kg(-1) min(-1) i.v.) tended to reduce basal RVC (control -11.8+/-1.4, +L-NAME -7.9+/-1.8 ml min(-1) mmHg(-1) x 10(-2)), and significantly increased basal FF (control +15.9+/-0.8, +L-NAME +31.0+/-3.7%). In the presence of L-NAME, renal vasoconstrictor responses to Ang II were not significantly modified (-38+/-3% vs -35+/-13% at 30 ng kg(-1) min(-1)), but Ang II now induced dose-dependent decreases in GFR, Uv and UNaV (-51+/-11%, -41+/-14% and -31+/-17%, respectively, at an infusion rate of Ang II, 30 ng kg(-1) min(-1)). When evaluated over the range of 1-30 ng kg(-1) min(-1), the effect of Ang II on GFR and Uv were statistically significant (P < 0.05), but on UNaV did not quite achieve statistical significance (P=0.066). However, there was no associated change in FENa observed, suggesting a non-tubular site of interaction between Ang II and NO. 5. In contrast to its effects after pretreatment with L-NAME alone, Ang II (1-30 ng kg(-1) min(-1)) failed to reduce renal vascular conductance in rats pretreated with the combination of L-NAME and the selective angiotensin AT1 receptor antagonist, GR117289 (1 mg kg(-1) i.v.). This suggests that the renal vascular effects of Ang II are mediated through AT1 receptors. Over the same dose range, Ang II also failed to significantly reduce GFR or Uv. 6. In conclusion, the renal haemodynamic effects of Ang II in the rat kidney appear to be modulated by cyclooxygenase-derived prostaglandins and NO. The precise site(s) of such an interaction cannot be determined from the present data, but the data suggest complex interactions at the level of the glomerulus.     

Reduction of renal functional reserve in kidney transplant recipients: a possible role of arachidonic acid metabolism alterations

AIM: Renal functional reserve (RFR), resulting from an increase in glomerular filtration (GFR) after protein load, is a matter of debate. In kidney transplant recipients most studies have failed to show conclusive results, reporting either the absence, the reduction or the presence of renal reserve in normo-functioning kidneys. The aim of this study was to investigate RFR in kidney transplant patients as well as the possible hormonal vasoactive alterations underlying the reduction of renal reserve reported in some patients. PATIENTS AND METHODS: We studied 8 controls and 25 patients, the latter with no history of acute rejection for at least 12 months and GFR >50 ml/min. The 25 patients were divided into 2 groups based on the presence (10) or the absence (15) of RFR. RESULTS: Both the RFR group and the controls experienced a similar increase of GFR after oral protein load: 24.3 +/- 15.57% vs 24.4 +/- 10.8%. The group without RFR showed a paradoxical reduction of GFR after oral protein load: 13.3 +/- 13.2% (p <0.001). We analyzed the filtration fraction (FF) and observed that the group without RFR had higher values than the group with RFR and the controls: 0.35 +/- 0.11 vs 0.29 +/- 0.07 (p = 0.01) and vs 0.26 +/- 0.02 (p = 0.04). The hyperfiltration state observed in the group without RFR was sustained by a high level of thromboxane. The urine ratio TxB2/6ketoPgF1alpha was higher in the group without RFR than in the RFR group 0.78 +/- 0.2 vs 0.64 +/- 0.1 (p = 0.01). This ratio decreased only in the RFR group after a meat meal. In all the patients, changes of TxB2/6ketoPGF1alpha were inversely correlated to changes of GFR after a meat meal (r = -0.6, p = 0.01). CONCLUSIONS: In conclusion, these data demonstrate that kidney transplant recipients with good organ function can be grouped according to the presence of RFR. RFR appears to be inversely correlated with the TxB2/6ketoPGF1alpha ratio, and its decrease seems to be linked to the failure of thromboxane to decrease and prostacycline to increase after a meat meal.     

A micropuncture study of the renal response to haemorrhage in rats: assessment of the role of vasopressin

The acute effects of haemorrhage (15 ml (kg body wt)-1) on renal function at whole-kidney and single-nephron levels were studied in Inactin-anaesthetized rats. In order to assess the role of vasopressin in mediating the haemodynamic effects, responses in untreated Long-Evans rats were compared with those in Brattleboro rats (which lack circulating vasopressin) and in Long-Evans rats treated with a V1 receptor antagonist. In time-control animals, there were no significant changes in mean arterial pressure (MAP), excretion rates, glomerular filtration rate (GFR), superficial-nephron GFR (SNGFR) or fluid reabsorption in the superficial proximal tubules during the course of the experiment. Following haemorrhage, the immediate reduction in MAP was followed in each group by partial recovery for 30 min; thereafter, MAP was stable. In untreated Long-Evans rats, haemorrhage was followed by a 26% reduction in GFR (P < 0.001, measured 60-150 min post-haemorrhage) and a larger reduction (45%, P < 0.001) in SNGFR, so that the SNGFR/GFR ratio fell significantly ((27.9 +/- 1.9) x 10(-6), control period; (20.2 +/- 2.2) x 10(-6) post-haemorrhage, P < 0.01). Slightly greater reductions in GFR and SNGFR were seen in Brattleboro rats and V1 antagonist-treated Long-Evans rats, which corresponded to slightly greater haemorrhage-induced reductions in blood pressure in these groups; the falls in the SNGFR/GFR ratio were similar to that in untreated Long-Evans rats. In all three groups of bled rats, fractional reabsorption by the proximal convoluted tubule increased slightly 30-60 min after haemorrhage, but during the subsequent period (60-150 min) returned to values indistinguishable from those during the control period. The results suggest that the renal haemodynamic changes that follow moderate haemorrhage include a preferential reduction in the GFR of superficial nephrons. Vasopressin appears to play no role in this response. Increases in fractional reabsorption in the proximal tubules are seen only during the immediate post-haemorrhage period.     

Impact of gender on the renal response to angiotensin II

BACKGROUND: It is clear that women with renal disease progress to end stage at a slower rate than do men. We hypothesized that this protection may result from gender-mediated differences in responses to angiotensin II (Ang II), which has known hemodynamic effects that are thought to promote renal disease progression. We examined sex differences in renin-angiotensin system (RAS) function by measuring renal hemodynamic function and circulating plasma components of the RAS at baseline and in response to graded infusions of Ang II. METHODS: We studied two groups of normal healthy subjects, 24 men and 24 women, mean age 28 +/- 1 years, ingesting a controlled sodium and protein diet. We examined baseline concentrations of angiotensin converting enzyme, plasma renin activity, Ang II, and aldosterone. Inulin and paraaminohippurate clearance techniques were used to estimate effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) at baseline and in response to graded Ang II infusion (0.5, 1.5, and 2.5 ng/kg/min). RESULTS: Mean baseline values for mean arterial pressure and aldosterone were lower in women, whereas values for plasma Ang II, GFR, ERPF, and filtration fraction (FF) did not differ. In response to Ang II, both groups exhibited a similar increase in mean arterial pressure and a decline in ERPF. GFR was maintained during Ang II infusion only in men, resulting in an augmentation of FF. In women, GFR declined in parallel with ERPF, and the FF response was significantly blunted. 17beta-Estradiol plasma concentrations influenced the ERPF response to Ang II infusion, with higher levels predicting a blunting of the decrease. The GFR response was not affected. CONCLUSIONS: The renal microcirculation in sodium-replete women may respond differently to Ang II than that of men, with the female sex predicting a lesser augmentation of FF and possibly a blunted increase in intraglomerular pressure. The mechanism remains obscure, but these contrasting responses may help to explain gender-mediated differences in renal disease progression.     

The localisations in liposomal membranes of the tetrahydrofuran ring moieties of the annonaceous acetogenins, annonacin and sylvaticin, as determined by 1H NMR spectroscopy

We studied 34 apparently healthy children and 2 propositi from kindreds with familial juvenile hyperuricaemic nephropathy (FJHN) - a disorder characterised by early onset, hyperuricaemia, gout, familial renal disease and a similarly low urate clearance relative to glomerular filtration rate (GFR) [fractional excretion of uric acid (FEur) 5.1+/-1.6%] in young men and women. In addition to the propositi, 17 asymptomatic children were hyperuricaemic -- mean plasma urate (368+/-30 micromol/l), twice that of controls (154+/-41 micromol/l). Eight of them had a normal GFR ( > 80 ml/min per 1.73 m2), and 11 renal dysfunction, which was severe in 5. The FEur in the 14 hyperuricaemic children with a GFR > 50 ml/min was 5.0+/-0.5% and in the 5 with a GFR < or =50 ml/min was still low (11.5+/-0.2%) compared with controls (18.4+/-5.1%). The 17 normouricaemic children (185+/-37 micromol/l) had a normal GFR (>80 ml/min) and FEur (14.0+/-5.3%). The results highlight the dominant inheritance, absence of the usual child/adult difference in FEur in FJHN and presence of hyperuricaemia without renal disease in 42% of affected children, but not vice versa. Since early allopurinol treatment may retard progression to end-stage renal failure, screening of all relatives in FJHN kindreds is essential.     

Cyclosporin does not inhibit the tubular secretion of creatinine

BACKGROUND: The immunosuppressive drug cyclosporin is known to impair renal function. The degree of renal dysfunction is usually estimated from the clearance of creatinine (CCr). Theoretically however, a fall in CCr can be caused by a decrease of GFR, an inhibition of the tubular secretion of creatinine, or the combination of both. CsA has convincingly been shown to decrease GFR, but detailed information on the effects of CsA on tubular secretion of creatinine is lacking. METHODS: We performed two studies to investigate the influence of CsA on tubular creatinine secretion. In study A we simultaneously measured CCr and GFR (using inulin) immediately before and 4 weeks after cessation of CsA therapy in 17 renal transplant patients. In study B, the rise in serum creatinine after administration of cimetidine, which blocks the tubular secretion of creatinine, was compared in renal transplant patients treated with either CsA (in whom secretion might already be inhibited) or azathioprine. RESULTS: Study A: After cessation of CsA there was an increase of GFR (54+/-15 vs 63+/-16 ml/min/1.73 m2, PCr (71+/-21 vs 82+/-23 ml/min/1.73 m2; PCr and GFR (a measure of the relative contribution of tubular secretion to the clearance of creatinine) did not change significantly (1.33+/-0.21 vs 1. 32+/-0.30). Study B: In nine couples of patients matched for GFR the relative rises in serum creatinine after administration of cimetidine were 26+/-21% and 22+/-7% for CsA and azathioprine treated patients respectively (NS). CONCLUSION: CsA does not substantially inhibit the tubular secretion of creatinine. A rise in serum creatinine after administration of CsA can thus be attributed completely to a fall in GFR.     

Contrasting renal effects of nicotine in smokers and non-smokers

BACKGROUND: Cigarette smoking is associated with acute increase in arterial pressure due to systemic vasoconstriction and decreased skin and coronary blood flow. Virtually all cardiovascular effects of cigarette smoking are due to nicotine. However, whether nicotine also affects the renal circulation and function in humans is at present unknown. METHODS: In the current study the acute effects of a 4-mg nicotine gum on arterial pressure, heart rate as well as renal haemodynamics and function were assessed in non-smokers and chronic smokers. RESULTS: In non-smokers, mean arterial pressure (+8 +/- 1 mmHg, P<0.001) and heart rate (+13 +/- 3 beats/min, P<0.001) increased whereas effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) decreased by 15 +/- 4% and 14 +/- 4% respectively; in addition, urinary cyclic GMP decreased by 51 +/- 12% in response to nicotine administration. In smokers, mean arterial pressure and heart rate increased similarly; however, in contrast with non-smokers, ERPF and GFR remained unchanged whereas urinary cyclic GMP rose by 87 +/- 43%. Changes in ERPF induced by nicotine were positively correlated with changes in urinary cyclic GMP. CONCLUSIONS: These findings indicate that nicotine administration is associated with renal vasoconstriction in healthy non-smokers, possibly through alteration of a cyclic-GMP-dependent vasoactive mechanism. Tolerance to the renal effect of nicotine was observed in chronic smokers, despite the maintenance of the systemic response to nicotine.     

Functional response of the rat kidney to inhibition of nitric oxide synthesis: role of cytochrome p450-derived arachidonate metabolites

1. We tested the hypothesis that nitric oxide (NO) exerts a tonic inhibitory influence on cytochrome P450 (CYP450)-dependent metabolism of arachidonic acid (AA). 2. N(omega)-nitro-L-Arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), increased mean blood pressure (MBP), from 91+/-6 to 137+/-5 mmHg, renal vascular resistance (RVR), from 9.9+/-0.6 to 27.4+/-2.5 mmHg ml(-1) min(-1), and reduced renal blood flow (RBF), from 9.8+/-0.7 to 6.5+/-0.6 ml min(-1)) and GFR from 1.2+/-0.2 to 0.6+/-0.2 ml 100 g(-1) min(-1)) accompanied by diuresis (UV, 1.7+/-0.3 to 4.3+/-0.8 microl 100 g(-1) min (-1)), and natriuresis (U(Na)V, 0.36+/-0.04 to 1.25+/-0.032 micromol 100 g(-1) min(-1)). 3. 12, 12 dibromododec-enoic acid (DBDD), an inhibitor of omega hydroxylase, blunted L-NAME-induced changes in MBP, RVR, UV and U(Na)V by 63+/-8, 70+/-5, 45+/-8 and 42+/-9%, respectively, and fully reversed the reduction in GFR by L-NAME. Clotrimazole, an inhibitor of the epoxygenase pathway of CYP450-dependent AA metabolism, was without effect. 4. BMS182874 (5-dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfo namide), an endothelin (ET)A receptor antagonist, also blunted the increases in MBP and RVR and the diuresis/natriuresis elicited by L-NAME without affecting GFR. 5. Indomethacin blunted L-NAME-induced increases in RVR, UV and U(Na)V. BMS180291 (1S-(1alpha,2alpha,3alpha,4alpha)]-2-[[3-[4-[(++ +pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl ]methyl]benzenepropanoic acid), an endoperoxide receptor antagonist, attenuated the pressor and renal haemodynamic but not the renal tubular effects of L-NAME. 6. In conclusion, the renal functional effects of the CYP450-derived mediator(s) expressed after inhibition of NOS with L-NAME were prevented by inhibiting either CYP450 omega hydroxylase or cyclooxygenase or by antagonizing either ET(A) or endoperoxide receptors. 20-hydroxyeicosatetraenoic acid (20-HETE) fulfils the salient properties of this mediator.     

Renal depressor mechanisms of physical training in patients with essential hypertension

To clarify characteristics of the patients in whom exercise training lowers blood pressure and to elucidate the mechanisms by which exercise training lowers blood pressure, we evaluated 24-h blood pressure, glomerular filtration rate (GFR), renal blood flow (RBF), filtration fraction (FF), plasma renin activity (PRA), plasma aldosterone concentration (PAC), plasma norepinephrine concentration (PNE), and incremental area of insulin/glucose (sigmaI/sigmaG) during 75 g oral glucose tolerance test, and assessed arterial baroreceptor function (BSI) before and after a 3-week exercise training program (four 6-min sessions daily at 75% VO2 max). Patients were classified as responders (n = 15) if they showed statistically significant reduction in the multiple comparison of 24-h mean arterial pressure (MAP), or as nonresponders (n = 15) if they did not. Although there were no significant differences between responders and nonresponders in age, weight, MAP, GFR, RBF, RPF, FF, PNE, sigmaI/sigmaG, or BSI before exercise, renal vascular resistance (RVR; P < .05), PRA (P < .05), and PAC (P < .05) were significantly higher in responders than in nonresponders. The fractional excretion of sodium (FENa) (P < .05) were significantly lower in responders than in nonresponders. After exercise training, FF (P < .01), RVR (P < .05), PNE (P < .05) PRA (P < .01), and sigmaI/sigmaG (P < .05) decreased significantly only in responders. The decrease in MAP significantly correlated with the reductions in FF (r = 0.46, P < .05), PNE (r = 0.52, P < .01) and RVR (r = 0.40, P < .05). Thus, in patients who have higher RVR and PRA, exercise training lowered blood pressure in parallel to a reduction in RVR associated with decreases in sympathetic tone and improvement of insulin resistance. Our results suggest that exercise-induced changes in renal hemodynamics may contribute to the reduction in blood pressure in these patients.     

Donor age and graft function

We evaluated survival and renal function of cadaveric donor grafts according to donor age. The median age of the pediatric donors was 7.0 (0.7-16) years in 46 patients [median age 11.8 years (range) 3-16.8 years]. The median age of the adult donors was 34.4 (19-54) years in 59 patients [median age 12.1 years (range) 7-17.3 years]. Thirty patients were treated with azathioprine and prednisolone and 75 with cyclosporine A and prednisolone. The glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF) were determined by the clearances of 51chromium-EDTA and 125iodine-hippurate 1-48 months after kidney transplantation. There was no difference in graft survival between pediatric and adult grafts. There were also no differences in GFR in patients receiving grafts from pediatric or adult donors; 2-3 months after transplantation the GFR in recipients of pediatric grafts was 62 +/- 20 ml/min per 1.73 m2 compared with 61 +/- 21 in those receiving adult grafts. The ERPF in recipients of adult grafts was significantly higher in the 1st month after transplantation: 486 +/- 239 versus 362 +/- 158 ml/min per 1.73 m2. From the 4th to the 6th month after transplantation this difference disappeared: the ERPF of grafts from pediatric donors was 279 +/- 131 ml/min per 1.73 m2 compared with 273 +/- 123 ml/min per 1.73 m2 in grafts from adult donors. Using the single-kidney GFR and ERPF on an age-matched group of probands with minor diseases as references, 2-3 months after transplant the mean GFR of grafts from pediatric donors increased to 118% +/- 51%, whereas the GFR of adult donor grafts fell to 60% +/- 22% over the same period. After 4-6 months the ERPF in pediatric grafts was 96% +/- 55% compared with 50% +/- 22% in adult grafts. We conclude that graft survival and function in children with either a pediatric or an adult graft may not differ because graft function adapts to the requirement of the recipient.     

Renal hemodynamics during norepinephrine and low-dose dopamine infusions in man

OBJECTIVE: To characterize the effects of pressor doses of norepinephrine and low-dose dopamine (3 micrograms/kg/min) on renal hemodynamics in man, as well as to determine the clinical relevance of combining dopamine with norepinephrine. DESIGN: Prospective, single-blind, randomized study. SETTING: Clinical research unit of a tertiary care hospital. SUBJECTS. Six healthy male volunteers ranging in age between 20 and 28 yrs. INTERVENTIONS: The subjects were assigned randomly to four treatments (1 wk apart) in which renal hemodynamics and electrolyte excretion were assessed. Treatments consisted of 180-min infusions of the following: a) 0.9% sodium chloride (control); b) pressor doses of norepinephrine; c) dopamine at 3 micrograms/kg/min; and d) pressor doses of norepinephrine and dopamine at 3 micrograms/kg/min. Pressor doses of norepinephrine was defined as doses required to increase mean arterial pressure (MAP) by 20 mm Hg. MEASUREMENTS AND MAIN RESULTS: Glomerular filtration rate and renal blood flow were derived from inulin and para-aminohippurate clearances, respectively. Urine output and urine solute excretion were also determined. The mean norepinephrine dose required to increase MAP by 22 +/- 2 mm Hg was 118 +/- 30 ng/kg/min (range 76 to 164). After the addition of dopamine, similar doses of norepinephrine resulted in an MAP increase of 15 +/- 4 mm Hg. Glomerular filtration rate and urine output were comparable under all conditions. The infusion of norepinephrine decreased renal blood flow from 1241 +/- 208 to 922 +/- 143 mL/min/1.73 m2 (p = .03). The addition of dopamine returned renal blood flow to baseline values. The clearance of urine sodium increased significantly with the infusion of dopamine alone (p = .03). All subjects completed the four treatment periods. Adverse events, manifested mostly as palpitations and flushing, were rare and self-limiting. CONCLUSIONS: The addition of dopamine (3 micrograms/kg/min) to pressor doses of norepinephrine normalized renal blood flow in healthy volunteers. These hemodynamic changes were not reflected in urine output and glomerular filtration rate; hence, these monitoring parameters may be unreliable indicators of renal function in the setting of vasopressor therapy. In addition, systemic effects were observed with dopamine (3 micrograms/kg/min), as indicated by a decrease in MAP.     

Renal reserve is normal in adults born with unilateral renal agenesis and is not related to hyperfiltration or renal failure

This study was carried out to examine the renal hemodynamic response in adult patients with single kidneys born with unilateral renal agenesis. A group of 21 patients with unilateral renal agenesis were divided into three groups according to their glomerular filtration rate (GFR): 112 +/- 3 ml/min x 1.73 m2 in group A, 68 +/- 3.2 ml/min x 1.73 m2 in group B, and 40.7 +/- 3.3 ml/min x 1.73 m2 in group C. Mean arterial blood pressure was significantly higher in the patients of group C who were also proteinuric. The renal hemodynamic response to an oral protein load (2 g/kg of protein as beefsteak) was normal in all groups and unrelated to hyperfiltration or to renal failure and proteinuria. The study indicates that in patients with renal agenesis, the hemodynamic response to a protein challenge is similar to that of kidney donors, renal transplant recipients and uninephrectomized patients. The paper also demonstrates that the renal response to a protein challenge is inadequate to identify patients with renal agenesis who are at risk of developing renal disease. Finally, in renal agenesis with renal disease, creatinine clearance overestimated the GFR by an average of 32.7%.     

Platelet serotonin in patients with analgesic-induced headache

OBJECTIVE: To determine the effect of area postrema AP on DOCA-salt induced hypertension in rat, with emphasis on renal hemodynamics. METHOD: Blood pressure, salt and water balances and renal hemodynamics were observed in AP ablated and sham-operated rats treated with DOCA-salt. RESULTS: In AP intact (API) rats, after one week of DOCA-salt treatment BP began elevating to statistical significance at the end of the second week (MAP 15.9 +/- 0.7 vs. 13.5 +/- 0.5 kPa), followed by a plateau period from the third to fifth week. In AP ablated (APX) rats, BP raised during the first week of DOCA-salt treatment. However, the elevation gradually disappeared and BP returned to baseline at the fifth week. Sodium balance study showed that DOCA-salt treatment induced significant sodium retention in API rat, while the sodium metabolism remained stable in APX group except in the first week. Basal renal hemodynamic parameters (GFR, RPF, UNaV, UV) were not changed at neither the beginning nor the end of the study. However, a small dose of hypertonic saline (7% NaCl 0.3 ml) injection caused a brisk rising of these four parameters in APX but not API group. CONCLUSION: AP plays an important role in normal salt and water metabolism and might be involved in pathogenesis of DOCA-salt hypertension through regulation for renal hemodynamics and body fluid homeostasis.     

Maintenance of baseline angiotensin II potentiates insulin hypertension in rats

Chronic insulin infusion in rats increases mean arterial pressure (MAP) by a mechanism dependent on angiotensin II (Ang II). However, the fact that plasma renin activity (PRA) decreases with insulin infusion suggests that Ang II sensitivity is increased and that the parallel reduction in Ang II may partly counteract any hypertensive action of insulin. This study tested that hypothesis by clamping Ang II at baseline levels during chronic insulin infusion. Sprague-Dawley rats were instrumented with artery and vein catheters, and MAP was measured 24 hours per day. In seven angiotensin clamped rats (AC rats), renin-angiotensin II system activity was clamped at normal levels throughout the study by continuous intravenous infusion of the angiotensin-converting enzyme inhibitor benazepril at 5 mg/kg per day (which decreased MAP by 18+/-2 mm Hg) together with intravenous Ang II at 5 ng/kg per minute. Control MAP in AC rats after clamping averaged 99+/-1 mm Hg, which was not different from the 101+/-2 mm Hg measured before clamping Ang II levels. Control MAP in the 8 vehicle-infused rats averaged 105+/-2 mm Hg. A 7-day infusion of insulin (1.5 mU/kg per minute IV) plus glucose (20 mg/kg per minute IV) increased MAP in both groups of rats; however, the increase in MAP was significantly greater in AC rats (12+/-1 versus 5+/-1 mm Hg). This enhanced hypertensive response to insulin in AC rats was associated with a greater increase in renal vascular resistance (153+/-10% versus 119+/-6% of control) and a significant increase in renal formation of thromboxane (149+/-11% of control). Thus, decreased Ang II during insulin infusion limits the renal vasoconstrictor and hypertensive actions of insulin, and this may be caused, at least in part, by attenuation of renal thromboxane production.