Renovascular adaptive changes in chronic hypoxic polycythemia

BACKGROUND: Chronic hypoxia in rats produces polycythemia, and the plasma fraction falls, reducing renal plasma flow (RPF) relative to renal blood flow (RBF). Polycythemia also causes increased blood viscosity, which tends to reduce RBF and renal oxygen delivery. We studied how renal regulation of electrolyte balance and renal tissue oxygenation (which is crucial for erythropoietin regulation) are maintained in rats during hypoxic exposure. METHODS: Rats of two strains with differing polycythemic responses, with surgically implanted catheters in the urinary bladder, femoral artery, and left renal and right external jugular veins, were exposed to a simulated high altitude (0.5 atm) for 0, 1, 3, 14, and 30 days, after which RPF (para-aminohippurate clearance), glomerular filtration rate (GFR, polyfructosan clearance), hematocrit and blood gases were measured, and RBF, renal vascular resistance and hindrance (resistance/viscosity), renal oxygen delivery, and renal oxygen consumption were calculated. RESULTS: During chronic hypoxia RBF increased, but RPF decreased because of the polycythemia. GFR remained normal because the filtration fraction (FF) increased. Renal vascular resistance decreased, and renal vascular hindrance decreased more markedly. Renal oxygen delivery and consumption both increased. CONCLUSIONS: During chronic hypoxia GFR homeostasis apparently took precedence over RBF autoregulation. The large decrease in renal vascular hindrance suggested that renal vascular remodeling contributes to GFR regulation. The reduced hindrance also prevented a vicious cycle of increasing polycythemia and blood viscosity, decreasing RBF, and increasing renal hypoxia and erythropoietin release.     

Isolation of 48 genetic markers appropriate for high throughput genotyping of inbred rat strains by B1 repetitive sequence-representational difference analysis

1. We examined whether zaprinast, a putative cGMP-specific phosphodiesterase inhibitor, affects neural control of renal function in pentobarbital-anaesthetized dogs. 2. Renal nerve stimulation (1 Hz, 1 ms duration) reduced urine flow rate, urinary Na+ excretion (UNaV) and fractional excretion of Na+ (FENa) with little change in either renal blood flow (RBF) or glomerular filtration rate (GFR). 3. Intrarenal arterial infusion of zaprinast (10 and 100 micrograms/kg per min) increased basal urine flow rate, UNaV and FENa but not RBF or GFR. Zaprinast infusion (100 micrograms/kg per min) also increased renal venous plasma cGMP concentration and urinary cGMP excretion. 4. Renal nerve stimulation-induced reductions in UNaV and FENa were attenuated during zaprinast infusion, whereas the reduction in urine flow rate was resistant to zaprinast. 5. Renal nerve stimulation increased the renal venous plasma noradrenaline concentration and renal noradrenaline efflux, which remained unaffected during infusion of zaprinast (100 micrograms/kg per min). 6. The results of the present study suggest that zaprinast induces natriuresis and counteracts adrenergically induced antinatriuresis by acting on renal tubular sites in the dog kidney in vivo.     

Haemodynamic and renal effects of felodipine in young and elderly subjects

OBJECTIVE: To study the influence of age on renal and haemodynamic effects of the calcium antagonist felodipine. METHODS: Eight young (mean age 27 years) and eight elderly (mean age 75 years) healthy normotensive subjects were given felodipine intravenously for 120 min aiming at close to therapeutic plasma level concentration. Renal blood flow (RBF) and renal vascular resistance (RVR) was estimated from para-aminohippuric acid (PAH) clearance 51CrEDTA clearance was used to measure glomerular filtration rate (GFR) and used in the calculations of fractional excretion (FE) of electrolytes. Impedance cardiography was performed to assess stroke volume and for the calculation of cardiac output and ejection fraction. RESULTS: At the end of felodipine infusion, the concentration of felodipine was on average 10.0 nmol x l(-1) in young and 12.0 nmol x l(-1) in elderly subjects (NS). During felodipine infusion blood pressure (BP) decreased from 138/76 to 120/68 in elderly subjects. The BP in young subjects was 126/74 at basal and 125/70 after infusion of felodipine. The systemic and renal vascular resistance decreased to a similar extent in young and elderly subjects after felodipine infusion. Felodipine caused a decrease in systemic vascular resistance from 25.6 to 23.3 in elderly and from 23.8 to 21.8 in the young subjects. Mean values for RVR at baseline and during infusion of felodipine were significantly higher in the elderly (10.1-15.1) than in the young subjects (5.4-6.7). Felodipine reduced RVR by 10% in the young and by 12% in the elderly at the end of infusion. The young subjects had 31% higher GFR than the elderly subjects at the start of infusion. Felodipine infusion did not affect GFR. There were no effects on stroke volume and ejection fraction. An initial natriuretic effect was found after infusion of felodipine in the young subjects. The fractional excretion of all electrolytes tended to increase after both felodipine and placebo, more in the elderly than in the young subjects. CONCLUSION: The effects of felodipine on central and renal haemodynamics previously observed in young and middle-aged subjects also seem to exist in the elderly. Volume expansion seems to increase the excretion of electrolytes more in elderly than in young people, and therefore the effect of felodipine on natriuresis is more evident in young subjects.     

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.     

Aneurysm clips: evaluation of MR imaging artifacts at 1.5 T

PURPOSE: Endothelin-1 (ET-1), a peptide produced by the vascular endothelium, causes profound renal vasoconstriction by binding to ET-A receptors. The present study examined the renal actions of ET-1 after ET-A receptors were blocked by BE-18257B to unmask the functions of ET-B receptors. MATERIALS AND METHODS: Renal hemodynamics and clearance measurements were obtained in anesthetized dogs after intrarenal infusion of BE-18257B at 100 ng./kg./min. (Group 1), after intrarenal infusion of ET-1 at 2 ng./kg./min. (Group 2), or after intrarenal infusion of ET-1 superimposed on BE-18257B (Group 3). RESULTS: In Group 1, BE-18257B infusion did not alter arterial pressure, renal blood flow (RBF), GFR or tubular function. In Group 2, ET-1 infusion led to a significant decrease in RBF and GFR (37 and 40%, respectively) without altering arterial pressure. Urinary volume and sodium excretion were not changed but osmolality decreased significantly. In Group 3, BE-18257B infusion significantly attenuated the decrease in RBF caused by ET-1 and increased GFR by 40% without altering arterial pressure, associated with significant diuresis and natriuresis. CONCLUSION: Renal vasoconstriction caused by ET-1 is attenuated by ET-A receptor blockade with BE-18257B, which unmasks the hemodynamic and tubular actions of ET-B receptors. As a result, it limits the ET-1 induced decrease in RBF and raises GFR, and leads to a diuresis and natriuresis.     

The effects of a converting enzyme inhibitor (captopril) and angiotensin II on fetal renal function

1. Renal function was studied in chronically catheterized fetal sheep (119-128 days gestation), before and during treatment of the ewe with the angiotensin converting enzyme (ACE) inhibitor, captopril, which crosses the placenta and blocks the fetal renin angiotensin system. 2. An i.v. dose of 15 mg (about 319 micrograms kg-1) of captopril to salt-replete ewes followed by an infusion to the ewe of 6 mg h-1 (about 128 micrograms kg-1 h-1) caused a fall in fetal arterial pressure (P < 0.01), and a rise in fetal renal blood flow (RBF) from 67.9 +/- 5.6 to 84.9 +/- 8.3 ml min-1 (mean +/- s.e. mean) (P < 0.05). Renal vascular resistance and glomerular filtration rate (GFR) fell (P < 0.01); fetal urine flow (P < 0.01); fetal urine flow (P < 0.01) and sodium excretion declined (P < 0.05). 3. Ewes were treated for the next 2 days with 15 mg captopril twice daily. On the 4th day, 15 mg was given to the ewe and fetal renal function studied for 2 h during the infusion of captopril (6 mg h-1) to the ewe. Of the 9 surviving fetuses, 3 were anuric and 3 had low urine flow rates. When 6 micrograms kg-1 h-1 of angiotensin II was infused directly into the fetus RBF fell from 69 +/- 10.1 ml min-1 to 31 +/- 13.9 ml min-1, GFR rose (P < 0.05) and urine flow (P < 0.01) and sodium excretion increased in all fetuses. 4. It is concluded that the small fall in fetal arterial pressure partly contributed to the fall in fetal GFR but in addition, efferent arteriolar tone fell so that the filtration pressure fell further. Thus maintenance of fetal renal function depends on the integrity of the fetal renin angiotensin system. These findings explain why use of ACE inhibitors in human pregnancy is associated with neonatal anuria.     

Cardiovascular and renal effects of hypoxia in conscious carotid body-denervated rats

The contribution of peripheral arterial chemoreceptors to cardiovascular and renal responses to acute hypocapnic hypoxia is currently not well understood. We compared the effects of normobaric hypoxia on mean arterial blood pressure (MABP), heart rate, glomerular filtration rate (GFR), renal blood flow (RBF), and renal volume and electrolyte excretion in conscious unilaterally nephrectomized carotid body-denervated (n = 10) and sham-operated (n = 10) control rats. Thirty minutes of normobaric hypoxia (12.5% O2) resulted in significant reductions in arterial PO2 and PCO2 as well as decreases in MABP, GFR, RBF, and renal sodium, potassium, and water excretion. These effects occurred more rapidly and/or were significantly more pronounced in carotid body-denervated than in sham-operated rats. These data indicate that moderate acute hypocapnic hypoxia has profound effects on systemic and renal hemodynamics as well as on renal excretory function in conscious rats. We conclude that stimulation of the peripheral arterial chemoreceptors can partially offset the hypoxia-induced decreases in MABP, RBF, GFR, urine flow, and urinary sodium and potassium excretion, thereby helping to maintain cardiovascular as well as fluid and electrolyte homeostasis.     

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.     

Mechanisms of portal hypertension-induced alterations in renal hemodynamics, renal water excretion, and renin secretion

Clinical states with portal venous hypertension are frequently associated with impairment in renal hemodynamics and water excretion, as well as increased renin secretion. In the present investigation, portal venous pressure (PVP) was increased in anesthetized dogs undergoing a water diuresis. Renal arterial pressure was maintained constant in all studies. As PVP was increased from 6 to 20 mm Hg, decreases in cardiac output (2.5-2.0 liter/min, P less than 0.05) and mean arterial pressure (140-131 mm Hg, P less than 0.05) were observed. Increases in PVP were also associated with decreases in glomerular filtration rate (GFR, 40-31 ml/min, P less than 0.001), renal blood flow (RBF, 276-193 ml/min, P less than 0.001), and increases in renin secretion (232-939 U/min, P less than 0.025) in innervated kidneys. No significant change in either GFR or RBF and a decrease in renin secretion occurred with increases in PVP in denervated kidneys. To dissociate the changes in cardiac output and mean arterial pressure induced by increase PVP from the observed decreases in GFR and RBF, studies were performed on animals undergoing constriction of the thoracic inferior vena cava. In these studies, similar decreases in cardiac output and mean arterial pressure were not associated with significant changes in GFR or RBF. Increases in PVP also were associated with an antidiuresis as urine osmolality increased from 101 to 446 mosmol/kg H2O (P less than 0.001). This antidiuresis was significantly blunted but not abolished by acute hypophysectomy. In hypophysectomized animals, changes in free water clearance and urine flow were linearly correlated as PVP was increased. These studies indicate that increases in PVP result in decreases in GFR and RBF and increases in renin secretion mediated by increased renal adrenergic tone. Increased PVP is also associated with antidiuresis; this antidiuresis is mediated both by vasopressin release and by diminished tubular fluid delivery to the distal nephron.     

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.     

Renal cortical blood flow distribution in obstructive nephropathy in rats

To examine the role of intrarenal hemodynamics in in obstructive nephropathy, we determined cortical blood flow distribution (CBFD) in rats with bilateral ureteral occlusion (BUO) and unilateral ureteral occlusion (UUO) during and after release of obstruction. Prior to release of obstruction of 24 hours' duration, we found that outer cortical perfusion decreased by 20+/-5% in both BUO and UUO rats. Furthermore, one hour after release of BUO, there was rapid normalization of CBFD associated with a modest return of glomerular filtration rate (GFR), an almost complete return of renal blood flow (RBF), and a marked postobstructive diuresis. In contrast, after release of UUO, we observed that outer cortical perfusion remained decreased by 21+/-31%, both GFR and RBF remained markedly depressed, and no diuresis occurred. These data demonstrate (1) marked ischemia of the outer cortex in both BUO and UUO during obstruction, (2) a rapid return of CBFD to a normal pattern after release of BUO, but (3) persistent outer cortical ischemia following release of UUO.     

Fiber growth initiation in hair follicles of goats treated with melatonin

Amphotericin B (AmB) is the drug of choice for most systemic fungal infections, but doses are frequently reduced because of nephrotoxicity. We investigated the role of thromboxane as a mediator for this nephrotoxicity. Vehicle or amphotericin (0.60 mg/kg) was infused into the left renal artery in four groups of rats, and renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured. Group 1 received vehicle for 90 min. Group 2 received vehicle followed by a 30 minute AmB infusion which caused a significant and reversible fall in the RPF and GFR. Group 3 received vehicle followed by AmB infusion, but were infused with a bolus of ibuprofen (20 mg/kg) 45 minutes before AmB. This group exhibited an insignificant attenuation in the fall in RPF and GFR. Group 4 received vehicle followed by AmB, but were infused with a bolus and continuous infusion of the thromboxane receptor antagonist SQ29,548. This group demonstrated an attenuation in the fall in RPF and a significant decrease in GFR compared to AmB control rats. In addition, the rat glomeruli were incubated with AmB (4 ug/ml). Supernatant levels of thromboxane B2 were significantly elevated in the presence of AmB vs buffer alone. We conclude that the reduction in RPF and GFR observed with AmB infusion in the rat is partially mediated by release of thromboxane.     

Renal responses of the fetal lamb to fetal or maternal volume expansion

Fetal and maternal glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, sodium excretion, and fractional sodium reabsorption were measured in a chronically instrumented sheep preparation. Fetal GFR was essentially stable between 110 and 135 days of gestation (term = 147 days). There was a significant increase in GFR after 135 days. After the infusion of 50 ml of normal saline over a 30-minute period, fetal GFR and sodium excretion increased significantly. Fractional sodium reabsorption was significantly decreased. Thus, the fetus is capable of responding to volume expansion with saline with an increase in GFR and a decrease in fractional sodium reabsorption. After the infusion of 1000 ml of normal saline into the ewe in 1 hour, maternal GFR and RPF rose significantly. Sodium excretion rose 6-fold and fractional sodium reabsorption fell significantly. After the infusion of saline into the ewe, there was no change in fetal GFR, RPF, sodium excretion, urine volume, or fractional sodium reabsorption. Since there were no changes in fetal renal function after maternal volume expansion with saline there was no evidence for the transplacental passage of a natriuretic factor from ewe to fetus.     

Results on a pilot study of cultures of human lacteal secretions and benign and malignant breast tumors

The inhibitory action of indomethacin administered as a single-dose injection (4mg/kg) was examined under general anaesthesia in dogs, moderate volume expansion having been induced with physiological saline infusion. At 20 to 30 min after the administration of indomethacin, excretion of Na and water showed a fall of the same extent, GFR remaining stable and the effective plasma flow (CPAH) declining. RBF estimated by the 86Rb method decreased from 411 +/- 96 ml/min/100 g to 292 +/- 53 ml/min/100 g (p less than 0.01). This fall was coupled with an intrarenal redistribution of blood flow. While the cortical fraction of renal blood flow increased from 79% to 83.9% (p less than 0.001), its outer medullary fraction decreased from 17% to 13.2% (p less than 0.001) and its inner medullary fraction from 4.0% to 2.8% (p less than 0.05). The renal, primarily the medullary, vasculature is assumed on these grounds to be under the influence of a continuous secretion of prostaglandins which thus seem to be involved in the physiological control of intrarenal distribution of blood flow and of sodium and water excretion.     

Cytokine inhibition preserves renal hemodynamic function following mesangial cell immune injury

BACKGROUND: We assessed the effect of a cytokine inhibitor, compound SKF 86002 (a bicyclic imidazole), on changes in renal hemodynamics (renal blood flow and glomerular filtration rate) that occur acutely following immune injury of glomerular mesangial cells. METHODS: Injury was induced in Munich-Wistar rats by the administration of a monoclonal antibody against the mesangial cell membrane antigen Thy 1.1. An acute drop in renal blood flow (RBF) and glomerular filtration rate (GFR) occurred within one hour of injury. RESULTS: Pretreatment of animals with the cytokine inhibitor SKF 86002 prevented this drop. SKF 86002 had no effect on glomerular synthesis of vasoconstrictor eicosanoids. CONCLUSIONS: The observations indicate that in mesangial cell immune injury, cytokines mediate renal hemodynamic impairment.     

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)     

Human lactoferrin receptor activity in non-encapsulated Haemophilus influenzae

We recently reported that attenuation of vasoactive agent-induced calcium signal and cell contraction of mesangial cell by insulin-like growth factor 1 (IGF-1), observed in normal mesangial cells, is totally abolished in spontaneously hypertensive rat (SHR) mesangial cells. This phenomenon might be related to the well-known aberrant regulation of SHR glomerular hemodynamics. Since it has been reported that in vivo IGF-1 infusion increases renal plasma flow (RPF) and glomerular filtration rate (GFR), we examined whether the modulation of renal function by IGF-1 is altered in SHR. We performed in vivo renal clearance studies using eight-week-old SHR and control Wistar Kyoto rats (WKY) before and after IGF-1 (5 micrograms/kg) infusion into the left renal artery for 20 minutes. Mean arterial pressure was not affected by IGF-1 in both WKY and SHR. In WKY, IGF-1 increased GFR and RPF, and decreased renal vascular resistance (RVR). However, GFR, RPF, and RVR were not altered by IGF-1 in SHR, while systemic infusion of angiotensin II antagonist, CV-11974, increased GFR and RPF. The present data show that the modulation of renal hemodynamics by IGF-1 is absent in SHR. This might be related the pathophysiology of the development of hypertension.     

Noradrenaline modulates the electrical activity of white adipocytes by a cAMP-dependent mechanism

The two-compartment open model is currently used to assess the glomerular filtration rate (GFR) after a single intravenous injection or a constant rate intravenous infusion. This model needs multiple blood samples from a patient, thus numerous limited sampling models have been so far developed to reduce the number of blood samples. In the present study, the three-, four- and n-compartment closed models have been developed to assess GFR after and during a constant rate intravenous infusion, which include the renal and all possible non-renal elimination pathways. Although more non-renal elimination compartments were included in the modelling, the results show it only leads to the increase in the similar analytical solutions for these compartments and the analytical solution for the blood compartment is the same as that in the two-compartment open model. Theoretically, the developed models can be used to assess GFR with a single blood sample at any sampling time with several urine samples.     

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.     

Triplet repeat disorders

Bosentan is a nonspecific antagonist for endothelin (ET) receptors, and BQ123 is a specific inhibitor for ET-A receptors. We compared the effects of bosentan (10 mg/kg intravenously, i.v.) and BQ123 (10 mg/kg/h i.v.) on blood pressure and renal function in deoxycorticosterone acetate (DOCA)-salt rats, Dahl salt-sensitive (Dahl-S) rats, and normotensive Wistar rats. In normotensive Wistar rats, bosentan and BQ123 decreased blood pressure. Only BQ123 decreased glomerular filtration rate (GFR) and filtration fraction. These results indicate that ET-A receptors play a role in glomerular function. In DOCA-salt rats, bosentan and BQ123 caused a decrease in blood pressure to normal range and a decrease in renal vascular resistances. Bosentan decreased filtration fraction. Paradoxically, BQ123 caused a decrease in GFR. In Dahl-S rats, bosentan and BQ123 decreased blood pressure, but blood pressure did not reach normal ranges. Bosentan did not modify renal function, but BQ123 caused a decrease in the GFR and filtration fraction. Our results confirm the importance of specific and nonspecific ET antagonists in decreasing blood pressure in models of salt-dependent hypertension. However nonspecific inhibition of ET action did not improve renal function and specific inhibition of ET-A receptors by BQ123 temporarily worsened renal function.