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.     

Cromakalim suppresses hypertonic saline-induced renal vasoconstriction in anaesthetized dogs

1. Intrarenal arterial infusion of hypertonic saline (HS) transiently increased and then gradually reduced renal blood flow (RBF) in anaesthetized dogs. Glomerular filtration rate (GFR) but not filtration fraction decreased at the end of the infusion. 2. In the presence of a potassium channel opener cromakalim (0.3 microgram/kg per min), HS infusion failed to reduce RBF; the initial increase in RBF was maintained throughout the infusion. Since cromakalim also prevented the decrease in GFR, HS infusion lowered filtration fraction. 3. The results suggest that cromakalim inhibits both pre-and postglomerular vasoconstriction induced by HS infusion.     

Cloning, overexpression, purification, and spectroscopic characterization of human S100P

OBJECTIVES: We sought to study the renal circulatory effects of adenosine in patients with chronic congestive heart failure (CHF). BACKGROUND: Renal blood flow (RBF) is often reduced in patients with chronic CHF and may lead to decreased renal function. The cause of reduced RBF is multifactorial and involves systemic as well as local vasoregulatory mechanisms. Stimulation of renal adenosine A1 receptors in animal models has resulted in a significant vasoconstriction of afferent and efferent glomerular arterioles and deterioration of renal function. Although adenosine serum levels have been shown to be elevated in patients with CHF, their effect on the renal circulation in this patient population has not been studied. METHODS: Nine patients with CHF from left ventricular systolic dysfunction were studied. The effects of adenosine at a dose of 10(-5) mol/liter infused directly into the main renal artery on heart rate, renal artery blood pressure, renal artery cross-sectional area (measured by intravascular ultrasound), renal Doppler blood flow velocity (measured by a Doppler flow wire in the renal artery), RBF and renal vascular resistance (RVR) were evaluated. RESULTS: Infusion of adenosine resulted in no significant effect on heart rate or renal artery blood pressure but caused a substantial increase in RVR (11,204 +/- 1,469 to 31,494 +/- 3,911 dynes x s x cm(-5), p = 0.0005), which led to a marked fall in RBF in every patient (mean values 376 +/- 36 to 146 +/- 22 ml/m2, p = 0.0002). These changes in RVR and RBF were associated with no significant change in renal artery cross-sectional area (0.389 +/- 0.040 to 0.375 +/- 0.033 cm2, p = 0.3). CONCLUSIONS: Stimulation of renal adenosine receptors in patients with CHF results in marked renal vasoconstriction that leads to an important reduction in RBF. Lack of change in renal artery cross-sectional area suggests that adenosine affects intrarenal resistance blood vessels rather than large conductance vessels. These results may indicate a rationale for investigation of renal adenosine receptor blockade for enhancement of RBF and improvement of renal function in patients with chronic CHF.     

Effects of cilazapril on renal haemodynamics and function in hypertensive patients: a randomised controlled study versus hydrochlorothiazide

In this study the efficacy and safety of short-term cilazapril administration on renal haemodynamics were evaluated in mild to moderate hypertensive subjects. Our final goal was to evaluate whether the reduction in blood pressure achieved by treatment was associated with maintained renal function. After a run-in period with placebo, 40 hypertensive subjects without renal or cardiac diseases were randomly allocated to a double-blind 4 week controlled trial with cilazapril 5 mg once a day (20 patients) or hydrochlorothiazide 25 mg once a day (20 patients). Renal haemodynamics measurements included effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) by radionuclide study using 131I-hippuran and 99mTc, according to the methods described by Schlegel and Gates, respectively. Effective renal blood flow [ERBF = ERPF/(1-Ht)], filtration fraction (FF = GFR/ERPF) and renal vascular resistance (RVR = MBP x 80/ERBF) were calculated. At the end of cilazapril and hydrochlorothiazide administration significant decreases (p < 0.001) in SBP, DBP and MBP vs baseline values were observed. In the cilazapril group a significant decrease (p < 0.001) in RVR and FF and a significant increase (p < 0.001) in ERPF and ERBF were also found. In the hydrochlorothiazide group a significant decrease (p < 0.001) in RVR was found. No important side effects were observed with either treatment. In conclusion our data indicate that both cilazapril and hydrochlorothiazide reduced blood pressure equally well but only cilazapril improved renal blood flow and reduced filtration fraction.     

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.     

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.     

Influence of nitric oxide in the chronic phase of two-kidney, one clip renovascular hypertension

Chronic two-kidney, one clip (2K1C) renovascular hypertension is characterized by a largely angiotensin-independent elevated blood pressure (BP). We hypothesized that the long-term effect of hypertension would compromise endothelium-derived nitric oxide (NO) and diminish its influence in controlling renal perfusion. We determined the influence of endothelium-derived NO on renal hemodynamics and the angiotensin-NO interaction regulation of renal perfusion in rats with chronic 2K1C hypertension. Renal blood flow (RBF) was measured by radioactive microspheres in rats with either early-phase (4 weeks after clipping, n=7) or chronic-phase (13 to 16 weeks after clipping, n=7) 2K1C hypertension. The systemic and renal response to NO synthesis inhibition was determined with 10 mg/kg body wt N omega-nitro-L-arginine methyl ester (L-NAME). In rats with early-phase 2K1C hypertension, BP was 149+/-3 mm Hg, which increased by 42+/-3 mm Hg with L-NAME (P<.001). L-NAME decreased RBF by 20% (P<.02) and 17% (P<.005) and increased renal vascular resistance (RVR) by 58% (P<.005) and 62% (P<.02) in the nonclipped and clipped kidneys, respectively. In rats with chronic 2K1C hypertension, BP was 166+/-3 mm Hg, and L-NAME increased this by 35+/-6 mm Hg (P<.001). In the nonclipped and clipped kidneys of chronic 2K1C hypertensive rats, L-NAME decreased RBF by 20% (P<.01) and 17% (P<.01) and increased RVR by 51% (P<.005) and 60% (P<.02), respectively. There were no differences in L-NAME-induced changes between early- and chronic-phase 2K1C hypertensive rats. Next, we treated seven chronic-phase 2K1C hypertensive rats with 10 mg/kg body wt losartan, which reduced BP by only 7.7% (P<.005). After losartan, L-NAME increased BP by 41+/-3 mm Hg (P<.001), decreased RBF to the nonclipped kidney by 44% (P<.05), and increased RVR by 110% (P<.005); the decrease in RBF was significantly greater compared with untreated chronic-phase controls (P<.05). In the clipped kidney, L-NAME decreased RBF by 26% (P<.05) and increased RVR by 76% (P <.05). Thus, angiotensin blockade did not attenuate the systemic or renal vasoconstriction to L-NAME. Our results suggest that in both early and chronic phases of 2K1C hypertension, NO contributes significant dilator tone to buffer the hypertension and maintains perfusion of both kidneys by counterbalancing angiotensin-independent vasoconstriction.     

Increased blood viscosity in iron-depleted elite athletes

The vascular effects of angiotensin converting enzyme inhibitors are mediated by the inhibition of the dual action of angiotensin converting enzyme (ACE): production of angiotensin II and degradation of bradykinin. The deleterious effect of converting enzyme inhibitors (CEI) on neonatal renal function have been ascribed to the elevated activity of the renin-angiotensin system. In order to clarify the role of bradykinin in the CEI-induced renal dysfunction of the newborn, the effect of perindoprilat was investigated in anesthetized newborn rabbits with intact or inhibited bradykinin B2 receptors. Inulin and PAH clearances were used as indices of GFR and renal plasma flow, respectively. Perindoprilat (20 microg/kg i.v.) caused marked systemic and renal vasodilation, reflected by a fall in blood pressure and renal vascular resistance. GFR decreased, while urine flow rate did not change. Prior inhibition of the B2 receptors by Hoe 140 (300 microg/kg s.c.) did not prevent any of the hemodynamic changes caused by perindoprilat, indicating that bradykinin accumulation does not contribute to the CEI-induced neonatal renal effects. A control group receiving only Hoe 140 revealed that BK maintains postglomerular vasodilation via B2 receptors in basal conditions. Thus, the absence of functional B2 receptors in the newborn was not responsible for the failure of Hoe 140 to prevent the perindoprilat-induced changes. Species- and/or age-related differences in the kinin-metabolism could explain these results, suggesting that in the newborn rabbit other kininases than ACE are mainly responsible for the degradation of bradykinin.     

Glomerular haemodynamics during renal artery clamping and haemorrhage in the dog

The influence of gradual decline in renal perfusion pressure (RPP) due either to renal artery clamping (C) or to haemorrhagic hypotension (HH) was studied using micropuncture techniques in anaesthetized dogs. The decrease in renal blood flow (RBF) was more profound and set in earlier during HH than during C, where perfect autoregulation was observed down to a mean arterial blood pressure of 85 mmHg. Glomerular filtration rate (GFR) was also only slightly decreased during C, with no change in filtration fraction (FF); again, a much greater decrease in GFR with an increase in FF was seen in HH. The excretion of water, electrolytes and urea were also more decreased during HH than during C. Similar changes were seen at the single nephron (SN) level. Opposite changes were observed in arteriolar resistances: during C a decrease in total arteriolar resistance (RT) amounting to -22% at a RPP of 84 mmHg and -13% at 60 mmHg was seen, due exclusively to a drop in afferent resistance (RA), but during HH there was a significant increase in RT by +36% at RPP of 110 mmHg, +39% at 85 mmHg and +68% at 60 mmHg. This increase was mainly due to an increase in efferent resistance (RE) rather than in RA: +42 vs. +31%, respectively, at 110 mmHg and +67 vs +19% respectively, at 85 mmHg. It was not until a RPP of 60 mmHg was reached that this difference between RE and RA disappeared, being +67% for RE and +69% for RA. The ultrafiltration coefficient, Kf, did not change during C and only decreased slightly with the biggest drop in RPP during HH (2.84 microliters mmHg-1 min-1 during HH vs. 4.19 microliters mmHg-1 min-1 before HH). The SNGFR/GFR ratio remained unchanged during C but declined with decreasing RPP during HH, which probably indicates a 'redistribution' of RBF to the deeper regions of the renal cortex. In conclusion, major differences in renal function were observed between C and HH whose cause is unknown.     

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.     

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.     

The use of a novel monitoring apparatus and modified Belzer hydroxyethyl starch perfusate for analysis of glomerular filtration during hypothermic perfusion preservation

The present study describes an experimental model for measurement of glomerular filtration during hypothermic perfusion preservation (HPP). To facilitate glomerular filtration during HPP, perfusate oncotic pressure was reduced by lowering the concentration of hydroxyethyl starch. Lewis rats underwent HPP at a mean perfusion pressure of 40-46 mmHg. An isograft model was used to demonstrate that retrieval and preparation for HPP did not impact adversely on renal function. Total cold ischemic time (CIT) consisted of the time from retrieval and preparation for perfusion (2 hr) added to the time of HPP. Tubular function studies demonstrated identical concentrations of Na+ and iohexol in ureteral effluent (UE) compared with circulating perfusate and, as such, established that UE flow represented a direct measure of glomerular filtration. Glomerular filtration rate (GFR) was then monitored during HPP by collecting UE in a beaker housed within a computerized Mettler balance system. GFR evolved in a characteristic, biphasic pattern during HPP, increasing from baseline values to reach a peak level at 4.8+/-0.3 hr of CIT and declining progressively thereafter. At 2.5 hr, time of peak values, 10 hr, 19.5 hr, and 24 hr of CIT, GFR values were 29+/-6 microl/min, 39+/-7 microl/min, 20+/-4 microl/min (n=15; P<0.01), 7+/-2 microl/min (n=14; P<0.001), and 14+/-6 microl/min (n=5), respectively. Intrarenal perfusate flows at the same time intervals were 4180+/-292 microl/min, 4083+/-290 microl/min, 3577+/-294 microl/min (P=NS), 1948+/-393 microl/min (P<0.001), and 2175+/-743 microl/min, respectively. Filtration fraction (FF) initially changed in parallel to glomerular filtration. Thereafter, FF either declined at a disproportionately slow rate compared with GFR (n=8) or increased rapidly (n=7). The data suggest that (1) primary change(s) in glomerular dynamics occur during HPP and (2) declining perfusate flow during the later stages of HPP reflects increasing renal vascular resistance localized at a postglomerular level. The data provide an experimental basis for investigating the clinical utility of monitoring glomerular filtration during HPP.     

Losartan attenuates modest but not strong renal vasoconstriction induced by nitric oxide inhibition

Previous studies showed variable success of angiotensin II (ANG II) antagonists to oppose systemic and renal vasoconstriction during long-term nitric oxide synthase (NOS) inhibition. We explored in short-term experiments whether the systemic and renal vasodilatory response to angiotensin II type 1 (AT1)-receptor blockade depends on the extent of NOS blockade. In the first series of experiments, anesthetized rats underwent clearance studies during continuous monitoring of mean arterial pressure (MAP), renal blood flow (RBF, flow probe), and renal vascular resistance (RVR). Compared with control animals, low-dose infusion of the NOS-inhibitor nitro-L-arginine (NLA) increased MAP and RVR, decreased glomerular filtration rate, RBF, and sodium excretion, and had no effect on plasma and kidney ANG II content. High-dose NLA induced stronger effects, did not affect plasma ANG II, and reduced kidney ANG II to approximately 60%. In the second series of experiments, we studied the effect of low- and high-dose NLA on autoregulation of RBF. NLA induced a dose-dependent increase in MAP and decrease in RBF but left autoregulation intact. The AT1-receptor antagonist losartan restored MAP and RBF during low-dose NLA but had no depressor or renal vasodilating effect during high-dose NLA. In summary, short-term NOS blockade causes a dose-dependent pressor and renal vasoconstrictor response, without affecting renal autoregulation, and AT1-receptor blockade restores systemic pressor and renal vasoconstrictive effects of mild NOS inhibition but fails to exert vasorelaxation during strong NOS blockade. Both levels of NOS inhibition did not importantly alter intrarenal ANG II levels. Apparently the functional role of endogenous ANG II as determinant of vascular tone is diminished during strong NOS inhibition.     

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.     

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.     

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.     

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.     

Renal hemodynamics after lung transplantation. A prospective study

Renal function impairment is common after solid organ transplantation, due to the nephrotoxicity of cyclosporine. Moreover, in patients with severe respiratory failure, renal function is often impaired. This renal function impairment may predispose patients to further renal function impairment after lung transplantation. Therefore, renal hemodynamics were measured in 44 patients before lung transplantation and 1, 6, 12, 18, 24, and 30 months after transplantation. After transplantation, a decline in renal function occurred, with a progressive fall in glomerular filtration rate (GFR) of 33 +/- 4% at 12 months and 42 +/- 9% at 30 months. Effective renal blood flow fell by 22 +/- 5% at 12 months and remained stable thereafter. Changes in effective renal plasma flow (ERPF) were less pronounced than those of effective renal blood flow, due to a fall in hematocrit after transplantation. Blood pressure and renal vascular resistance increased significantly, consistent with the effects of cyclosporine. Prior to transplantation, renal function impairment with intense renal vasoconstriction had been found in a subset of the patients. Remarkably, the decrease in renal function after transplantation was less pronounced in patients with renal function impairment prior to transplantation, as indicated by significant negative correlations between pretransplantation GFR and the percentage change in GFR after transplantation, and pretransplantation ERPF and the percentage change in ERPF after transplantation. This suggests that the net course of renal hemodynamics after lung transplantation is the result of the opposed effects of cyclosporine nephrotoxicity and the favorable effects of the normalization of respiratory status. In conclusion, after lung transplantation a decline in renal function occurs that is less pronounced in patients with renal function impairment and intense renal vasoconstriction prior to transplantation. Such a renal function impairment, therefore, should not be considered a contraindication to lung transplantation.     

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.     

Effects of smoking on renal hemodynamics in healthy volunteers and in patients with glomerular disease

Patients with renal disease who smoke have a poor renal functional prognosis, but the mechanisms involved have not been explored. In this controlled study, the effects of smoking and sham smoking were compared in 15 healthy normotensive volunteers. All were occasional smokers and abstained from smoking for 48 h as documented by urinary cotinine measurements. These data were compared with those of seven patients with biopsy-confirmed IgA glomerulonephritis, also occasional smokers. Renal clearance examinations were obtained after hydration in the supine position before and while smoking two cigarettes or sham cigarettes in random order on 2 consecutive days. GFR and effective renal plasma flow were determined using In111-diethylenetriamine penta-acetic acid and 131I-hippurate with a dual tracer infusion clearance technique. In an ancillary study with six volunteers, the effect of smoking was compared with the effect of nicotine-containing chewing gum. In healthy volunteers, sham smoking caused a minor but significant increase of mean arterial pressure (MAP) and GFR with no significant change of effective renal plasma flow, filtration fraction (FF), or renovascular resistance. Smoking caused a significant and more marked increase of MAP (from baseline 92.8+/-8.98 to 105+/-7.78 mmHg) and heart rate (from 61.7+/-7.52 to 86.4+/-9.87 min(-1)), accompanied by a significant increase in arginine vasopressin (from 1.27+/-0.72 to 19.9+/-27.2 pg/ml) and epinephrine (from 37+/-13 to 140+/-129 pg/ml). During smoking, GFR decreased in all but one volunteer (from 120+/-17.7 to 102+/-19.3 ml/min per 1.73 m2), and this was accompanied by a significant decrease of FF (from 21.3+/-4.24 to 17.4+/-3.41%) and an increase in renovascular resistance (from 97.6+/-27.2 to 108+/-30.4 mmHg x min/ml per 1.73 m2). These findings were reproduced with nicotine-containing chewing gum. In contrast, when patients with IgA glomerulonephritis smoked, a similar increment in MAP was noted, the changes of FF were not uniform, and a small but consistent increase of urinary albumin/creatinine ratio was observed. An additional 20 volunteers were subjected to the smoking arm of the study for statistical evaluation of the GFR change in patients. The difference between the change of GFR between all volunteers (n = 35) and patients (n = 7) was significant (P < 0.005). It is concluded that the known effects of smoking and nicotine on the sympathetic nervous system and on systemic hemodynamics are accompanied by significant acute changes in renal hemodynamics and albuminuria. These findings are of interest because of the known effects of smoking on progression of renal disease.