Increase In Renal Vascular Resistance Research Articles

EVALUATION OF RENAL FUNCTION IN ISOLATED PERFUSED KIDNEY AFTER AT1 RECEPTOR BLOCKADE IN RATS SUBMMITED TO HYPERLIPIDIC DIET.

The aim of this study was to evaluate the Angiotensin II effect on renal function. Male Wistar rats (n=8/group) were divided in Control Group (CG), commercial rat feeding, and Hyperlipidic Group (HG) by addition of 30% unsalted butter in commercial diet to rats during 8 weeks, with starts immediately after weaning. At the end of the protocol, the renal function was evaluated in isolated right kidney perfused with Krebs‐Henseleit solution containing 6g of previously dialyzed bovine serum albumin. The kidney was connected in the system and after 30 minutes (basal period) were injected Losartan (10mg/100 ml) and it was analyzed 30 minutes after losartan. The parameters evaluated were renal vascular resistance (RVR), urinary flow (UF), perfusion pressure (PP), renal plasmatic flow (RPF), glomerular filtration rate (GFR), sodium tubular transport (%TNa+) and potassium tubular transport (%TK+). In HG during the basal period there was an increase in RVR (HG:7.2 ± 0.85 vs CG:4.83 ± 0.49, mmHg.mL.g‐1.min‐1) and in PP (HG: 130±6.7 vs CG:111.5±2.9, mmHg). However, there was no change in GFR, %TNa+ and %TK+. After losartan, the HG showed a reduction in PP (21%) and RVR (44%), and increase RPF (44%), without changes in the FU and GFR, when compared with basal period. In conclusion, the increased of RVR and PP observed in HG is probably associated with increase of local Angiotensin II. Financial Support: Mackpesquisa (059/2011).

Changes in Renal Doppler Ultrasonographic Parameters in Patients Managed with Rigid Ureteroscopy

There has been no study evaluating the intrarenal hemodynamic changes after ureteroscopy in the published literature. To determine preoperative and postoperative intrarenal vascular parameters such as resistive index (RI), pulsatility index (PI), peak systolic velocity (PSV), end-diastolic velocity (EDV), measure changes on these values (ΔRI, ΔPI, ΔPSV, ΔEDV) after ureteroscopy (URS) and compare the outcomes with the results of normal contralateral kidneys, and finally investigate possible parameters that would affect renal vascular resistance changes. We prospectively studied 47 patients who underwent rigid URS. Preoperative gray-scale and Doppler ultrasonography (CDUS) measurements were obtained 24 h before URS. Similarly, postoperative CDUS measurements were done 24 h after the operation. The degree of hydronephrosis and location of stones in the obstructed kidneys, diameters of both kidneys, and thickness of renal parenchyma were evaluated with gray-scale US followed by CDUS with calculation of the intrarenal RI, PI, PSV, and EDV values for each kidney. For the operated kidneys, statistically significant P values were noticed when RI and PI values were considered (P < 0.001). ΔRI and ΔPI of the operated kidneys were also significantly greater than the values for non-operated kidneys (P < 0.001). However, it was not the case for ΔPSV and ΔEDV values. In Spearman correlation coefficient analysis, ΔRI was found to be correlated with the parameters: "operative time" and "irrigation fluid volume". No significant relation was documented between ΔRI and the other parameters: age, gender, side of ureteroscopy, stone location, and degree of hydronephrosis. Significant changes in RI and PI values in patients treated with URS reveal that URS can cause a significant increase in renal vascular resistance. With the increase in operative time and irrigation fluid volume used during the operation, RI seems to be significantly increased.

Nitric oxide in afferent arterioles after uninephrectomy depends on extracellularl-arginine

Uninephrectomy (UNX) causes hyperperfusion of the contralateral remaining kidney via increased nitric oxide (NO) synthesis. Although the exact mechanism remains largely unknown, we hypothesize that this would be localized to the afferent arteriole and that it depends on cellular uptake of l-arginine. The experiments were performed in rats 2 days (early) or 6 wk (late) after UNX and compared with controls (Sham) to study acute and chronic effects on NO metabolism. Renal blood flow was increased after UNX (21 ± 2 ml·min(-1)·kg(-1) in sham, 30 ± 3 in early, and 26 ± 1 in late, P < 0.05). NO inhibition with N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME) caused a greater increase in renal vascular resistance in early UNX compared with Sham and late UNX (138 ± 24 vs. 88 ± 10, and 84 ± 7%, P < 0.01). The lower limit of autoregulation was increased both in early and late UNX compared with Sham (P < 0.05). L-NAME did not affect the ANG II-induced contraction of isolated afferent arterioles (AA) from Sham. AA from early UNX displayed a more pronounced contraction in response to L-NAME (-57 ± 7 vs. -16 ± 7%, P < 0.05) and in the absence of L-arginine (-41 ± 4%, P < 0.05) compared with both late UNX and Sham. mRNA expression of endothelial NO synthase was reduced, whereas protein expression was unchanged. Cationic amino acid transporter-1 and -2 mRNA was increased, while protein was unaffected in isolated preglomerular resistance vessels. In conclusion, NO-dependent hyperperfusion of the remaining kidney in early UNX is associated with increased NO release from the afferent arteriole, which is highly dependent on extracellular L-arginine availability.

Bradykinin and excitatory reno‐renal reflexes

The inflammatory mediator, bradykinin, when given into the renal artery elicits renal nerve dependent increases in renal vascular resistance. This study examined how renal interstitial bradykinin infusion regulated contralateral renal sympathetic nerve activity (RSNA) and the contribution of TRP channels in the response. Groups of chloralose/urethane anaesthetised male Wistar rats (n=6) were prepared for renal interstitial infusion at 1ml/h of bradykinin, 3×10−9 g/L, 6×10−9 g/L and 1.2×10−8g/L, into the ipsilateral kidney and measurement of RSNA to the contralateral kidney. Data, means±SEM were subject to two‐way ANOVA and significance taken at P&lt;0.05. Bradykinin infusion had no effect on blood pressure, at 103±3mmHg, but increased RSNA from a basal value, 2.2±0.3mV/s, to 2.7±0.5, 3.1±0.6 and 4.0±0.6mV/s at the highest dose. The RSNA responses to bradykinin were abolished by denervation of the ipsilateral kidney and by co‐infusion of the TRP channel blocker, capsazepine, 5 μg/ml, with the bradykinin. These data demonstrate that bradykinin, which is associated with renal injury and failure, can activate sensory nerves within the kidney to elicit a renal sympatho‐excitation.

Sildenafil reduces polyuria in rats with lithium-induced NDI

Lithium (Li)-treated patients often develop urinary concentrating defect and polyuria, a condition known as nephrogenic diabetes insipidus (NDI). In a rat model of Li-induced NDI, we studied the effect that sildenafil (Sil), a phosphodiesterase 5 (PDE5) inhibitor, has on renal expression of aquaporin-2 (AQP2), urea transporter UT-A1, Na(+)/H(+) exchanger 3 (NHE3), Na(+)-K(+)-2Cl(-) cotransporter (NKCC2), epithelial Na channel (ENaC; α-, β-, and γ-subunits), endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase. We also evaluated cGMP levels in medullary collecting duct cells in suspension. For 4 wk, Wistar rats received Li (40 mmol/kg food) or no treatment (control), some receiving, in weeks 2-4, Sil (200 mg/kg food) or Li and Sil (Li+Sil). In Li+Sil rats, urine output and free water clearance were markedly lower, whereas urinary osmolality was higher, than in Li rats. The cGMP levels in the suspensions of medullary collecting duct cells were markedly higher in the Li+Sil and Sil groups than in the control and Li groups. Semiquantitative immunoblotting revealed the following: in Li+Sil rats, AQP2 expression was partially normalized, whereas that of UT-A1, γ-ENaC, and eNOS was completely normalized; and expression of NKCC2 and NHE3 was significantly higher in Li rats than in controls. Inulin clearance was normal in all groups. Mean arterial pressure and plasma arginine vasopressin did not differ among the groups. Sil completely reversed the Li-induced increase in renal vascular resistance. We conclude that, in experimental Li-induced NDI, Sil reduces polyuria, increases urinary osmolality, and decreases free water clearance via upregulation of renal AQP2 and UT-A1.

Effect of the technique for assisting renal blood circulation on ischemic kidney in acute cardiorenal syndrome

The technique for assisting renal blood circulation may be a useful therapeutic method in acute cardiorenal syndrome (ACRS), because renal ischemic dysfunction due to the reduced renal blood circulation is a powerful negative prognostic factor in ACRS. We constructed a circuit assisting renal arterial pressure and flow, and performed renal-selective blood perfusion (RSP) to the left kidney in a goat model of ACRS induced by right ventricular rapid pacing (n=8), with the right kidney left intact as an internal control. Upon induction of ACRS, renal arterial flow (RAF), creatinine clearance (CCr), and renal oxygen consumption (RVO(2)) of the left kidney decreased to 49, 48, and 63% of the respective baseline values accompanied by a significant increase in renal vascular resistance (RVR), and similar results were observed in the right kidney. Then, RSP improved RVR and increased left RAF, CCr, and RVO(2) up to 91, 86, and 93% of baseline values, respectively, without a significant change in systemic hemodynamics. The RSP-treated kidney showed significantly higher CCr and urinary excretion of water and sodium compared to the contralateral kidney. Additional infusion of prostaglandin E(1) with RSP decreased RVR further and enabled the left RAF to increase up to 129% of the baseline value, without a significant change in systemic hemodynamic parameters. The CCr and RVO(2) did not change significantly, and urinary excretion of water and sodium showed a tendency to increase. These findings suggest that the technique for assisting renal blood circulation for both kidneys may offer a new treatment strategy for patients with ACRS.

Chronic tempol treatment attenuates the renal hemodynamic effects induced by a heme oxygenase inhibitor in streptozotocin diabetic rats

Heme oxygenase-1 (HO-1) is induced by oxidative stress and plays an important role in protecting the kidney from oxidant-mediated damage in the streptozotocin (STZ) rat model of type-1 diabetes mellitus (DM-1). HO-derived metabolites, presumably carbon monoxide (CO), mediate vasodilatory influences in the renal circulation, particularly in conditions linked to elevated HO-1 protein expression or diminished nitric oxide (NO) levels. We tested the hypothesis that diabetes increases oxidative stress and induces HO-1 protein expression, which contributes to regulate renal hemodynamics in conditions of low NO bioavailability. Two weeks after the induction of diabetes with STZ (65 mg/kg iv), Sprague-Dawley rats exhibited higher renal HO-1 protein expression, hyperglycemia, and elevated renal nitrotyrosine levels than control normoglycemic animals. In anesthetized diabetic rats, renal vascular resistance (RVR) was increased, and in vivo cortical NO levels were reduced (P < 0.05) compared with control animals. Acute administration of the HO inhibitor Stannous mesoporphyrin (SnMP; 40 μmol/kg iv) did not alter renal hemodynamics in control rats, but greatly decreased glomerular filtration rate and renal blood flow, markedly increasing RVR in hyperglycemic diabetic rats. Chronic oral treatment with the SOD mimetic tempol prevented the elevation of nitrotyrosine, the HO-1 protein induction, and the increases in RVR induced by SnMP in the diabetic group, without altering basal NO concentrations or RVR. Increasing concentrations of a CO donor (CO-releasing molecule-A1) on pressurized renal interlobar arteries elicited a comparable relaxation in vessels taken from control or diabetic animals. These results suggest that oxidative stress-induced HO-1 exerts vasodilatory actions that partially maintain renal hemodynamics in uncontrolled DM-1.

Mechanisms of K+ induced renal vasodilation in normo‐ and hypertensive rats in vivo

We investigated the mechanisms behind K(+) -induced renal vasodilation in vivo in normotensive Sprague-Dawley (SD) rats and spontaneously hypertensive rats (SHR). Renal blood flow (RBF) was measured utilizing an ultrasonic Doppler flow probe. Renal vascular resistance (RVR) was calculated as the ratio of mean arterial pressure (MAP) and RBF (RVR = MAP/RBF). Test drugs were introduced directly into the renal artery. Inward rectifier K(+) (K(ir) ) channels and Na(+) ,K(+) -ATPase were blocked by Ba(2+) and ouabain (estimated plasma concentrations ∼20 and ∼7 μm) respectively. Confocal immunofluorescence microscopy demonstrated K(ir) 2.1 channels in pre-glomerular vessels of SD and SHR. Ba(2+) caused a transient (6-13%) increase in baseline RVR in both SD and SHR. Ouabain had a similar effect. Elevated renal plasma [K(+) ] (∼12 mm) caused a small and sustained decrease (5-13%) in RVR in both strains. This decrease was significantly larger in SHR than in SD. The K(+) -induced vasodilation was attenuated by Ba(2+) in control SD and SHR and by ouabain in SD. Nitric oxide (NO) blockade using l-NAME treatment increased MAP and decreased RBF in both rat strains, but did not affect the K(+) -induced renal vasodilation. K(+) -induced renal vasodilation is larger in SHR, mediated by K(ir) channels in SD and SHR, and in addition, by Na(+) ,K(+) -ATPase in SD. In addition, NO is not essential for K(+) -induced renal vasodilation.

Role of Endothelin‐1 in Ischemic Acute Renal Failure in Rats

The role of endothelin-1 in ischemic acute renal failure in rats is described. After 45 min of ischemia, mean blood pressure was increased by 11% and renal blood flow (RBF) and renal surface blood flow (RSBF) rates were reduced by about 30% resulting in a 70% increase in renal vascular resistance (RVR) compared with nonischemic control rats. Higher levels of endothelin-1 were also found in the kidneys and plasma of ischemic rats. Endothelin-1-induced ischemia seems to play a significant role in the pathogenesis of acute renal failure. During reperfusion, injection of endothelin-1 (0.1–0.3 nmolkg−1) into post-ischemic rats did not affect RBF, RSBF or RVR. However, injection of the α-stimulant, 1-phenylephrine (1–10μg kg−1), dose-dependently reduced RBF and RSBF, regardless of whether renal ischemia had occurred. The endothelin-1 insensitivity of post-ischemic rats may be due to inactivation of the vasocontractile systems or activation of the vasodilative systems.

Searching for mechanisms that matter in early septic acute kidney injury: an experimental study

IntroductionIn almost half of all sepsis patients, acute kidney injury (AKI) develops. However, the pathobiologic differences between sepsis patients with and without AKI are only poorly understood. We used a unique opportunity to examine dynamic inflammatory, renal hemodynamic, and microvascular changes in two clinically relevant large-animal models of sepsis. Our aim was to assess variability in renal responses to sepsis and to identify both hemodynamic and nonhemodynamic mechanisms discriminating individuals with AKI from those in whom AKI did not develop.MethodsThirty-six pigs were anesthetized, mechanically ventilated, and instrumented. After a recovery period, progressive sepsis was induced either by peritonitis (n = 13) or by continuous intravenous infusion of live Pseudomonas aeruginosa (n = 15). Eight sham operated-on animals served as time-matched controls. All animals received standard intensive care unit (ICU) care, including goal-directed hemodynamic management. Before, and at 12, 18, and 22 hours of sepsis, systemic and renal (ultrasound flow probe) hemodynamics, renal cortex microcirculation (laser Doppler), inflammation (interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), oxidative stress (thiobarbituric acid reactive species (TBARS), nitrite/nitrate concentrations (NOx), and renal oxygen kinetics and energy metabolism were measured.ResultsIn 14 (50%) pigs, AKI developed (62% in peritonitis, 40% in bacteria infusion model). Fecal peritonitis resulted in hyperdynamic circulation, whereas continuous bacteria infusion was associated with normodynamic hemodynamics. Despite insults of equal magnitude, comparable systemic hemodynamic response, and uniform supportive treatment, only those pigs with AKI exhibited a progressive increase in renal vascular resistance. This intrarenal vasoconstriction occurred predominantly in the live-bacteria infusion model. In contrast to AKI-free animals, the development of septic AKI was preceded by early and remarkable inflammatory response (TNF-α, IL-6) and oxidative stress (TBARS).ConclusionsThe observed variability in susceptibility to septic AKI in our models replicates that of human disease. Early abnormal host response accompanied by subsequent uncoupling between systemic and renal vascular resistance appear to be major determinants in the early phase of porcine septic AKI. Nonuniform and model-related renal hemodynamic responses that are unpredictable from systemic changes should be taken into consideration when evaluating hemodynamic therapeutic interventions in septic AKI.

Renal denervation modulates angiotensin receptor expression in the renal cortex of rabbits with chronic heart failure

Excessive sympathetic drive is a hallmark of chronic heart failure (HF). Disease progression can be correlated with plasma norepinephrine concentration. Renal function is also correlated with disease progression and prognosis. Because both the renal nerves and renin-angiotensin II system are activated in chronic HF we hypothesized that excessive renal sympathetic nerve activity decreases renal blood flow in HF and is associated with changes in angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R) expression. The present study was carried out in conscious, chronically instrumented rabbits with pacing-induced HF. We found that rabbits with HF showed a decrease in mean renal blood flow (19.8±1.6 in HF vs. 32.0±2.5 ml/min from prepace levels; P<0.05) and an increase in renal vascular resistance (3.26±0.29 in HF vs. 2.21±0.13 mmHg·ml(-1)·min in prepace normal rabbits; P<0.05) while the blood flow and resistance was not changed in HF rabbits with the surgical renal denervation. Renal AT1R expression was increased by ∼67% and AT2R expression was decreased by ∼87% in rabbits with HF; however, kidneys from denervated rabbits with HF showed a near normalization in the expression of these receptors. These results suggest renal sympathetic nerve activity elicits a detrimental effect on renal blood flow and may be associated with alterations in the expression of angiotensin II receptors.

Interaction of the Anti-Inflammatory Annexin A1 Protein and Tacrolimus Immunosuppressant in the Renal Function of Rats

Background: Tacrolimus (FK) is currently widely used in transplant immunosuppression and the treatment of autoimmune diseases. However, FK induces nephrotoxicity which is characterized by functional and structural renal injury. The ubiquitous protein annexin A1 (ANXA1) has potent anti-inflammatory effects and protects against ischemia/reperfusion injury. We investigated the effects of exogenous ANXA1 treatment in an experimental model of acute FK nephrotoxicity. Methods: Munich-Wistar rats received a low-salt diet for 1 week and were randomized to treatment with ANXA1 (Ac2-26 peptide 0.5 mg/kg/day s.c.), FK (6 mg/kg/day p.o.), association (FK+ANXA1) and vehicles (1 ml/kg/day) for 7 days. Results: FK induced a significant decrease in glomerular filtration rate and renal blood flow, and a significant increase in renal vascular resistance. In addition, FK caused extensive acute tubule-interstitial damage and an increase in anti-inflammatory ANXA1 expression in renal tissue. Exogenous ANXA1 treatment reduced FK-induced tubular dilatation and macrophage infiltration. For the first time, we observed that FK augmented ANXA1 expression in renal tissue. Conclusion: Exogenous ANXA1 treatment partially protected against FK-induced tubular injury and macrophage infiltration, and may be targeted in renal intervention strategies.

Nitric oxide and renal haemodynamics during postnatal maturation: Role of angiotensin receptors

To investigate whether renal haemodynamic effects of nitric oxide (NO) in the newborn are mediated by activation of angiotensin type 1 (AT1) or/and type 2 (AT2) receptors, three experiments were carried out in conscious, chronically instrumented lambs aged ~one (N=5) and ~six weeks (N=6). Measurements were made before and after I.V. administration of antagonists selective to the AT1 receptor (ZD 7155, experiment 1), the AT2 receptor (PD 123319, experiment 2), and both receptors (ZD 7155+PD 123319, experiment 3) before and after administration of the L‐arginine analogue, L‐NAME. After ZD 7155 and ZD 7155+PD 123319, but not PD 123319 alone, renal vascular resistance (RVR) decreased in both age groups by ~25%. At one week, the RVR increase after L‐NAME was ~20% with ZD 7155, and ZD 7155 plus PD 123319, and ~16% with PD 123319 alone. At six weeks, the RVR increase after L‐NAME was ~40% with ZD 7155, and ZD 7155+PD 123319, and ~30% with PD 123319 alone. Therefore, ANG II modulates baseline renal haemodynamics as well as the renal haemodynamic effects of NO in an age‐dependent manner, through activation of both AT1 and AT2 receptors.

Adult renal function is modified by perinatal taurine status in conscious male rats

Perinatal taurine exposure influences renal function in adult female offspring. This study tests the hypothesis that prenatal rather than postnatal taurine exposure alters renal function in adult conscious male rats. Female Sprague Dawley rats were fed normal rat chow and tap water alone (Control), tap water containing 3% β-alanine (taurine depletion, TD) or tap water containing 3% taurine (taurine supplementation, TS) either from conception until delivery (fetal period; TDF or TSF) or from delivery until weaning (lactation period; TDL or TSL). After weaning, male offspring were fed with the normal rat chow and tap water ad libitum. At 7-8 weeks of age, renal function was studied in conscious, restrained rats. Mean arterial pressures were slightly higher in rats receiving taurine supplementation during either the fetal or lactation periods (compared to Control and TD groups), but heart rates were not significantly different among groups. Effective renal blood flows were lower in TDF, TDL, and TSF rats (TDF 4.6±0.8 ml/min/g kidney weight (KW), TDL 3.0±0.9 ml/min/g KW, and TSF 2.8±0.7 ml/min/g KW) than in TSL (7.7±0.9 ml/min/g KW) or Control rats (7.3±1.6 ml/min/g KW). These differences were correlated with significant increases in renal vascular resistance in TDF, TDL, and TSF groups compared to TSL and Control rats. In contrast, glomerular filtration rates were not significantly different among groups. Although basal water and sodium excretion were slightly lower in TDL and TSF rats compared to other groups, their diuretic and natriuretic responses to an acute saline load were not different from Control. The present data indicate that in adult male rats, both perinatal supplementation and depletion of taurine can alter renal hemodynamics, and these effects are differentially time-dependent.

Altered whole kidney blood flow autoregulation in a mouse model of reduced beta-ENaC.

Renal blood flow (RBF) autoregulation is mediated by at least two mechanisms, the fast acting myogenic response (approximately 5 s) and slow acting tubuloglomerular feedback (TGF; approximately 25 s). Previous studies suggest epithelial Na(+) channel (ENaC) family proteins, beta-ENaC in particular, mediate myogenic constriction in isolated renal interlobar arteries. However, it is unknown whether beta-ENaC-mediated myogenic constriction contributes to RBF autoregulation in vivo. Therefore, the goal of this investigation was to determine whether the myogenic mediated RBF autoregulation is inhibited in a mouse model of reduced beta-ENaC (m/m). To address this goal, we evaluated the temporal response of RBF and renal vascular resistance (RVR) to a 2-min step increase in mean arterial pressure (MAP). Pressure-induced changes in RBF and RVR at 0-5, 6-25, and 110-120 s after step increase in MAP were used to assess the contribution of myogenic and TGF mechanisms and steady-state autoregulation, respectively. The rate of the initial increase in RVR, attributed to the myogenic mechanism, was reduced by approximately 50% in m/m mice, indicating the speed of the myogenic response was inhibited. Steady-state autoregulation was similar between beta-ENaC +/+ and m/m mice. Although the rate of the secondary increase in RVR, attributed to TGF, was similar in beta-ENaC +/+ and m/m mice, however, it occurred over a longer period (+10 s), which may have allowed TGF to compensate for a loss in myogenic autoregulation. Our findings suggest beta-ENaC is an important mediator of renal myogenic constriction-mediated RBF autoregulation in vivo.

Involvement of protein kinase C-CPI-17 in androgen modulation of angiotensin II-renal vasoconstriction

Previous studies suggested that androgens augmented renal vascular responses to angiotensin II (Ang II). The protein kinase C (PKC)-CPI-17 pathway is involved in vascular constriction. We tested the hypothesis that this pathway may contribute to androgenic amplification of Ang II-renal vasoconstriction in the New Zealand genetically hypertensive (NZGH) rat. NZGH underwent sham operation, castration, or castration with testosterone replacement at 5 weeks of age. When the rats were 16-17 weeks of age, mean arterial pressure (MAP) and renal vascular resistance (RVR) responses to intravenous Ang II infusion (20, 40, and 80 ng/kg/min) were recorded before and after treatment with a PKC inhibitor, chelerythrine. mRNA expression of PKC isoforms and CPI-17 protein expression were analysed in renal cortex. MAP and RVR responses to Ang II were enhanced in androgen-replete NZGH. The Ang II-induced increase in RVR was significantly lower in castrated NZGH (ranged from 100 +/- 8% to 161 +/- 9% of baseline) than in sham-operated NZGH (ranged between 123 +/- 3% and 237 +/- 19% of baseline). Testosterone treatment restored RVR responses to Ang II in castrated rats. Chelerythrine treatment markedly reduced the MAP and RVR responses to Ang II in each group and attenuated the differential MAP and RVR responses to Ang II amongst the three groups. PKCdelta and PKCepsilon mRNA levels were significantly reduced by castration and increased by testosterone treatment. In contrast, no significant differences in protein expression were detected for these PKC isoforms. Castration decreased while testosterone treatment increased CPI-17 and phospho-CPI-17 expression. Collectively, these results suggest that androgens modulate renal vascular responses to Ang II in part via an effect on the PKC-CPI-17 signalling pathway.

Beneficial effect of insulin-like growth factor-1 on hypoxemic renal dysfunction in the newborn rabbit

Acute normocapnic hypoxemia can cause functional renal insufficiency by increasing renal vascular resistance (RVR), leading to renal hypoperfusion and decreased glomerular filtration rate (GFR). Insulin-like growth factor 1 (IGF-1) activity is low in fetuses and newborns and further decreases during hypoxia. IGF-1 administration to humans and adult animals induces pre- and postglomerular vasodilation, thereby increasing GFR and renal blood flow (RBF). A potential protective effect of IGF-1 on renal function was evaluated in newborn rabbits with hypoxemia-induced renal insufficiency. Renal function and hemodynamic parameters were assessed in 17 anesthetized and mechanically ventilated newborn rabbits. After hypoxemia stabilization, saline solution (time control) or IGF-1 (1 mg/kg) was given as an intravenous (i.v.) bolus, and renal function was determined for six 30-min periods. Normocapnic hypoxemia significantly increased RVR (+16%), leading to decreased GFR (-14%), RBF (-19%) and diuresis (-12%), with an increased filtration fraction (FF). Saline solution resulted in a worsening of parameters affected by hypoxemia. Contrarily, although mean blood pressure decreased slightly but significantly, IGF-1 prevented a further increase in RVR, with subsequent improvement of GFR, RBF and diuresis. FF indicated relative postglomerular vasodilation. Although hypoxemia-induced acute renal failure was not completely prevented, IGF-1 elicited efferent vasodilation, thereby precluding a further decline in renal function.

Tempol normalizes renal vascular resistance in rabbits with pacing induced heart failure

The cardio-renal syndrome represents a major complication in heart failure (HF) patients. We hypothesize that in rabbits with HF elevated renal vascular resistance (RVR) is due, in part, to reactive oxygen species (ROS) and angiotensin II type 1 receptor (AT1R) activation and a reduction in AT2R expression. After HF, RVR increased from sham (+0.45±0.24 mm Hg/ml/min) which tempol prevented (-0.21±0.05 mm Hg/ml/min, P=0.02 vs. no treatment) and the response to losartan, an AT1R inhibitor, was abolished (see table). The relative expression of AT1R to AT2R was normalized by tempol treatment in HF rabbits (see table). These results suggest the increase in RVR in HF is due, in part, to aberrant AT1R and AT2R expression and increases in ROS and could implicate a potential therapeutic strategy to improve the cardio-renal syndrome. *P<0.05 vs. sham, †P<0.05 vs. HF, ‡P<0.05 vs. respective baseline, #P<0.05 vs. sham tempol.

Nitric Oxide Bioavailability and Its Potential Relevance to the Variation in Susceptibility to the Renal and Vascular Complications in Patients With Type 2 Diabetes

OBJECTIVE—We compared the renal and systemic vascular (renovascular) response to a reduction of bioavailable nitric oxide (NO) in type 2 diabetic patients without nephropathy and of African and Caucasian heritage.RESEARCH DESIGN AND METHODS—Under euglycemic conditions, renal blood flow was determined by a constant infusion of paraminohippurate and changes in blood pressure and renal vascular resistance estimated before and after an infusion of l-Ng-monomethyl-l-arginine.RESULTS—In the African-heritage group, there was a significant fall in renal blood flow (Δ−46.0 ml/min per 1.73 m2; P < 0.05) and rise in systolic blood pressure (Δ10.0 mmHg [95% CI 2.3–17.9]; P = 0.017), which correlated with an increase in renal vascular resistance (r2 = 0.77; P = 0.004).CONCLUSIONS—The renal vasoconstrictive response associated with NO synthase inhibition in this study may be of relevance to the observed vulnerability to renal injury in patients of African heritage.

Altered reactivity to α2‐adenergic stimulation in the vasculature of the Obese Zucker rat

Obesity is associated with marked changes in adrenergic vasoconstriction of the resistance circulation. Stimulation of α1 receptors with phenylephrine promotes increased hindlimb vascular resistance (HVR) and decreased mesenteric resistance (MVR) in obese Zucker rats (OZR). Effects of obesity on constrictor reactivity to α2 receptor stimulation are unknown. Anesthetized lean Zucker rats (LZR) and OZR were instrumented with arterial catheters and flow probes around the mesenteric and renal arteries and distal aorta to measure MVR, renal vascular resistance (RVR) and HVR. I.v. injections of clonidine caused drops in blood pressure consistent with the central actions of clonidine that were similar in LZR and OZR. To rule out central effects reactivity was evaluated after 2 mg/kg mecamylamine. Clonidine (0.05–5 μg) caused increases in HVR that were similar in OZR and LZR. However, increases in MVR were greater in OZR vs. LZR (62±5 vs. 49±6 % of basal) as were increases in RVR (10±2 vs. 25±7%). To determine if NO deficit explains increased constriction, experiments were repeated with 500 μg/kg L‐NAME. Increases in MVR (72±4 vs 73±6%) and RVR (11±2 vs. 25±8%) persisted suggesting a difference in reactivity to α2‐receptor stimulation rather than loss of buffering NO. Together, these data indicate that loss of α1 vasoreactivity in the splanchnic and renal beds may be offset by increases in α2 vasoreactivity. (HL076533‐03)