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This study investigated the role of [α.sub.1D]-adrenoceptor in the modulation of renal haemodynamics in rats with left ventricular hypertrophy (LVH). LVH was established in Wistar-Kyoto (WKY) rats with isoprenaline (5.0 mg x [(kg body mass).sup.-1], by subcutaneous injection every 72 h) and caffeine (62 mg x [L.sup.-1] in drinking water, daily for 14 days). Renal vasoconstrictor responses were measured for noradrenaline (NA), phenylephrine (PE), and methoxamine (ME) before and immediately after low or high dose intrarenal infusions of BMY 7378, a selective [α.sub.1D]-adrenoceptor blocker. The rats with LVH had higher mean arterial blood pressure and circulating NA levels, but lower renal cortical blood perfusion compared with the control group (all P Key words: BMY 7378, renal cortical blood perfusion, noradrenaline, phenylephrine, methoxamine. Cette etude a examine le role de recepteur [α.sub.1D]-adrenergique dans la modulation de l'hemodynamique renale chez des rats affectes d'une hypertrophie ventriculaire gauche (HVG). L'HVG a ete provoquee chez des rats Wistar-Kyoto (WKY) par l'isoprenaline (5,0 mg x [(kg de masse corporelle).sup.-1], s.c., a toutes les 72 h) et la cafeine (62 mg x [L.sup.-1] dans l'eau de consommation, pendant 14 jours). La vasoconstriction renale en reponse a la noradrenaline (NA), a la phenylephrine (PE) et a la methoxamine (ME) a ete mesuree avant et immediatement apres une infusion intra-renale de BMY 7378, un bloqueur selectif de recepteur [α.sub.1D]-adrenergique, utilise a faible ou forte dose. Le groupe HVG presentait un tension arterielle moyenne et des niveaux circulants de NA plus eleves, mais une perfusion sanguine corticale renale plus faible comparativement au controle (P < 0,05). La magnitude de la vasoconstriction renale du groupe HVG en reponse a la ME etait attenuee (P < 0,05), contrairement a la NA et la PE, comparativement au groupe controle (HVG vs. C, 38 vs. 50 %). La magnitude de la chute de la vasoconstriction en reponse a la NA, a la PE et a la ME en presence d'une dose plus elevee de BMY 7378 etait significativement plus elevee dans le groupe HVG que le controle (HVG vs. C, 45 vs. 25 % (NA), 52 vs. 33 % (PE), 66 vs. 53 % (ME), P < 0,05). Ces donnees indiquent que la vasoconstriction renale en reponse a des agonistes adrenergiques est affectee lors de l'HVG. De plus, le sous-type [α.sub.1D] du recepteur adrenergique joue un role cle dans la modulation des reponses vasculaires dans cet etat pathologique. [Traduit par la Redaction] Mots-cles: BMY 7378, perfusion sanguine corticale renale, noradrenaline, phenylephrine, methoxamine., Introduction Left ventricular hypertrophy (LVH) is characterized by hyperactivity of the heart and an elevated sympathetic activity. Hence, the increase in the left ventricular mass in LVH is proportional to [...]

New Findings: What is the central question of this study?Are renal functional responses to intrarenal angiotensin 1–7 (Ang (1–7)) infusion dependent on the level of the endogenous renin–angiotensin system (RAS) in the two‐kidney one‐clip (2K1C) and deoxycorticosterone acetate (DOCA)‐salt animal models of hypertension?What is the main finding and its importance?The renal actions of Ang (1–7) are dependent on the relative endogenous levels of each arm of the classical angiotensin II–angiotensin II type 1 receptor (AT1R) axis and those of the Ang (1–7)–Mas receptor axis. These findings support the hypothesis that a balance exists between the intrarenal classical and novel arms of the RAS, and in particular the relative abundance of AT1R to Mas receptor, which may to a large extent determine the renal excretory response to Ang (1–7) infusion. This study investigated the action of angiotensin 1–7 (Ang (1–7)) on renal haemodynamic and excretory function in the two‐kidney one‐clip (2K1C) and deoxycorticosterone acetate (DOCA)‐salt rat models of hypertension, in which the endogenous renin–angiotensin system (RAS) activity was likely to be raised or lowered, respectively. Rats were anaesthetised and prepared for the measurement of mean arterial pressure and kidney function during renal interstitial infusion of Ang (1–7) or saline. Kidney tissue concentrations of angiotensin II (Ang II) and Ang (1–7) were determined. Intrarenal infusion of Ang (1–7) into the clipped kidney of 2K1C rats increased urine flow (UV), absolute (UNaV) and fractional sodium (FENa) excretions by 110%, 214% and 147%, respectively. Renal Ang II concentrations of the clipped kidney were increased with no major changes in Ang (1–7) concentration. By contrast, Ang (1–7) infusion decreased UV, UNaV, and FENa by 27%, 24% and 21%, respectively in the non‐clipped kidney in which tissue Ang (1–7) concentrations were increased, but renal Ang II concentrations were unchanged compared to sham animals. Ang (1–7) infusion in DOCA‐salt rats had minimal effects on glomerular filtration rate but significantly decreased UV, UNaV and FENa by ∼30%. Renal Ang (1–7) concentrations were higher and Ang II concentrations were lower in DOCA‐salt rats compared to sham rats. These findings demonstrate that the intrarenal infusion of exogenous Ang (1–7) elicits different renal excretory responses the magnitude of which is dependent on the balance between the endogenous renal Ang II–AT1 receptor axis and Ang (1–7)–Mas receptor axis. [ABSTRACT FROM AUTHOR]

Pathophysiological states, including cardiovascular and renal diseases, are characterized by oxidative stress but what is less clear is whether physiological challenges incur a degree of altered oxidative metabolism. To this end, this study examined whether exposure to a high dietary sodium intake could cause an oxidative stress at the kidney. Animals, placed on either 0.3% or 3% sodium diets for 2 wk, were given a lethal dose of anesthetic, and kidneys were removed to analyze both NAD(P)H oxidase (NOX) and superoxide dismutase (SOD) expression and activities in the cortex and medulla. Placing animals on the high-sodium diet raised sodium and water excretion and caused an ~14-fold increase in urinary excretion of 8-isoprostane, a marker of oxidative stress, which was attenuated by chronic treatment with apocynin to prevent NAD(P)H oxidase activity. The protein expression of the NAD(P)H oxidase subunits NOX2 and p47phox and overall NAD(P)H oxidase activity were approximately doubled in the cortex of the rats on the high-sodium diet compared with those on the normal sodium intake while both SOD activity and expression were unchanged. By contrast, neither NOX nor SOD protein expression or activity were altered in the medulla when the rats were placed on the high-sodium intake. These data suggest that an elevation in dietary sodium intake can lead to increased generation of reactive oxygen species and a state of oxidative stress in the cortex but not to such a degree that it extends to the medulla. renal cortex; renal medulla; oxidative stress; nicotinamide adenine dinucleotide phosphate oxidase; superoxide dismutase doi: 10.1152/ajpregu.00541.2009.

It was hypothesized that renal sympathetic nerve activity (RSNA) and neuronal nitric oxide synthase (nNOS) are involved in the acute inhibition of renin secretion and the natriuresis following slow NaCl loading (NaLoad) and that RSNA participates in the regulation of arterial blood pressure (MABP). This was tested by NaLoad after chronic renal denervation with and without inhibition of nNOS by S-methyl-thiocitrulline (SMTC). In addition, the acute effects of renal denervation on MABP and sodium balance were assessed. Rats were investigated in the conscious, catheterized state, in metabolic cages, and acutely during anesthesia. NaLoad was performed over 2 h by intravenous infusion of hypertonic solution (50 [micro]mol*[min.sup.-1]*kg body [mass.sup.-1]) at constant body volume conditions. SMTC was coinfused in amounts (20 [micro]g*[min.sup.-1]*[kg.sup-1]) reported to selectively inhibit nNOS . Directly measured MABPs of acutely and chronically denervated rats were less than control (15% and 9%, respectively, P < 0.005). Plasma renin concentration (PRC) was reduced by renal denervation (14.5 [+ or -] 0.2 vs. 19.3 [+ or -] 1.3 mIU/l, P < 0.005) and by nNOS inhibition (12.4 [+ or -] 2.3 vs. 19.6 [+ or -] 1.6 mlU/l, P < 0.005). NaLoad reduced PRC (P < 0.05) and elevated MABP modestly (P < 0.05) and increased sodium excretion six-fold, irrespective of renal denervation and SMTC. The metabolic data demonstrated that renal denervation lowered sodium balance during the first days after denervation (P < 0.001). These data show that renal denervation decreases MABP and renin secretion. However, neither renal denervation nor nNOS inhibition affects either the renin downregulation or the natriuretic response to acute sodium loading. Acute sodium-driven renin regulation seems independent of RSNA and nNOS under the present conditions. plasma renin concentration; total body sodium; blood pressure; sodium excretion

The processes involved in the renal damage resulting from ischemia-reperfusion injury are poorly understood. This study examined the contribution of prostaglandins and nitric oxide (NO) in the vascular responses to ischemia-reperfusion injury in the kidneys of normotensive and hypertensive rats. Groups of Wistar and stroke-prone spontaneously hypertensive rats (SHRSP) were dosed with polyethylene glycol vehicle, aspirin (53.5 mg x [kg.sup.-1] x [day.sup.-1]), NO-aspirin (100 mg x [kg.sup.-1] x [day.sup.-1]), or celecoxib (10 mg x [kg.sup.-1] x [day.sup.-1]) for 7 days. On day 7, rats were anesthetized with chloralose/urethane and the left kidney was exposed to a 30-min period of ischemia followed by 90-rain reperfusion. Renal cortical and medullary perfusions were monitored throughout using laser-Doppler flowmetry. In the vehicle- and celecoxib-treated Wistar rats, cortical and medullary postischemic perfusion was reduced to 66 and 62% and 53 and 62%, respectively (all P < 0.05), of baseline. The ischemia-induced reductions in cortical and medullary flux were ameliorated in the aspirin and NO-aspirin groups where flux fell to 96 and 78% and 105 and 83%, respectively (P < 0.05). There was a fall in cortical and medullary flux in the postischemic period in the vehicle-treated SHRSP to 82 and 77% (P < 0.05). These findings show that nonselective cyclooxygenase (COX) inhibition, and to an even greater extent NO donation, provided protection to the renal vasculature from ischemic injury in the Wistar rat but not in the SHRSP. This would suggest that prostaglandins are less important in the development of renal ischemia-reperfusion injury during hypertension and both COX isoforms must be inhibited to offset the decrease in renal hemodynamics. NO-NSAIDs; hypertension

This study investigated the impact of intrarenal angiotensin 1–7 (Ang [1–7]) infusion on renal excretory function in a rat model of hypertension. Eleven‐week‐old spontaneously hypertensive rats (SHRs, n = 7) and Han Wistar controls (NCR, n = 7) were anaesthetised with sodium pentobarbital (60 mg/kg i.p.) and prepared for the measurement of mean arterial pressure (MAP) and left renal function during renal interstitial infusion of Ang (1–7) (50 ng/min). The kidneys were harvested, the renal cortex and medulla separated, prepared for measurement of Ang II and Ang (1–7) and Western blot determination of AT1 and Mas receptor protein expression. MAP, glomerular filtration rate (GFR), urine flow (UF) and absolute sodium excretion (UNaV) were 109 ± 16 mmHg, 4.4 ± 1.0 mL/min/kg, 102 ± 16 µL/min/kg and 16 ± 3 µmol/min/kg, respectively in the NCR and 172 ± 24 mmHg, 3.4 ± 0.7 mL/min/kg, 58 ± 30 μL/min/kg and 8.6 ± 4.8 μmol/min/kg respectively in the SHR. Ang (1–7) increased UF (31%), UNaV (50%) and fractional sodium excretion (FENa+) (22%) in the NCR group (all p < 0.05) but had no effect on GFR in either group. The magnitudes of the Ang (1–7)‐induced increases in UF and UNaV were significantly blunted in the SHR group (model × drug p < 0.05). The renal cortical AT1: Mas receptor expression ratio was significantly higher in the SHR group (p < 0.05) but renal Ang II and Ang (1–7) levels were not statistically different between groups. The Ang (1–7)‐induced increases in sodium and water excretion were impaired in the SHR group in the context of an unstimulated RAS. The decrease in responsiveness of the SHR kidney to Ang (1–7) appears to be associated with higher levels of AT1 receptor expression in the renal cortex. [ABSTRACT FROM AUTHOR]

The dependence of the response of the kidneys in terms of hemodynamics and tubular function to somatosensory stimulation on the renal nerve is investigated in anesthetized rats with intact or resected renal nerves stimulated with subcutaneous injection of capsaicin. The pressor and antinatriuresis response was abolished in subjects with resected renal nerves.

The magnitude and pattern of the renal sympathetic nerve activity responses and the functional correlates were compared to two distinct cases in hypertensive and normotensive rats by subcutaneously treating the rodents with capsaicin. Both the exposure to poisonous fumes and the administration of capsaicin had caused the stimulation of the somatosensory system, which led to the increase in blood pressure. The changes in renal hemodynamics and decreased water and sodium excretion were all found to be minimal.

The role of vagal function in the modulation of somatosensory-induced alterations in the power spectral pattern of renal nerve activity was analyzed in spontaneously hypertensive (SHR) and normotensive Wistar rats. Administration of capsaicin increased renal nerve activity and elevated blood pressure in SHR and normotensive Wistar rats. However, renal nerve activity in SHR rats were higher after capsaicin treatments compared to normotensive Wistar rats due to major deficiencies in vagal influence on the renal sympathetic nerve output.

Left renal nerves of rats were stimulated electrically to lower renal blood flow by 15, 30 and 45%, and the level of mRNA for renin and angiotensinogen were measured to evaluate the effect of short spells of nerve stimulation on renin and angiotensinogen expression within the kidney. While 1 hour stimulations led to a proportional decrease in sodium extraction and increase in plasma renin activity, stimulations for a longer period were required to enhance renal renin mRNA levels. A minimal enhancement of angiotensinogen mRNA level and low rates of nerve activity were observed.

This study examined the effect of leptin and orexin‐A on autonomic baroreflex control in conscious Wistar rats exposed to high‐fat (45% fat) or normal (3.4%) diet for 4 weeks. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were monitored during the generation of baroreflex gain curves and acute volume expansion (VEP). Intracerebroventricular (ICV) leptin (1 μg/min) increased RSNA in the normal diet group (0.31 ± 0.04 vs 0.23 ± 0.03 mV/s) and MAP in the high‐fat diet group (115 ± 5 vs 105 ± 5 mm Hg, P <.05). Orexin‐A (50 ng/min) increased RSNA, HR and MAP in the high‐fat diet group (0.26 ± 0.03 vs 0.22 ± 0.02 mV/s, 454 ± 8 vs 417 ± 12 beats/min, 117 ± 1 vs 108 ± 1 mm Hg) and the normal diet group (0.18 ± 0.05 vs 0.17 ± 0.05 mV/s, 465 ± 10 vs 426 ± 6 beats/min, 116 ± 2 vs 104 ± 3 mm Hg). Baroreflex sensitivity for RSNA was increased during ICV leptin by 50% in the normal diet group, compared to 14% in the high‐fat diet group (P <.05). Similarly, orexin‐A increased baroreflex sensitivity by 56% and 50% in the high‐fat and normal diet groups, respectively (all P <.05). During ICV saline, VEP decreased RSNA by 31 ± 5% (P <.05) after 10 minutes and the magnitude of this response was blunted during ICV infusion of leptin (17 ± 2%, P <.05) but not orexin‐A in the normal diet group. RSNA response to VEP was not changed during ICV leptin or orexin‐A in the high‐fat diet group. These findings indicate possible central roles for leptin and orexin‐A in modulating the baroreflexes under normal or increased fat intake in conscious rats and potential therapeutic approaches for obesity associated hypertension. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Does immunosuppression restore the baroreflex control of renal sympathetic nerve activity (RSNA) in an animal model of kidney injury?What is the main finding and its importance?Tacrolimus, a calcineurin inhibitor, restored the high‐ and low‐pressure baroreflex control of RSNA following cisplatin‐induced renal injury. Cisplatin administration causes depression of renal haemodynamic and excretory function and is associated with renal sympatho‐excitation and loss of baroreflex regulation of renal sympathetic nerve activity (RSNA). This study investigated whether administration of the immunosuppressant tacrolimus in this cisplatin‐mediated renal injury model could restore, or the acute intra‐renal infusion of tumour necrosis factor α (TNF‐α) could blunt, the high‐ or low‐pressure baroreflex control of RSNA. Groups of control and cisplatin‐treated (5 mg kg−1, i.p. on day 0) rats received either saline or tacrolimus (0.25 mg kg−1 day−1, i.p.) for 7 days prior to study. Rats were anaesthetised and prepared for measurement of mean arterial pressure (MAP), heart rate (HR) and RSNA. Baroreflex gain curves were generated and the degree of renal sympatho‐inhibition determined (area under the curve (AUC) reported as %RSNA min) during acute volume expansion. Intrarenal TNF‐α infusion (0.3 µg kg−1 h−1) in control rats decreased baroreflex gain by 32% (P < 0.05) compared to intra‐renal saline infusion. In the cisplatin group (MAP: 98 ± 14 mmHg; HR: 391 ± 24beats min−1), the baroreflex gain for RSNA was 39% (P < 0.05) lower than that for the control group (MAP: 91 ± 7 mmHg; HR: 382 ± 29 beats min−1). In cisplatin‐treated rats given daily tacrolimus (MAP: 84 ± 12 mmHg; HR: 357 ± 30 beats min−1), the baroreflex gain and renal sympatho‐inhibition (AUC, 2440 ± 1071 vs. 635 ± 498% min) were restored to normal values. These findings provide evidence for the view that cisplatin administration initiates an injury involving inflammation which may contribute to the deranged baroreflex regulation of RSNA. This phenomenon appears mediated in part via the renal innervation. [ABSTRACT FROM AUTHOR]

Wu, Xiao Chun, Peter J. Harris, and Edward J. Johns. Nitric oxide and renal nerve-mediated proximal tubular reabsorption in normotensive and hypertensive rats. Am. J. Physiol. 277 (Renal Physiol. 46): F560-F566, 1999.--In Inactin-anesthetized Wistar rats with an intact renal innervation, intratubular nitro-L-arginine methyl ester (L-NAME, [10.sup.-4] M) increased proximal fluid uptake ([J.sub.va], at 2.47 [+ or -] 0.61 x [10.sup.-4] [mm.sup.3] [multiplied by] [mm.sup.-2] [multiplied by] [s.sup.-1]) by 17% (P [is less than] 0.05), whereas coadministration with sodium nitroprusside (SNP, [10.sup.-4] M) decreased [J.sub.va] by 18% (P [is less than] 0.01). Similar manipulation of NO generation was without effect in groups of Wistar rats subjected to acute renal denervation. Intratubular aminoguanidine ([10.sup.-4] M), a selective inducible nitric oxide synthase (NOS) blocker, had no effect on [J.sub.va] in intact kidneys of Wistar rats, but the neuronal NOS (nNOS) blocker, 7-nitroindazole ([10.sub.-4] M and [10.sup.-6] M) increased [J.sub.va] by 19-23% (both P [is less than] 0.001). In stroke-prone spontaneously hypertensive rats (SHRSP), [J.sub.va] values in the innervated kidneys were lower (P [is less than] 0.05) than in the corresponding Wistar groups and were unchanged by intratubular L-NAME or L-NAME plus SNP. The tonic attenuation of proximal epithelial transport by NO was dependent on the renal sympathetic nerves and appeared to be generated by the nNOS isoform of the enzyme. This role of NO was not evident in the SHRSP. nitric oxide synthase; renal sympathetic nerves; proximal tubular sodium reabsorption; stroke-prone spontaneously hypertensive rats

Left ventricular hypertrophy (LVH) is associated with decreased responsiveness of renal α1-adrenoreceptors subtypes to adrenergic agonists. Nitric oxide donors are known to have antihypertrophic effects however their impact on responsiveness of renal α1-adrenoreceptors subtypes is unknown. This study investigated the impact of nitric oxide (NO) and its potential interaction with the responsiveness of renal α1-adrenoreceptors subtypes to adrenergic stimulation in rats with left ventricular hypertrophy (LVH). This study also explored the impact of NO donor on CSE expression in normal and LVH kidney. LVH was induced using isoprenaline and caffeine in drinking water for 2 weeks while NO donor (L-arginine, 1.25g/Lin drinking water) was given for 5 weeks. Intrarenal noradrenaline, phenylephrine and methoxamine responses were determined in the absence and presence of selective α1-adrenoceptor antagonists, 5- methylurapidil (5-MeU), chloroethylclonidine (CeC) and BMY 7378. Renal cortical endothelial nitric oxide synthase mRNA was upregulated 7 fold while that of cystathione γ lyase was unaltered in the NO treated LVH rats (LVH-NO) group compared to LVH group. The responsiveness of renal α1A, α1B and α1D-adrenoceptors in the low dose and high dose phases of 5-MeU, CEC and BMY7378 to adrenergic agonists was increased along with cGMP in the kidney of LVH-NO group. These findings suggest that exogenous NO precursor up-regulated the renal eNOS/NO/cGMP pathway in LVH rats and resulted in augmented α1A, α1B and α1D adrenoreceptors responsiveness to the adrenergic agonists. There is a positive interaction between H2S and NO production in normal animals but this interaction appears absent in LVH animals. [ABSTRACT FROM AUTHOR]