Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals

2008 ◽  
Vol 294 (2) ◽  
pp. F362-F370 ◽  
Author(s):  
Mattias Carlström ◽  
Russell D. Brown ◽  
Jenny Edlund ◽  
Johan Sällström ◽  
Erik Larsson ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Blood Pressure Response ◽  
Chronic Administration ◽  
Renal Tissue ◽  
Tubuloglomerular Feedback ◽  
Before And After ◽  
Nitric Oxide Deficiency ◽  
Pressure Natriuresis ◽  
Salt Sensitive Hypertension

Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either NG-nitro-l-arginine methyl ester (l-NAME) or l-arginine. Blood samples for ADMA, SDMA, and l-arginine analysis were taken and the renal tissue was used for histology and determination of NO synthase (NOS) proteins. TGF characteristics were determined by stop-flow pressure technique before and after administration of 7-nitroindazole (7-NI) or l-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to l-NAME was attenuated and l-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF response were greater in the hydronephrotic group. 7-NI administration increased TGF reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, neuronal NOS (nNOS) inhibition had no effect. l-Arginine attenuated TGF response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and endothelial NOS proteins were lower in animals with hydronephrosis. Reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF mechanism, plays an important role in the development of hypertension.

scholarly journals The endocrine system in chronic nitric oxide deficiency

2007 ◽  
Vol 156 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Félix Vargas ◽  
Juan Manuel Moreno ◽  
Rosemary Wangensteen ◽  
Isabel Rodríguez-Gómez ◽  
Joaquín García-Estañ
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Blood Pressure Response ◽  
Endocrine System ◽  
Special Focus ◽  
No Production ◽  
Regulatory Systems ◽  
Reported Study ◽  
Nitric Oxide Deficiency ◽  
Glucose And Lipid Homeostasis

The experimental model of chronic inhibition of nitric oxide (NO) production has proven to be a useful tool to study cardiovascular and renal lesions produced by this type of hypertension, which are similar to those found in human hypertension. It also offers a unique opportunity to study the interaction of NO with the humoral systems, known to have a role in the normal physiology of vascular tone and renal function. This review provides a thorough and updated analysis of the interactions of NO with the endocrine system. There is special focus on the main vasoactive factors, including the renin-angiotensin-aldosterone system, catecholamines, vasopressin, and endothelin among others. Recent discoveries of crosstalk between the endocrine system and NO are also reported. Study of these humoral interactions indicates that NO is a molecule with ubiquitous function and that its inhibition alters virtually to all other known regulatory systems. Thus, hypothyroidism attenuates the pressor effect of NO inhibitor N-nitro-L-arginine methyl ester, whereas hyperthyroidism aggravates the effects of NO synthesis inhibition; the sex hormone environment determines the blood pressure response to NO blockade; NO may play a homeostatic role against the prohypertensive effects of mineralocorticoids, thyroid hormones and insulin; and finally, NO deficiency affects not only blood pressure but also glucose and lipid homeostasis, mimicking the human metabolic syndrome X, suggesting that NO deficiency may be a link between metabolic and cardiovascular disease.

Systemic and regional hemodynamics after nitric oxide synthase inhibition: role of a neurogenic mechanism

1994 ◽  
Vol 267 (1) ◽  
pp. R84-R88 ◽  
Author(s):  
M. Huang ◽  
M. L. Leblanc ◽  
R. L. Hester
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Cardiac Output ◽  
No Synthase ◽  
Before And After ◽  
Regional Hemodynamics ◽  
Autonomic Blockade ◽  
Infusion Of Norepinephrine ◽  
Oxide Synthase

The study tested the hypothesis that the increase in blood pressure and decrease in cardiac output after nitric oxide (NO) synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME) was partially mediated by a neurogenic mechanism. Rats were anesthetized with Inactin (thiobutabarbital), and a control blood pressure was measured for 30 min. Cardiac output and tissue flows were measured with radioactive microspheres. All measurements of pressure and flows were made before and after NO synthase inhibition (20 mg/kg L-NAME) in a group of control animals and in a second group of animals in which the autonomic nervous system was blocked by 20 mg/kg hexamethonium. In this group of animals, an intravenous infusion of norepinephrine (20-140 ng/min) was used to maintain normal blood pressure. L-NAME treatment resulted in a significant increase in mean arterial pressure in both groups. L-NAME treatment decreased cardiac output approximately 50% in both the intact and autonomic blocked animals (P < 0.05). Autonomic blockade alone had no effect on tissue flows. L-NAME treatment caused a significant decrease in renal, hepatic artery, stomach, intestinal, and testicular blood flow in both groups. These results demonstrate that the increase in blood pressure and decreases in cardiac output and tissue flows after L-NAME treatment are not dependent on a neurogenic mechanism.

scholarly journals Serum levels of NG, NG-dimethyl-L-arginine, a potential endogenous nitric oxide inhibitor in dialysis patients.

1997 ◽  
Vol 8 (9) ◽  
pp. 1437-1442
Author(s):  
B Anderstam ◽  
K Katzarski ◽  
J Bergström
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Serum Levels ◽  
Model Systems ◽  
Dialysis Dose ◽  
Control Subjects ◽  
Before And After ◽  
Endogenous Nitric Oxide ◽  
Experimental Model Systems ◽  
The One

Nitric oxide (NO) is involved in blood pressure regulation, and its synthesis is inhibited by methylarginines. It has been hypothesized that one of these, asymmetrical dimethylarginine (ADMA), may contribute to dialysis-associated hypertension because it accumulates in the plasma of hemodialysis (HD) patients in a concentration high enough (4 mumol/L) to inhibit NO synthesis in experimental model systems. A precolumn HPLC technique was used to quantify methylarginines (ADMA and symmetrical dimethylarginine [SDMA]) in plasma from HD patients before and after dialysis, from continuous ambulatory peritoneal dialysis (CAPD) patients, and from healthy subjects. Plasma ADMA concentrations were 0.59 +/- 0.22 (SD) mumol/L in HD patients predialysis (n = 19) and 0.70 +/- 0.27 mumol/L in CAPD patients (n = 11), versus about half of the concentration in control subjects (0.36 +/- 0.08 mumol/L, n = 7). The concentrations of SDMA (not an inhibitor of NO formation) were approximately four to five times the ADMA concentrations in both HD and CAPD patients, in contrast to a ratio of 1:1 in the control subjects. Methylarginine concentrations were reduced by 23% and 40% postdialysis, as calculated from ADMA and SDMA values, respectively. No significant correlations were observed between ADMA concentrations, on the one had, and blood pressure, creatinine and dialysis dose (Kt/V urea), on the other hand. It is concluded that plasma levels of ADMA are considerably lower than those reported earlier in patients treated with HD and also below the levels that hitherto have been thought to have clinical relevance. The role of ADMA in inhibiting NO in dialysis-associated hypertension is questioned.

Tubuloglomerular feedback in ACE-deficient mice

1999 ◽  
Vol 276 (5) ◽  
pp. F751-F757 ◽  
Author(s):  
Timothy Traynor ◽  
Tianxin Yang ◽  
Yuning G. Huang ◽  
John H. Krege ◽  
Josie P. Briggs ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Pressure Response ◽  
Signal Transmission ◽  
Macula Densa ◽  
Mutant Mice ◽  
Tubuloglomerular Feedback ◽  
Ang Ii ◽  
Null Mutant ◽  
Nacl Concentration ◽  
Null Mutant Mice

In these experiments, we used a strain of angiotensin converting enzyme (ACE) germline null mutant mice, generated by J. H. Krege and co-workers (J. H. Krege, S. W. M. John, L. L. Langenbach, J. B. Hodgin, J. R. Hagaman, E. S. Bachman, J. C. Jennette, D. A. O’Brien, and O. Smithies. Nature 375: 146–148, 1995), to examine the effect of chronic ACE deficiency on the magnitude of tubuloglomerular feedback (TGF) responses. The genotype was determined by PCR on DNA extracted from the tail and was verified after each experiment by assessment of the blood pressure response to an injection of ANG I. To assess TGF responsiveness, we determined the change in stop-flow pressure (PSF) caused by increasing NaCl concentration at the macula densa by using micropuncture techniques. When loop of Henle flow rate was increased from 0 to 40 nl/min, PSF fell from a mean of 42.3 ± 1.95 to 33.6 ± 2.09 mmHg ( n = 6, P = 0.005) in wild-type mice (+/+), fell from 40.6 ± 2.35 to 38.6 ± 1.93 mmHg in heterozygous (+/−) mice ( n = 7, P = 0.014), and did not change in homozygous ACE (−/−) mice [36.7 ± 2.02 mmHg vs. 36.4 ± 2.01 mmHg; n = 4, P = not significant (NS)]. During an infusion of ANG II at a dose that did not significantly elevate blood pressure (70 ng ⋅ kg−1 ⋅ min−1), TGF response magnitude (PSF 0 − PSF 40) increased from 6.5 ± 1.4 to 9.8 ± 1.19 mmHg in +/+ ( P = 0.006), from 1.14 ± 0.42 to 4.6 ± 1.3 mmHg in +/− ( P = 0.016), and from 0.42 ± 0.25 to 4.02 ± 1.06 in −/− mice ( P = 0.05). Absence of TGF responses in ACE null mutant mice and restoration of near-normal responses during an acute infusion of ANG II supports previous conclusions that ANG II is an essential component in the signal transmission pathway that links the macula densa with the glomerular vascular pole.

scholarly journals Cerebral Blood Flow Changes during Cortical Spreading Depression are Not Altered by Inhibition of Nitric Oxide Synthesis

1994 ◽  
Vol 14 (6) ◽  
pp. 939-943 ◽  
Author(s):  
Zheng Gang Zhang ◽  
Michael Chopp ◽  
Kenneth I. Maynard ◽  
Michael A. Moskowitz
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Arterial Blood Pressure ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Arterial Blood ◽  
Nos Inhibitors ◽  
Before And After ◽  
Male Wistar Rats

CBF increases concomitantly with cortical spreading depression (CSD). We tested the hypothesis that CBF changes during CSD are mediated by nitric oxide (NO). Male Wistar rats (n = 23) were subjected to KCl-induced CSD before and after administration of nitric oxide synthase (NOS) inhibitors N-nitro-l-arginine (L-NNA) or N-nitro-l-arginine methyl ester (L-NAME) and in nontreated animals. CBF, CSD, and mean arterial blood pressure were recorded. Brain NOS activity was measured in vitro in control, L-NNA, and L-NAME-treated rats by the conversion of [3H]arginine to [3H]citrulline. Our data show that the NOS inhibitors did not significantly change regional CBF (rCBF) during CSD, even though cortical NOS activity was profoundly depressed and systemic arterial blood pressure was significantly increased. Our data suggest that rCBF during CSD in rats is not regulated by NO.

scholarly journals Possible involvement of nitric oxide on the blood pressure response to centrally acting anti-hypertensive drug.

1999 ◽  
Vol 79 ◽  
pp. 41
Author(s):  
Nobufumi Ono ◽  
Yoshinobu Yatomi ◽  
Shuuji Hara ◽  
Misa Fukuzawa ◽  
Takeshi Kuroda
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Blood Pressure Response ◽  
Pressure Response ◽  
Hypertensive Drug

NO production by cNOS and iNOS reflects blood pressure changes in LPS-challenged mice

2003 ◽  
Vol 285 (4) ◽  
pp. E871-E875 ◽  
Author(s):  
Marcella M. Hallemeesch ◽  
Ben J. A. Janssen ◽  
Wouter J. de Jonge ◽  
Peter B. Soeters ◽  
Wouter H. Lamers ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Blood Pressure Response ◽  
No Production ◽  
Baseline Conditions ◽  
Pressure Changes ◽  
Oxide Synthase ◽  
Nos Isoforms ◽  
Firm Evidence ◽  
Lps Treatment

Increased nitric oxide (NO) production is the cause of hypotension and shock during sepsis. In the present experiments, we have measured the contribution of endothelial (e) and inducible (i) nitric oxide synthase (NOS) to systemic NO production in mice under baseline conditions and upon LPS treatment (100 μg/10 g ip LPS). NO synthesis was measured by the rate of conversion of l-[ guanidino-15N2]arginine to l-[ ureido-15N]citrulline, and the contribution of the specific NOS isoforms was evaluated by comparing NO production in eNOS-deficient [(–/–)] and iNOS(–/–) mice with that in wild-type (WT) mice. Under baseline conditions, NO production was similar in WT and iNOS(–/–) mice but lower in eNOS(–/–) mice [WT: 1.2 ± 0.2; iNOS(–/–): 1.2 ± 0.2; eNOS(–/–): 0.6 ± 0.3 nmol · 10 g body wt–1· min–1]. In response to the challenge with LPS (5 h), systemic NO production increased in WT and eNOS(–/–) mice but fell in iNOS(–/–) mice [WT: 2.7 ± 0.3; eNOS(–/–): 2.2 ± 0.6; iNOS(–/–): 0.7 ± 0.1 nmol · 10 g body wt–1· min–1]. After 5 h of LPS treatment, blood pressure had dropped 14 mmHg in WT but not in iNOS(–/–) mice. The present findings provide firm evidence that, upon treatment with bacterial LPS, the increase of NO production is solely dependent on iNOS, whereas that mediated by cNOS is reduced. Furthermore, the data show that the LPS-induced blood pressure response is dependent on iNOS.

scholarly journals Heme oxygenase metabolites inhibit tubuloglomerular feedback (TGF)

2008 ◽  
Vol 295 (4) ◽  
pp. F1207-F1212 ◽  
Author(s):  
YiLin Ren ◽  
Martin A. D'Ambrosio ◽  
Hong Wang ◽  
Ruisheng Liu ◽  
Jeffrey L. Garvin ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heme Oxygenase ◽  
Tubuloglomerular Feedback ◽  
Afferent Arteriole ◽  
Nacl Concentration ◽  
Before And After ◽  
Low Levels ◽  
And Function ◽  
Oxide Synthase

Tubuloglomerular feedback (TGF) is the mechanism by which the macula densa (MD) senses increases in luminal NaCl concentration and sends a signal to constrict the afferent arteriole (Af-Art). The kidney expresses constitutively heme oxygenase-2 (HO-2) and low levels of HO-1. HOs release carbon monoxide (CO), biliverdin, and free iron. We hypothesized that renal HOs inhibit TGF via release of CO and biliverdin. Rabbit Af-Arts and attached MD were simultaneously microperfused in vitro. The TGF response was determined by measuring Af-Art diameter before and after increasing NaCl in the MD perfusate. When HO activity was inhibited by adding stannous mesoporphyrin (SnMP) to the MD perfusate, the TGF response increased from 2.1 ± 0.2 to 4.1 ± 0.4 μm ( P = 0.003, control vs. SnMP, n = 7). When a CO-releasing molecule, (CORM-3; 50 μM), was added to the MD perfusate, the TGF response decreased by 41%, from 3.6 ± 0.3 to 2.1 ± 0.2 μm ( P < 0.001, control vs. CORM-3, n = 12). When CORM-3 at 100 μM was added to the perfusate, it completely blocked the TGF response, from 4.2 ± 0.4 to −0.2 ± 0.3 μm ( P < 0.001, control vs. CORM-3, n = 6). When biliverdin was added to the perfusate, the TGF response decreased by 79%, from 3.4 ± 0.3 to 0.7 ± 0.4 μm ( P = 0.001, control vs. biliverdin, n = 6). The effects of SnMP and CORM-3 were not blocked by inhibition of nitric oxide synthase. We concluded that renal HO inhibits TGF probably via release of CO and biliverdin. HO regulation of TGF is a novel mechanism that could lead to a better understanding of the control of renal microcirculation and function.

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