Inducible Nitric Oxide Synthase Inhibition Attenuates Renal Hemodynamics During Pregnancy

Alexander, Barbara T.; Cockrell, Kathy; Cline, Farrah D.; Granger, Joey P.

doi:10.1161/hy0202.103288

Cited by 11 publications

(13 citation statements)

References 30 publications

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“…These hypotheses are supported by previous results implicating iNOS in experimental hypertension [14]. In contrast with our hypothesis, there is evidence that iNOS has an important role in the renal hemodynamic changes of pregnancy, and iNOS inhibition decreased glomerular filtration in pregnant rats [15], although renal iNOS apparently is not up-regulated in RUPP rats [12]. …”

Section: Introductionsupporting

confidence: 86%

“…Although we have not measured iNOS activity in this study, the 1400 W that we used (1 mg/kg) totally prevented vascular injury attributable to LPS-induced iNOS in rats (ED 50 = 0.3 mg/kg) [16]. Interestingly, other iNOS inhibitors were shown to increase blood pressure in normal rats [15], possibly as a result of non-selective iNOS inhibition, whereas our findings showed antihypertensive effects with 1400 W, possibly as a result of selective iNOS inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…The authors have examined the effects of iNOS inhibitors only in normal rats, and not in the RUPP model, and they showed that iNOS inhibition attenuated the increase in glomerular filtration rate observed in pregnant rats [15], thus suggesting that iNOS has a role in mediating the renal hemodynamic changes during pregnancy. Moreover, the same group has shown that renal iNOS expression decreases by 11% in the RUPP model as compared with normal pregnancy [12].…”

Section: Discussionmentioning

confidence: 99%

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Antihypertensive effects of inducible nitric oxide synthase inhibition in experimental pre‐eclampsia

Amaral

Pinheiro

Guimaraes

et al. 2013

J Cellular Molecular Medi

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Upregulation of inducible nitric oxide synthase (iNOS) has been reported in both experimental and clinical hypertension. However, although pro-inflammatory cytokines that up-regulate iNOS contribute to pre-eclampsia, no previous study has tested the hypothesis that a selective iNOS inhibitor (1400 W) could exert antihypertensive effects associated with decreased iNOS expression and nitrosative stress in pre-eclampsia. This study examined the effects of 1400 W in the reduced uteroplacental perfusion pressure (RUPP) placental ischaemia animal model and in normal pregnant rats. Sham-operated and RUPP rats were treated with daily vehicle or 1 mg/kg/day N-[3-(Aminomethyl) benzyl] acetamidine (1400 W) subcutaneously for 5 days. Plasma 8-isoprostane levels, aortic reactive oxygen species (ROS) levels and nicotinamide adenine dinucleotide phosphate (NADPH)-dependent ROS production were evaluated by ELISA, dihydroethidium fluorescence microscopy and lucigenin chemiluminescence respectively. Inducible nitric oxide synthase expression was assessed by western blotting analysis and aortic nitrotyrosine was evaluated by immunohistochemistry. Mean arterial blood pressure increased by ∼30 mmHg in RUPP rats, and 1400 W attenuated this increase by ∼50% (P < 0.05). While RUPP increased plasma 8-isoprostane levels, aortic ROS levels, and NADPH-dependent ROS production (P < 0.05), treatment with 1400 W blunted these alterations (P < 0.05). Moreover, while RUPP increased iNOS expression and aortic nitrotyrosine levels (P < 0.05), treatment with 1400 W blunted these alterations (P < 0.05). These results clearly implicate iNOS in the hypertension associated with RUPP. Our findings may suggest that iNOS inhibitors could be clinically useful in the therapy of pre-eclampsia, especially in particular groups of patients genetically more prone to express higher levels of iNOS. This issue deserves further confirmation.

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Section: Introductionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Antihypertensive effects of inducible nitric oxide synthase inhibition in experimental pre‐eclampsia

Amaral

Pinheiro

Guimaraes

et al. 2013

J Cellular Molecular Medi

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“…The use of isoform-"selective" NOS inhibitors has implicated neuronal and inducible NOS (nNOS and iNOS) (1,3), while lack of endothelial NOS (eNOS)-selective inhibitors has prevented direct investigation of eNOS. Alexander et al (4) reported an increase in nNOS protein abundance in rats at midterm, which coincides with maximal renal vasodilation (5), while an unexpected decline in eNOS protein abundance was also observed.…”

mentioning

confidence: 99%

Renal nitric oxide production in rat pregnancy: role of constitutive nitric oxide synthases

Smith¹,

Santymire

Erdely

et al. 2010

American Journal of Physiology-Renal Physiology

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Functional studies show that increased renal nitric oxide (NO) mediates the renal vasodilation and increased glomerular filtration rate that occur during normal pregnancy. We investigated whether changes in the constitutive NO synthases (NOS), endothelial (eNOS) and neuronal (nNOS), were associated with the increased renal NO production in normal midterm pregnancy in the rat. In kidneys from midterm pregnant (MP: 11-13 days gestation), late-term pregnant (LP: 18-20 days gestation), and similarly aged virgin (V) rats, transcript and protein abundance for eNOS and the nNOSα and nNOSβ splice variants, as well as the rate of L-arginine-to-L-citrulline conversion, were determined as a measure of NOS activity. At MP, renal cortical abundance of the total eNOS protein and phosphorylated (Ser(1177)) eNOS was reduced, and L-arginine-to-L-citrulline conversion in the cortical membrane fraction was decreased; these declines were also seen in LP. There were no changes in the eNOS transcript. In contrast, L-arginine-to-L-citrulline conversion in the soluble fraction of renal cortex increased at MP and then declined at LP. This MP increase was ablated by S-methylthiocitrulline, a nNOS inhibitor. Using Western blotting, we did not detect a change in the protein abundance or transcript of the 160-kDa nNOSα, but protein abundance and transcript of the nNOSβ were increased at MP in cortex. Collectively, these studies suggest that the soluble nNOSβ is responsible for the increased renal cortical NO production during pregnancy.

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“…NO, the product of NO synthases (NOSs), possesses anti-inflammatory and vasodilative activity and is anti-apoptotic through Akt signaling pathways (13)(14)(15)(16)(17). Sex hormones are known to regulate NO synthesis (18,19).…”

mentioning

confidence: 99%

Testosterone Is Responsible for Enhanced Susceptibility of Males to Ischemic Renal Injury

Park

Kim

Ahn

et al. 2004

Journal of Biological Chemistry

302

273

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Female mice are much more resistant to ischemia/ reperfusion (I/R)-induced kidney injury when compared with males. Although estrogen administration can partially reduce kidney injury associated with I/R, we demonstrated that the presence of testosterone, more than the absence of estrogen, plays a critical role in gender differences in susceptibility of the kidney to ischemic injury. Testosterone administration to females increases kidney susceptibility to ischemia. Dihydrotestosterone, which can not be aromatized to estrogen, has effects equal to those of testosterone. Castration reduces the I/R-induced kidney injury. In contrast, ovariectomy does not affect kidney injury induced by ischemia in females. Testosterone reduces ischemia-induced activation of nitric oxide synthases (NOSs) and Akt and the ratio of extracellular signal related kinase (ERK) to c-jun N-terminal kinase (JNK) phosphorylation. Pharmacological (N -nitro-L-arginine) or genetic (endothelial NOS or inducible NOS) inhibition of NOSs in females enhances kidney susceptibility to ischemia. Nitric oxide increases Akt phosphorylation and protects MadinDarby canine kidney epithelial cells from oxidant stress. Antagonists of androgen or estrogen receptors do not affect the gender differences. In conclusion, testosterone inhibits the post-ischemic activation of NOSs and Akt and the ratio of ERK to JNK phosphorylation through non-androgen receptor-medicated mechanisms, leading to increased inflammation and increased functional injury to the kidney. These findings provide a new paradigm for the design of therapies for ischemia/ reperfusion injury and may be important to our understanding of the pathophysiology of acute renal failure in pregnancy where plasma androgen levels are elevated.

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Inducible Nitric Oxide Synthase Inhibition Attenuates Renal Hemodynamics During Pregnancy

Cited by 11 publications

References 30 publications

Antihypertensive effects of inducible nitric oxide synthase inhibition in experimental pre‐eclampsia

Antihypertensive effects of inducible nitric oxide synthase inhibition in experimental pre‐eclampsia

Renal nitric oxide production in rat pregnancy: role of constitutive nitric oxide synthases

Testosterone Is Responsible for Enhanced Susceptibility of Males to Ischemic Renal Injury

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