Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats.

Abstract

Excess NO generation plays a major role in the hypotension and systemic vasodilatation characteristic of sepsis. Yet the kidney response to sepsis is characterized by vasoconstriction resulting in renal dysfunction. We have examined the roles of inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) on the renal effects of lipopolysaccharide administration by comparing the effects of specific iNOS inhibition, L -N 6 -(1-iminoethyl)lysine (L-NIL), and 2,4-diamino-6-hydroxy-pyrimidine vs. nonspecific NOS inhibitors (nitro-L -arginine-methylester). cGMP responses to carbamylcholine (CCh) (stimulated, basal) and sodium nitroprusside in isolated glomeruli were used as indices of eNOS and guanylate cyclase (GC) activity, respectively. LPS significantly decreased blood pressure and GFR (112 Ϯ 4 vs. 83 Ϯ 4 mmHg; 2.66 Ϯ 0.29 vs. 0.96 Ϯ 0.22 ml/min, P Ͻ 0.05) and inhibited the cGMP response to CCh. GC activity was reciprocally increased. L-NIL and 2,4-diamino-6-hydroxy-pyrimidine administration prevented the decrease in GFR (2.71 Ϯ 0.28 and 3.16 Ϯ 0.18 ml/min, respectively), restored the normal response to CCh, and GC activity was normalized. In vitro application of L-NIL also restored CCh responses in LPS glomeruli. Neuronal NOS inhibitors verified that CCh responses reflected eNOS activity. L-NAME, a nonspecific inhibitor, worsened GFR (0.41 Ϯ 0.15 ml/min), a reduction that was functional and not related to glomerular thrombosis, and eliminated the CCh response. No differences were observed in eNOS mRNA expression among the experimental groups. Selective iNOS inhibition prevents reductions in GFR, whereas nonselective inhibition of NOS further decreases GFR. These findings suggest that the decrease in GFR after LPS is due to local inhibition of eNOS by iNOS, possibly via NO autoinhibition. ( J. Clin. Invest. 1997. 100:439-448.)

Chronic Alcohol Consumption Affects Gastrointestinal Motility and Reduces the Proportion of Neuronal NOS‐Immunoreactive Myenteric Neurons in the Murine Jejunum

“…Studies of the effect of the endotoxin lipopolysaccharide on the GI tract have associated delay in gastric emptying and intestinal transit with increased expression of inducible NOS (iNOS) (Takakura et al, 1997;Fan et al, 2001;De Winter et al, 2002). The substantial concentrations of NO which can be generated by iNOS are known to autoinhibit the constitutive forms of NOS (cNOS), which may result in a condition in which iNOS is overexpressed, while cNOS is concurrently inhibited (Schwartz et al, 1997). In mice, Fleming et al demonstrated that ethanol exposure upregulates the basal gene expression of iNOS in the ileum (Fleming et al, 2001).…”

Transcriptional regulation of endothelial nitric oxide synthase expression in uterine artery endothelial cells by c-Jun/AP-1

“…However, whether other members of the AP-1 transcription factors play a role in the regulation of NOS3 expression in UAEC also needs to be investigated. Furthermore, the AP-1 family oncogene products can be rapidly induced by a variety of physiological and pathophysiological stimuli important for cell function, including hormones such as estrogen (Shiozawa et al, 2004), growth factors (Inoue et al, 1995;Zheng et al, 1999), shear stress (Li et al, 2003), protein kinase C activators (Navarro-Antolin et al, 2000), tumor necrosis factor-α (Hanazawa et al, 1994), lipopolysaccharide (Schwartz et al, 1997;Wong et al, 2004), and angiotensin II (Clark et al, 1992). In the uterine and placental circulations, the role of AP-1 in estrogen (Chen et al, 2006;Weiner et al, 1994) and angiogenic growth factors such as basic fibroblast growth factor (Zheng et al, 1999) as well as angiotensin II (Zheng et al, 2005) stimulation of endothelial NOS3 expression is currently unknown, which will be important to be investigated because of the key role(s) that these factors play in the regulation of uterine and placental vascular activity and reactivity during pregnancy.…”

“…However, many studies have also demonstrated that the expression level of NOS3 gene can be up-regulated by many physiological and pathophysiological factors, including estrogen (Chen et al, 2006;Weiner et al, 1994;Zheng et al, 2005), growth factors (Inoue et al, 1995;Zheng et al, 1999), shear stress (Li et al, 2003), and protein kinase C activators (NavarroAntolin et al, 2000), whereas the inflammatory cytokines tumor necrosis factor-α (Yoshizumi et al, 1993) and bacterial toxin lipopolysaccharide (Schwartz et al, 1997) down-regulates the expression of this vasodilatory enzyme. The regulation of NOS3 expression in endothelial cells can take place at the levels of transcription (i.e., NOS3 promoter activity) and post-transcription (i.e., mRNA stability) (Fleming and Busse, 2003).…”

Role of nitric oxide synthases in the infarct size‐reducing effect conferred by heat stress in isolated rat hearts

“…They have demonstrated that following similar L-NAME and L-NIL treatment, corresponding NOS isoforms were inhibited since LPS-induced hypotension was corrected. By the same manner, LPSinduced increase in both urinary excretion of nitrates-nitrites and cyclic GMP level was abolished (Schwartz et al, 1997;Lortie et al, 2000). Secondly, treatments had to be reversible since in this study we have investigated the role of NO as a trigger of the heat stress-induced cardioprotection and not as a mediator during the ischaemia-reperfusion sequence.…”

“…First, NOS isoforms had to be inhibited at the moment of heat stress. This point has been assessed by Schwartz et al (1997). They have demonstrated that following similar L-NAME and L-NIL treatment, corresponding NOS isoforms were inhibited since LPS-induced hypotension was corrected.…”