Inhibitory effect of CO on internal anal sphincter: heme oxygenase inhibitor inhibits NANC relaxation

Rattan, Satish; Chakder, Sushanta

doi:10.1152/ajpgi.1993.265.4.g799

Cited by 77 publications

(94 citation statements)

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“…Previous studies have shown that CO could regulate nonadrenergic/ noncholinergic intestinal relaxation (50,68), intrahepatic vascular resistance (58), pulmonary vascular resistance (59), and relaxation of tail artery tissues (66). Exogenously delivered CO has exerted potent protective functions in numerous experimental models of inflammation, sepsis/endotoxemia, hemorrhagic shock, autoimmune diseases, and fibrosis (7,18,52,57,65,70).…”

Section: Discussionmentioning

confidence: 99%

5-Aminolevulinic acid combined with ferrous iron induces carbon monoxide generation in mouse kidneys and protects from renal ischemia-reperfusion injury

Hou

Cai

Kitajima

et al. 2013

American Journal of Physiology-Renal Physiology

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(Fe 2ϩ ), which is used with 5-ALA. In the present study, we investigated the role of 5-ALA in the attenuation of acute renal IRI using a mouse model. Male Balb/c mice received 30 mg/kg 5-ALA with Fe 2ϩ 48, 24, and 2 h before IRI and were subsequently subjected to bilateral renal pedicle occlusion for 45 min. The endogenous CO concentration of the kidneys from the mice administered 5-ALA/Fe 2ϩ increased significantly, and the peak concentrations of serum creatinine and blood urea nitrogen decreased. 5-ALA/Fe 2ϩ treatments significantly decreased the tubular damage and number of apoptotic cells. IRIinduced renal thiobarbituric acid-reactive substance levels were also significantly decreased in the 5-ALA/Fe 2ϩ group. Furthermore, mRNA expression of HO-1, TNF-␣, and interferon-␥ was significantly increased after IRI. Levels of HO-1 were increased and levels of TNF-␣ and interferon-␥ were decreased in the 5-ALA/Fe 2ϩ -pretreated renal parenchyma after IRI. F4/80 staining showed reduced macrophage infiltration, and TUNEL staining revealed that there were fewer interstitial apoptotic cells. These findings suggest that 5-ALA/ Fe 2ϩ can protect the kidneys against IRI by reducing macrophage infiltration and decreasing renal cell apoptosis via the generation of CO.5-aminolevulinic acid; carbon monoxide; hemeoxygenase-1; kidney; ischemia-reperfusion injury; oxidative stress RENAL ISCHEMIA-REPERFUSION INJURY (IRI) is a complex pathophysiological process involving programmed cell death (PCD) and oxidant damage that leads to acute renal failure (AFR). The mortality rate of ARF remains between 50% and 70% among patients who receive intensive care who require dialysis and ranges between 25% and 100% in postoperative patients suffering from ARF. Renal IRI is unavoidable in renal transplantation and may lead to acute posttransplant tubular necrosis (21,24,49,55) and delayed graft function (27,47). Recent findings have indicated that carbon monoxide (CO), an endogenous byproduct of heme degradation through the heme oxygenase (HO) system, exerts cytoprotective effects by reducing the expression of proinflammatory mediators, preventing vascular constriction, decreasing platelet aggregation, and inhibiting apoptosis (41, 66). Subsequent studies have actively used exogenous CO to treat various experimental disease conditions. In the field of transplantation, CO has been shown to inhibit acute and chronic allograft rejection (37, 57) and the rejection of xenografts (53). Furthermore, studies in the area of renal disease have reported that CO-releasing molecules (CORMs) protect against the renal damage in ischemia-induced ARF in mice (63), cisplatin-induced nephrotoxicity in rats (60), and cold ischemia and reperfusion injury during kidney transplantation of both iso-and allografts in rats (5) and mice (55).5-Aminolevulinic acid (5-ALA), an intermediate in heme synthesis, is fundamental for aerobic energy metabolism. It is used as a photo sensitizer precursor for photodynamic diagnosis and photodynamic therapy to identify and kill tu...

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Section: Discussionmentioning

confidence: 99%

5-Aminolevulinic acid combined with ferrous iron induces carbon monoxide generation in mouse kidneys and protects from renal ischemia-reperfusion injury

Hou

Cai

Kitajima

et al. 2013

American Journal of Physiology-Renal Physiology

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“…Recent observation by Rich et al has provided evidence that CO elicits an increase in potassium current and thereby hyperpolarizes the resting membrane potential in rabbit corneal epithelial cells (29). Since the hyperpolarizing effects of CO has also been reported in other types of cells such as intestinal smooth muscle cells (30), electrophysiological properties of cultured Ito cells and the effect of CO on transmembrane currents should be evaluated to reveal a novel vasorelaxing mechanism of CO. Moreover, since sinusoidal endothelial cells per se may serve as another possible contractile element which alters fluid filtration via regulation of tone in their sieve plates (31), it is also necessary to elucidate involvement of such Ito cell-independent mechanisms for CO-mediated regulation of sinusoidal resistance.…”

Section: Discussionmentioning

confidence: 99%

Carbon monoxide: an endogenous modulator of sinusoidal tone in the perfused rat liver.

et al. 1995

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Heme oxygenase is a heme-oxidizing enzyme which generates biliverdin and carbon monoxide (CO). The present study was designed to elucidate whether CO endogenously produced by this enzyme serves as an active vasorelaxant in the hepatic microcirculation. Microvasculature of the isolated perfused rat liver was visualized by dual-color digital microfluorography to alternately monitor sinusoidal lining and fat-storing Ito cells. In the control liver, the CO flux in the venous effluent ranged at 0.7 nmol/min per gram of liver. Administration of a heme oxygenase inhibitor zinc protoporphyrin IX (1 ,uM) eliminated the baseline CO generation, and the vascular resistance exhibited a 30% elevation concurrent with discrete patterns of constriction in sinusoids and reduction of the sinusoidal perfusion velocity.The major sites of the constriction corresponded to local sinusoidal segments colocalized with Ito cells which were identified by imaging their vitamin A autofluorescence. The increase in the vascular resistance and sinusoidal constriction were attenuated significantly by adding CO (1 ,uM) or a cGMP analogue 8-bromo-cGMP (1 ,uM) in the perfusate. From these findings, we propose that CO can function as an endogenous modulator of hepatic sinusoidal perfusion through a relaxing mechanism involving Ito cells. (J. Clin. Invest. 1995. 96:2431-2437

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“…The SMCs from the IAS and RSM were isolated by a previously described method (27,32) using sequential enzymatic digestion, filtration, and centrifugation. Briefly, the smooth muscle tissues cut into 0.2 ϫ 0.2 mm blocks were incubated in filtered (0.22-m filter) KPS containing 0.1% collagenase and 0.01% trypsin inhibitor.…”

Section: Methodsmentioning

confidence: 99%

RhoA/ROCK pathway is the major molecular determinant of basal tone in intact human internal anal sphincter

Rattan

Singh

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Rattan S, Singh J. RhoA/ROCK pathway is the major molecular determinant of basal tone in intact human internal anal sphincter. Am J Physiol Gastrointest Liver Physiol 302: G664 -G675, 2012. First published January 12, 2012; doi:10.1152/ajpgi.00430.2011.-The knowledge of molecular control mechanisms underlying the basal tone in the intact human internal anal sphincter (IAS) is critical for the pathophysiology and rational therapy for a number of debilitating rectoanal motility disorders. We determined the role of RhoA/ROCK and PKC pathways by comparing the effects of ROCK-and PKCselective inhibitors Y 27632 and Gö 6850 (10 Ϫ8 to 10 Ϫ4 M), respectively, on the basal tone in the IAS vs. the rectal smooth muscle (RSM). Western blot studies were performed to determine the levels of RhoA/ROCK II, PKC-␣, MYPT1, CPI-17, and MLC20 in the unphosphorylated and phosphorylated forms, in the IAS vs. RSM. Confocal microscopic studies validated the membrane distribution of ROCK II. Finally, to confirm a direct relationship, we examined the enzymatic activities and changes in the basal IAS tone and p-MYPT1, p-CPI-17, and p-MLC20, before and after Y 27632 and Gö 6850. Data show higher levels of RhoA/ROCK II and related downstream signal transduction proteins in the IAS vs. RSM. In addition, data show a significant correlation between the active RhoA/ROCK levels, ROCK enzymatic activity, downstream proteins, and basal IAS tone, before and after ROCK inhibitor. From these data we conclude 1) RhoA/ ROCK and downstream signaling are constitutively active in the IAS, and this pathway (in contrast with PKC) is the critical determinant of the basal tone in intact human IAS; and 2) RhoA and ROCK are potential therapeutic targets for a number of rectoanal motility disorders for which currently there is no satisfactory treatment. smooth muscle tone; Rho kinase; rectoanal incontinence ALTHOUGH MULTIFACTORIAL, the basal tone in the IAS plays an important role in rectoanal incontinence (3,24). It has been shown before that the basal tone in the IAS in different species including humans is primarily myogenic in nature (2,5,7,17,25), because of the characteristic properties of the IAS smooth muscle cells (SMCs) (7,23,25). Knowledge of molecular determinants of basal tone in the IAS is critical for treating a number of rectoanal motility disorders such as fecal incontinence, Hirschsprung's disease, recurrent anal fissures, and hemorrhoids (3,17).Mechanisms underlying the agonists-induced sustained contraction of intestinal smooth muscle involve prolonged myosin light chain (MLC 20 ) phosphorylation (p-MLC 20 ), the phosphorylation of cytoskeleton filaments and associated proteins, increase in Ca 2ϩ influx, and Ca 2ϩ sensitization (19). It is well known that RhoA/ROCK and PKC play a significant role in this regard. In the phasic contraction, p-MLC 20 is rapidly dephosphorylated via myosin light chain phosphatase (MLCP). In the sustained contraction, on the other hand, this dephosphorylation is prevented or delayed primarily via MLCP inhibition by...

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Inhibitory effect of CO on internal anal sphincter: heme oxygenase inhibitor inhibits NANC relaxation

Cited by 77 publications

References 0 publications

5-Aminolevulinic acid combined with ferrous iron induces carbon monoxide generation in mouse kidneys and protects from renal ischemia-reperfusion injury

5-Aminolevulinic acid combined with ferrous iron induces carbon monoxide generation in mouse kidneys and protects from renal ischemia-reperfusion injury

Carbon monoxide: an endogenous modulator of sinusoidal tone in the perfused rat liver.

RhoA/ROCK pathway is the major molecular determinant of basal tone in intact human internal anal sphincter

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