Biomedical subjects

G Farrugia

Publications and source records attributed to G Farrugia.

At least 19 recordsLinked to original sources

PubMed2006

Treatment of gastroparesis: a multidisciplinary clinical review.

This clinical review on the treatment of patients with gastroparesis is a consensus document developed by the American Motility Society Task Force on Gastroparesis. It is a multidisciplinary effort with input from gastroenterologists and other specialists who are involved in the care of patients with gastroparesis. To provide practical guidelines for treatment, this document covers results of published research studies in the literature and areas developed by consensus agreement where clinical research trials remain lacking in the field of gastroparesis.

Consensus Statements as Topic↗

PubMed2006

Achalasia: physiology and etiopathogenesis.

Achalasia is a disorder of esophageal motility that has been well documented for over 300 years. Despite this, the initiating factor or factors and the underlying mechanisms leading to the characteristic features of achalasia, the absence of distal esophageal peristalsis and abnormal lower esophageal sphincter relaxation, are still not well understood. Recent work has shed light on changes in neurotransmission and cell signaling in the lower esophagus and lower esophageal sphincter that lead to achalasia. A number of recent reviews have thoroughly discussed diagnostic and therapeutic modalities and the reader is referred to these for in-depth review of these topics. The focus of this review will be on our current understanding of the physiology of esophageal peristalsis and lower esophageal sphincter function as it relates to achalasia and on available evidence for etiology and proposed pathophysiologic mechanisms.

Animals↗

PubMed2004

Otilonium bromide inhibits calcium entry through L-type calcium channels in human intestinal smooth muscle.

Otilonium bromide (OB) is used as an intestinal antispasmodic. The mechanism of action of OB is not completely understood. As Ca(2+) entry into intestinal smooth muscle is required to trigger contractile activity, our hypothesis was that OB blocked Ca(2+) entry through L-type Ca(2+) channels. Our aim was to determine the effects of OB on Ca(2+), Na(+) and K(+) ion channels in human jejunal circular smooth muscle cells and on L-type Ca(2+) channels expressed heterologously in HEK293 cells. Whole cell currents were recorded using standard patch clamp techniques. Otilonium bromide (0.09-9 micromol L(-1)) was used as this reproduced clinical intracellular concentrations. In human circular smooth muscle cells, OB inhibited L-type Ca(2+) current by 25% at 0.9 micromol L(-1) and 90% at 9 micromol L(-1). Otilonium bromide had no effect on Na(+) or K(+) currents. In HEK293 cells, 1 micromol L(-1) OB significantly inhibited the expressed L-type Ca(2+) channels. Truncation of the alpha(1C) subunit C and N termini did not block the inhibitory effects of OB. Otilonium bromide inhibited Ca(2+) entry through L-type Ca(2+) at concentrations similar to intestinal tissue levels. This effect may underlie the observed muscle relaxant effects of the drug.

Calcium↗

PubMed2004

Mediators of non-adrenergic non-cholinergic inhibitory neurotransmission in porcine jejunum.

The purpose of this study was to determine the non-adrenergic non-cholinergic inhibitory neurotransmitter in pig jejunum. Intracellular electrical activity was recorded from circular smooth muscle cells. Inhibitory junction potentials (IJPs) evoked by electrical field stimulation were inhibited by tetrodotoxin (1 micromol L(-1)), omega-conotoxin GVIA (0.1 micromol L(-1)) tetrodotoxin, apamin (1 micromol L(-1)), 1-[6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione (U-73122; 10 micromol L(-1)) but not by N omega-nitro-l-arginine (l-NNA; 100 micromol L(-1)), haemoglobin (10 micromol L(-1)), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 micromol L(-1)) or 9-(tetrahydro-2-furyl)adenine (SQ-22536; 10 micromol L(-1)). S-nitroso-N-acetylpenicillamine (SNAP) hyperpolarized the membrane potential. This was inhibited by ODQ (3 micromol L(-1)) and charybdotoxin (0.1 micromol L(-1)). Adenosine-5-triphosphate (ATP; 100 micromol L(-1)) and 2-methylthio ATP (2-MeS-ATP; 100 micromol L(-1)) did not hyperpolarize the membrane potential and 6-N-N-diethyl-beta- gamma -dibromomethylene-d-adenosine-5'-triphosphate (ARL67156; 100 micromol L(-1)) did not modify IJPs. Carbon monoxide (CO; 10%) and tricarbonyl dichlororuthenium dimer ([Ru(CO3Cl2)]2; 100 micromol L(-1)) hyperpolarized the membrane potential however zinc, copper and tin protoporphyrin IX (100 micromol L(-1)) did not alter IJPs. Vasoactive intestinal peptide (VIP) hyperpolarized the membrane potential but 4-Cl-d-Phe6-Leu17-VIP (1 micromol L(-1)) did not modify IJPs. Pituitary adenylate cyclase activating peptide (PACAP)38 (0.5 micromol L(-1)) hyperpolarized the membrane potential. This was inhibited by apamin (1 micromol L(-1)) but not by tetrodotoxin (1 micromol L(-1)). Pituitary adenylate cyclase activating peptide6-38 (1 micromol L(-1)) inhibited IJPs. These data suggest that inhibitory neurotransmission in pig jejunum is mediated partly by PACAP.

Adenosine Triphosphate↗

PubMed2004

Carbon monoxide is an endogenous hyperpolarizing factor in the gastrointestinal tract.

In all mammalian species examined to date, there is a 10 mV or more gradient in resting membrane potential across the wall of the gastric antrum, small intestine and colon, and an even larger gradient along the long axis of the stomach. These voltage gradients, which may be considered biological rheostats, are central to the ability of circular smooth muscle to vary the strength of contraction from weak to propulsive and occluding. In this short review, we consider recent data that support the hypothesis that carbon monoxide generated in interstitial cells of Cajal is a hyperpolarizing factor for circular smooth muscle and the root of the essential voltage gradients.

Animals↗

PubMed2003

Kit/stem cell factor receptor-induced phosphatidylinositol 3'-kinase signalling is not required for normal development and function of interstitial cells of Cajal in mouse gastrointestinal tract.

Signalling mediated by the receptor tyrosine kinase c-Kit is required for normal development of interstitial cells of Cajal (ICC). c-Kit activates several signalling pathways, including the phosphatidylinositol 3'-kinase (PI3'-kinase) pathway. The signals required for ICC development and maintenance are not well understood. Studies indicate a role for PI3'-kinase. We studied ICC function and morphology in mice homozygous for the tyrosine 719 to phenylalanine c-Kit mutation, which disrupts all PI3'-kinase binding to c-Kit. Functionally, the electrical slow waves in the jejunum and inhibitory junction potentials were normal in adult mutants. Morphologically, the distribution of ICC was not altered in mutants. There was no difference in the density of ICC in the jejunum of adults or newborns from quantitative analysis of c-Kit immunoreactivity. The number of ICC obtained in culture was the same using mutants or wild-type littermates. The density and organization of nerves in the jejunum of mutants was not affected. Deletion of c-Kit-induced PI3'-kinase signalling does not affect the function or development of ICC in the mouse. This is an important and counterintuitive result, given the role of PI3'-kinase signalling downstream of c-Kit and the role of both c-Kit and PI3'-kinase individually in ICC development.

Animals↗

PubMed2003

Coupling and innervation patterns of interstitial cells of Cajal in the deep muscular plexus of the guinea-pig.

Interstitial cells in the deep muscular plexus (ICC-DMP) are thought to be essential for neurotransmission in the circular muscle. There is evidence for gap junctions within the ICC-DMP network and between ICC-DMP and muscle cells; however, there is no evidence for functional coupling via these gap junctions. In addition, the innervation of individual ICC-DMP has not been studied. We investigated these questions by injecting the dye Lucifer yellow into ICC-DMP of guinea-pig ileum. Nerves were labelled immunohistochemically for protein gene product 9.5. Cells were imaged by confocal microscopy. Most (79%) of the dye-injected ICC-DMP were coupled to one to five other ICC-DMP, and 86% of them were coupled to one to five circular muscle cells. Octanol effectively blocked all coupling. Incubation in pH 6.8-7.0 reduced ICC-ICC coupling to 49% and ICC-muscle coupling to 32%. In contrast, pH 7.8-7.9 increased ICC-ICC and ICC-muscle coupling to 100%. Most ICC somata (95%) and processes (60%) were in close proximity with both nerve fibres and smooth muscle cells. These results provide direct evidence for functional coupling within the ICC-DMP network, and between this network and cells of the outer circular muscle layer and showed that coupling can be affected by pH.

Animals↗

PubMed2002

Local presentation of Steel factor increases expression of c-kit immunoreactive interstitial cells of Cajal in culture.

The binding of Steel factor (SF) to c-kit initiates a signaling pathway essential for development and maintenance of interstitial cells of Cajal (ICC). Soluble and membrane-bound isoforms of SF are expressed in the gastrointestinal tract, but the role for either isoform in supporting ICC development is unknown. The aim of this study was to determine the role of SF in supporting ICC in culture. ICC were cultured from dissociated mouse jejunum and grown with fibroblast cell lines that produced either soluble, membrane-bound or membrane-restricted SF. ICC were identified and counted by c-kit immunoreactivity. The number of c-kit immunoreactive cells was greater in the coculture system compared with cultures grown without SF-producing fibroblasts. All forms of SF-producing fibroblasts increased ICC number in culture but physical separation of the fibroblasts from the c-kit immunoreactive cells, the addition of exogenous SF to the culture medium, or fibroblast-conditioned media did not. These results are consistent with the hypothesis that the membrane-bound form of SF preferentially contributes to expression of c-kit-positive ICC under cell culture conditions.

Animals↗

PubMed2002

Physiological study of interstitial cells of Cajal identified by vital staining.

Interstitial cells of Cajal (ICC) form networks that intercalate between the enteric nervous system and smooth muscle cells and play a fundamental role in the control of gastrointestinal motility by initiating rhythmic electrical activity. In this report, we used a method to examine the physiological and morphological properties of ICC in living, intact tissues. ACK2, an anti-Kit antibody, was conjugated to a fluorescent probe and used to identify individual ICC for intracellular electrical recordings, to record changes in intracellular calcium concentration using fluorescent dyes and for confocal microscopy. Cyclic changes in intracellular calcium concentration were recorded in ICC with a frequency similar to the electrical slow wave. In addition, injection of a fluorescent dye into single ICC enabled the three-dimensional reconstruction of single myenteric plexus ICC within the intact network. The data show that ICC in intact networks from the myenteric plexus region in living tissues in the guinea-pig antrum exhibit an electrical slow wave, and that intracellular calcium oscillates at a frequency similar to the slow wave.

Aniline Compounds↗

PubMed2002

SCN5A is expressed in human jejunal circular smooth muscle cells.

Tetrodotoxin-resistant Na+currents are expressed in a variety of muscle cells including human jejunal circular smooth muscle (HJCSM) cells. The aim of this study was to determine the molecular identity of the pore-forming alpha-subunit of the HJCSM Na+ channel. Degenerate primers identified a cDNA fragment of 1.5 kb with 99% nucleotide homology with human cardiac SCN5A. The identified clone was also amplified from single smooth muscle cells by reverse transcriptase-polymerase chain reaction (RT-PCR). Northern blot analysis showed expression of full-length SCN5A. Laser capture microdissection was used to obtain highly purified populations of HJCSM cells. RT-PCR on the harvested cells showed that SCN5A was present in circular but not in longitudinal muscle. A similar result was obtained using a pan-Na+ channel antibody. The full-length sequence for SCN5A was obtained by combining standard polymerase chain reaction with 5' and 3' rapid amplification of cDNA end techniques. The intestinal SCN5A was nearly identical to the cardiac SCN5A. The data indicate that SCN5A is more widely distributed than previously thought and encodes the pore-forming alpha-subunit of the tetrodotoxin-resistant Na+ current in HJCSM cells.

Gene Expression Regulation↗

PubMed2002

Pan-colonic decrease in interstitial cells of Cajal in patients with slow transit constipation.

BACKGROUND: Interstitial cells of Cajal (ICC) are required for normal intestinal motility. ICC are found throughout the human colon and are decreased in the sigmoid colon of patients with slow transit constipation. AIMS: The aims of this study were to determine the normal distribution of ICC within the human colon and to determine if ICC are decreased throughout the colon in slow transit constipation. PATIENTS: The caecum, ascending, transverse, and sigmoid colons from six patients with slow transit constipation and colonic tissue from patients with resected colon cancer were used for this study. METHODS: ICC cells were identified with a polyclonal antibody to c-Kit, serial 0.5 microm sections were obtained by confocal microscopy, and three dimensional software was employed to reconstruct the entire thickness of the colonic muscularis propria and submucosa. RESULTS: ICC were located within both the longitudinal and circular muscle layers. Two networks of ICC were identified, one in the myenteric plexus region and another, less defined network, in the submucosal border. Caecum, ascending colon, transverse colon, and sigmoid colon displayed similar ICC volumes. ICC volume was significantly lower in the slow transit constipation patients across all colonic regions. CONCLUSIONS: The data suggest that ICC distribution is relatively uniform throughout the human colon and that decreased ICC volume is pan-colonic in idiopathic slow transit constipation.

Adolescent↗

PubMed2001

Haem oxygenase in enteric nervous system of human stomach and jejunum and co-localization with nitric oxide synthase.

Recent evidence suggests that carbon monoxide (CO) may be a neurotransmitter, similar to nitric oxide (NO) in the enteric nervous system. The distribution of haem oxygenase (HO), the biosynthetic enzyme for CO, has been determined in the enteric nervous system of animals, but little is known about the distribution of HO in human gastrointestinal tract. The present study investigated the expression of HO and its colocalization with NO synthase (NOS), the biosynthetic enzyme for NO, in human antrum and jejunum. HO isoforms were identified using immunohistochemistry and NOS was identified by immunohistochemistry or NADPH-d histochemistry. HO-2 immunoreactive (IR) cell bodies in enteric ganglia and nerve fibres in longitudinal and circular muscle were found in both antrum and jejunum. Co-localization of HO-2 and NOS was about 40% in HO-2 containing cell bodies of myenteric ganglia and only 10% or less in cell bodies of submucous ganglia. HO-1 immunoreactivity was not detected in antrum or jejunum. The results suggest that CO is produced in human enteric ganglion neurones and indicate a possible role of CO as a neurotransmitter and possible interaction between HO and NOS pathways in inhibitory neurotransmission in the human gastrointestinal tract.

Adult↗

PubMed2001

Loss of interstitial cells of cajal and inhibitory innervation in insulin-dependent diabetes.

BACKGROUND & AIMS: Gastrointestinal complications of long-standing diabetes include nausea, vomiting, abdominal pain, diarrhea, and constipation. The pathophysiology underlying these symptoms is poorly understood. Recent evidence suggests an important role for interstitial cells of Cajal in controlling gastrointestinal motility. The aim of this study was to determine changes in interstitial cells of Cajal and enteric innervation in a patient with insulin-dependent diabetes. METHODS: A full thickness jejunal biopsy was obtained from a 38-year-old insulin-dependent diabetic with evidence for diabetic gastroenteropathy. Immunohistochemistry, confocal microscopy, and 3-dimensional reconstruction techniques were used to quantify changes in the volume of interstitial cells of Cajal and enteric innervation. RESULTS: Interstitial cells of Cajal were markedly decreased throughout the entire thickness of the jejunum. A decrease in neuronal nitric oxide synthase, vasoactive intestinal peptide, PACAP, and tyrosine hydroxylase immunopositive nerve fibers was observed in circular muscle layer while substance P immunoreactivity was increased. CONCLUSIONS: The data suggest that long-standing diabetes is associated with a decrease in interstitial cells of Cajal volume and a decrease in inhibitory innervation, associated with an increase in excitatory innervation. The changes in interstitial cells of Cajal volume and enteric nerves may underlie the pathophysiology of gastrointestinal complications associated with diabetes and suggest future therapeutic targets.

Adult↗

PubMed2001

Mechanism mediating nitric oxide-induced inhibition in human jejunal longitudinal smooth muscle.

BACKGROUND: Enteric neurotransmission is a complex process involving multiple neurotransmitters, including nitric oxide (NO). Our aim was to evaluate the role and mechanism(s) of action of NO in normal human jejunal longitudinal smooth muscle. METHODS: Transmural strips of normal human jejunum obtained from subjects undergoing gastric bypass were studied in organ chambers. Effects of exogenous NO (7 x 10(-6) mol/L to 7 x 10(-5) mol/L) and electrical field stimulation (nonspecific release of endogenous neurotransmitters) on spontaneous contractile activity and on precontracted muscle strips (substance P, 10(-5) mol/L) were evaluated in the presence and absence of the competitive NO synthase inhibitor N(G)-amino-L-arginine (L-NNA, 10(-3) mol/L) and the specific soluble guanylyl cyclase inhibitor 1H-[1,2,4]-oxadiazaolo-[4,3-a]-quinoxalin-1-one (ODQ, 10(-5) mol/L and 10(-4) mol/L). RESULTS: Exogenous NO dose-dependently inhibited spontaneous contractility and relaxed precontracted smooth muscle strips. The effects of NO were markedly attenuated or completely inhibited in the presence of ODQ. Electric field stimulation under nonadrenergic, noncholinergic conditions also inhibited spontaneous contractility and relaxed precontracted smooth muscle strips; both of these effects were attenuated, but not completely inhibited, in the presence of both ODQ and L-NNA. CONCLUSIONS: NO is an endogenous inhibitory neurotransmitter in human jejunal longitudinal smooth muscle, acting at least in part via a mechanism mediated by guanylyl cyclase. Other (non-nitrergic) nonadrenergic, noncholinergic inhibitory neurotransmitters are likely active in this portion of the human gut.

Electric Stimulation↗

PubMed2001

Corporeal structural and vascular micro architecture with X-ray micro computerized tomography in normal and diabetic rabbits: histopathological correlation.

PURPOSE: The pathophysiology of diabetes mellitus induced erectile dysfunction is poorly understood. In patients with diffuse venous leakage structural changes in the corpora cavernosa have correlated with failure of the veno-occlusive mechanism. Three-dimensional (D) micro computerized tomography (CT) has proved to be an important imaging technique for the intact kidney, heart, liver and bone. We examined control and diabetic rabbit penises by 3-D micro CT and quantified any structural changes. MATERIALS AND METHODS: Male white New Zealand rabbits were treated with alloxan to induce diabetes or used as normal controls. Via aortic access at laparotomy the penile vascular tree was vasodilated with papaverine and perfused with radiopaque silicone rubber. X-ray micro CT was then performed at 21 microm. resolution and images were analyzed in 3-D using custom software. RESULTS: Nine diabetic rabbits with blood glucose greater than 400 mg./dl. and 9 control animals were used for micro CT analysis. Significant decreases (p <0.05) were observed in the mean sinusoidal and vascular volume fraction plus or minus standard error of mean of the corpus cavernosum in the diabetic (323.7 +/- 43.1 mm.3 and 37.9 +/- 2.0%, respectively) and control (510.1 +/- 47.4 mm.3 and 53.1 +/- 3.80%, respectively) groups. Also, the mean left and right cavernous artery luminal cross-sectional area in diabetics (0.15 +/- 0.02 and 0.16 +/- 0.01 mm.2, respectively) versus controls (0.2 +/- 0.01 and 0.2 +/- 0.01 mm.2, respectively) was significantly decreased (p <0.05). Furthermore, the mean left and right total cavernous artery luminal volume in diabetics (0.4 +/- 0.07 and 0.4 +/- 0.09 mm.3, respectively) versus controls (1.0 +/- 0.13 and 0.9 +/- 0.11 mm.3, respectively) was significantly decreased (p <0.05). CONCLUSIONS: Diabetic rabbit penises showed a significant decrease in corporeal vascular volume as well as decreased cavernous artery diameter and luminal volume compared to controls. This finding correlated well with the mean decrease in trabecular smooth muscle in control and severely diabetic rabbits on histopathological studies (42.2% +/- 1.5% versus 35.8% +/- 1.5%). This combination of potential arterial insufficiency as well as an increase in diffuse connective tissue may contribute to the overall pathophysiology of diabetic erectile dysfunction. These results suggest that 3-D x-ray micro CT with molecular analysis may be a powerful tool for examining the pathophysiology of diabetic erectile dysfunction.

Angiography↗

PubMed2001

Potassium outward currents in freshly dissociated rabbit corpus cavernosum myocytes.

PURPOSE: Cavernous smooth muscle cells have a key role in the control of penile erection and detumescence. In this study the types of smooth muscle cells and currents present in isolated rabbit corpus cavernosum myocytes were characterized. MATERIALS AND METHODS: Immunohistochemical methods were used to identify cavernous smooth muscle cells. Currents were recorded from freshly dissociated myocytes using the whole cell and amphotericin perforated patch clamp techniques. RESULTS: Cavernous myocytes were identified by alpha-smooth muscle actin and smooth muscle myosin immunoreactivity. Based on electrical properties at least 2 types of myocytes were present. Type I cells showed more depolarized membrane potentials, lower capacitance, higher input resistance and increased current densities at positive potentials than type II cells. In types I and II cells at voltages positive to 30 mV, maxi K+ channel (Ca2+ activated large conductance K+ channel or BK) blockade with iberiotoxin or charybdotoxin reduced outward currents by approximately 40% to 80% at 80 mV. Maxi K+ channel blocking did not affect cell membrane potential. Type II cells showed delayed rectifier K+ channel-type outward currents that were not detected in type I cells. Delayed rectifier K+ channel-type currents were resistant to iberiotoxin or charybdotoxin, activated at approximately -50 to -40 mV. and inactivated weakly. CONCLUSIONS: The data suggest that cavernous smooth muscle cells are heterogeneous with at least 2 subtypes identified based on membrane potential, capacitance, input resistance, current density and delayed rectifier K+ channel expression. The activation threshold suggests that delayed rectifier K+ channels are open at the resting membrane potential and, therefore, contribute to control and regulation of the cavernous myocyte excitability.

Animals↗

PubMed2000

Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies.

BACKGROUND: Idiopathic autonomic neuropathy is a severe, subacute disorder with a presumed autoimmune basis. It is indistinguishable from the subacute autonomic neuropathy that may accompany lung cancer or other tumors. Autoantibodies specific for nicotinic acetylcholine receptors in the autonomic ganglia are potentially pathogenic and may serve as serologic markers of various forms of autoimmune autonomic neuropathy. METHODS: We tested serum from 157 patients with a variety of types of dysautonomia. Immunoprecipitation assays with iodine-125-labeled epibatidine and solubilized human neuroblastoma acetylcholine receptors were used to detect autoantibodies that bound to or blocked ganglionic receptors. RESULTS: Ganglionic-receptor-binding antibodies were found in 19 of 46 patients with idiopathic or paraneoplastic autonomic neuropathy (41 percent), in 6 of 67 patients with postural tachycardia syndrome, idiopathic gastrointestinal dysmotility, or diabetic autonomic neuropathy (9 percent), and in none of 44 patients with other autonomic disorders. High levels of the binding antibodies correlated with more severe autonomic dysfunction (including the presence of tonic pupils). Levels of these antibodies decreased in patients who had clinical improvement. All seven patients with ganglionic-receptor-blocking antibodies had ganglionic-receptor-binding antibodies and had idiopathic or paraneoplastic autonomic neuropathy. CONCLUSIONS: Seropositivity for antibodies that bind to or block ganglionic acetylcholine receptors identifies patients with various forms of autoimmune autonomic neuropathy and distinguishes these disorders from other types of dysautonomia. The positive correlation between high levels of ganglionic-receptor antibodies and the severity of autonomic dysfunction suggests that the antibodies have a pathogenic role in these types of neuropathy.

Adult↗

PubMed2000

Carbon monoxide and nitric oxide as coneurotransmitters in the enteric nervous system: evidence from genomic deletion of biosynthetic enzymes.

Nitric oxide (NO) and carbon monoxide (CO) seem to be neurotransmitters in the brain. The colocalization of their respective biosynthetic enzymes, neuronal NO synthase (nNOS) and heme oxygenase-2 (HO2), in enteric neurons and altered intestinal function in mice with genomic deletion of the enzymes (nNOS(Delta/Delta) and HO2(Delta/Delta)) suggest neurotransmitter roles for NO and CO in the enteric nervous system. We now establish that NO and CO are both neurotransmitters that interact as cotransmitters. Small intestinal smooth muscle cells from nNOS(Delta/Delta) and HO2(Delta/Delta) mice are depolarized, with apparent additive effects in the double knockouts (HO2(Delta/Delta)/nNOS(Delta/Delta)). Muscle relaxation and inhibitory neurotransmission are reduced in the mutant mice. In HO2(Delta/Delta) preparations, responses to electrical field stimulation are nearly abolished despite persistent nNOS expression, whereas exogenous CO restores normal responses, indicating that the NO system does not function in the absence of CO generation.

Animals↗