Epidemiology of Primary Hypertension in the Young

This presentation is to provide a broad epidemiologic perspective on the problem of blood pressure in childhood and adolescence and a background for the presentations which follow, addressing the aspects of tracking, risk factors, and electrolytes. Two fundamental issues are addressed here: first, the different patterns of blood pressure by age, as observed in population surveys in the USA, Japan, and elsewhere around the world; and second, the relation of blood pressure to indices of growth and development at different ages during childhood and adolescence. The pattern of blood pressure by age in the young is often more complex than the simple linear pattern ascribed to adult populations. The relations of blood pressure to body measurements are strong but vary importantly with age. The implications of these observations for the design of future epidemiologic studies are discussed.     

Effect of 5-hydroxytryptamine on duodenal mucosal bicarbonate secretion in mice

BACKGROUND & AIMS: 5-hydroxytryptamine (5-HT) is an important neurotransmitter and intercellular messenger that modulates many gastrointestinal functions. Because little is known about the role of 5-HT in the regulation of duodenal bicarbonate secretion, we examined the role of 5-HT on duodenal bicarbonate secretion and define neural pathways involved in the actions of 5-HT. METHODS: Duodenal mucosa from National Institutes of Health Swiss mice was stripped of seromuscular layers and mounted in Ussing chambers. The effect of 5-HT on duodenal bicarbonate secretion was determined by the pH stat technique. Acetylcholine (ACh) release from duodenal mucosa was assessed by preincubating the tissue with [(3)H] choline and measuring 5-HT-evoked release of tritium. RESULTS: 5-HT added to the serosal bath markedly stimulated duodenal bicarbonate secretion and short circuit current (Isc) in a dose-dependent manner (10(-7) mol/L to 10(-3) mol/L; P < 0.0001), whereas mucosally added 5-HT was without effect. 5-HT-stimulated bicarbonate secretion was independent of luminal Cl(-). Pretreatment with tetrodotoxin (TTX) (10(-6) mol/L) or atropine (10(-5) mol/L) markedly reduced 5-HT-stimulated duodenal bicarbonate secretion (by 60% and 65%, respectively; P < 0.001) and Isc (by 45% and 27%, respectively; P < 0.001 and P < 0.05). Pretreatment with N(omega)-nitro-l-arginine methyl ester (l-NAME) (10(-3) mol/L), propranolol (10(-5) mol/L), or phentolamine (10(-5) mol/L) did not significantly alter 5-HT-stimulated duodenal mucosal bicarbonate secretion or Isc. 5-HT concentration-dependently evoked ACh release from duodenal mucosal preparations (P < 0.0001). TTX markedly inhibited 5-HT-evoked ACh release (P < 0.001). CONCLUSIONS: 5-HT is a potent activator of duodenal mucosal bicarbonate secretion in mice. Duodenal bicarbonate secretion induced by 5-HT in vitro occurs principally via a cholinergic neural pathway.     

Role of propolis on biochemical parameters in kidney and heart tissues against l-NAME induced oxidative injury in rats

Nitric oxide (NO), produced by endothelial NO synthase, is recognised as a central antiinflammatory and antiatherogenic principle in the vasculature. Epidemiological and clinical studies have demonstrated that a growing list of natural products, as components of the daily diet or phytomedical preparations, may improve vascular function by enhancing NO bioavailability. In this article, we investigated antioxidant effects of propolis on biochemical parameters in kidney and heart tissues of acute NO synthase inhibited rats by Nω-nitro-l-arginine methyl ester (l-NAME). There was increase (p?l-NAME treatment groups when compared with control rats, but NO levels were decreased in both kidney and heart tissues. There were statistically significant changes (p?l-NAME?+?propolis treated rats as compared with l-NAME-treated group. In summary, propolis may influence endothelial NO production.     

Nitric oxide: An autocrine regulator of Leydig cell steroidogenesis in the Asian catfish, Clarias batrachus

Nitric oxide has been recognized as an important inter- and intra-cellular modulator of testicular steroidogenesis in higher vertebrates with conflicting results. Moreover, its role in regulation of testicular steroidogenesis in ectothermic vertebrates is non-existent. The present study was, therefore, undertaken to examine whether Leydig cells of a freshwater catfish, Clarias batrachus produce nitric oxide (NO), if so, does it regulate its steroidogenic activity? The purified Leydig cells were stained histochemically for NADPH-diaphorase (NADPH-d) activity, and immunocytochemically for neuronal and inducible nitric oxide synthase (nNOS and iNOS) like molecules. Leydig cells were also incubated with NOS inhibitor, N-nitro-l-arginine methyl ester (l-NAME), and NO donor, sodium nitroprusside (SNP). NO and testosterone released in incubation medium were analyzed. A distinct positive NAPDH-d staining was observed in Leydig cells. These cells also exhibited immunoprecipitation of variable intensity with nNOS and iNOS antibodies. Further, l-NAME treatment caused significant suppression in NO production and elevation in testosterone secretion by Leydig cells. On the contrary, exposure of Leydig cells to SNP resulted in increased NO production with concomitant decline in testosterone level. Thus, the present study reports NO production by Leydig cells in fish for the first time, which appears to inhibit its own androgen production.     

Gastrointestinal safety and anti-inflammatory effects of a hydrogen sulfide-releasing diclofenac derivative in the rat

BACKGROUND & AIMS: Gastrointestinal damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs) remains a significant clinical problem. Hydrogen makes an important contribution to mucosal defense, and NSAIDs can suppress its synthesis. In this study, we evaluated the gastrointestinal safety and anti-inflammatory effects of a novel "HS-NSAID" (ATB-337) that consists of diclofenac linked to a hydrogen sulfide-releasing moiety. METHODS: The gastrointestinal injury-inducing effects of single or repeated administration of diclofenac versus ATB-337 were compared in rats, as were their effects on prostaglandin synthesis and cyclooxygenase-1 and -2 activities. The ability of these drugs to reduce carrageenan-induced paw edema and to elicit leukocyte adherence to the vascular endothelium (intravital microscopy) were also examined in rats. RESULTS: Diclofenac (10-50 micromol/kg) dose-dependently damaged the stomach, while ATB-337 did not. Repeated administration of diclofenac caused extensive small intestinal damage and reduced hematocrit by 50%. ATB-337 induced >90% less intestinal damage and had no effect on hematocrit. Diclofenac, but not ATB-337, elevated gastric granulocyte infiltration and expression of tumor necrosis factor alpha, lymphocyte function-associated antigen 1, and intercellular adhesion molecule 1. ATB-337 inhibited cycloxygenase-1 and cyclooxygenase-2 activity as effectively as diclofenac. ATB-337 did not induce leukocyte adherence, whereas diclofenac did, and was more potent at reducing paw edema. CONCLUSIONS: An HS-NSAID spares the gastric mucosa of injury despite markedly suppressing prostaglandin synthesis. This effect may be related to hydrogen sulfide-mediated inhibition of tumor necrosis factor-alpha expression and of the leukocyte adherence to vascular endothelium normally induced by cyclooxygenase inhibitors.     

The role of nitric oxide in the modulation of hepatic microcirculation and tissue oxygenation in an experimental model of hepatic steatosis

BACKGROUND: Impairment of hepatic microcirculation in fatty liver has been assumed to reduce tolerance of the liver against ischemia-reperfusion injury. The present study was aimed to investigate the role of nitric oxide (NO) in the regulation of hepatic microcirculation and tissue oxygenation in hepatic steatosis. METHODS: Sprague-Dawley rats (200-250 g) were fed a 2% cholesterol diet (n = 12) to induce hepatic steatosis or normal diet (n = 12) served as controls for 12 weeks. Hepatic blood flow, microcirculation, tissue oxyhemoglobin (HbO2) and cytochrome c oxidase radox status (Cyt Ox) in response to intravenous bolus administrations of l-arginine (300 mg/kg) or l-NAME (20 mg/kg) were assessed. RESULTS: Animals which developed moderate hepatic steatosis showed significant increase in tissue level of total lipids. Portal blood flow and hepatic microcirculation were significantly reduced as compared to controls (5.7 +/- 0.9 vs. 9.7 +/- 0.9 ml/min, P = 0.003 and 114.5 +/- 9.5 vs. 167.3 +/- 10.0 flux unit, P = 0.003). l-Arginine improved hepatic arterial and portal blood flows as well as microcirculation in fatty livers (P < 0.05), while l-NAME significantly worsened these parameters (P < 0.05). Hepatic tissue HbO2 and Cyt Ox were improved both in fatty and control livers following l-arginine, while l-NAME resulted in decreased HbO2 and Cyt Ox although a transit increase in tissue oxygenation was observed in fatty livers. CONCLUSIONS: NO is involved in the modulation of hepatic microcirculatory perfusion and oxygenation in cholesterol-induced hepatic steatosis. NO metabolisms may be regulated as a potential therapeutic strategy for impaired microcirculation in hepatic steatosis.     

Nebivolol alleviates aortic remodeling through eNOS upregulation and inhibition of oxidative stress in l-NAME-induced hypertensive rats

Purpose: To investigate the effect and mechanism of nebivolol on aortic remodeling in N-nitro-l-arginine methyl ester (l-NAME)-induced hypertension. Methods: Male Sprague–Dawley rats were treated with equal volumes of drinking water or l-NAME (60 mg/kg/day), alone or in combination with nebivolol (8 mg/kg/day) or atenolol (80 mg/kg/day) by gavage for 8 weeks. Systolic blood pressure (SBP), aortic morphometry, plasma nitric oxide (NO) levels, nitric oxide synthase (NOS) activity, and relaxation of aorta to acetylcholine were determined. Protein expression of endothelial NOS (eNOS), Akt, and NADPH oxidase (Nox) was evaluated. Results: l-NAME-treated rats showed an elevated SBP associated with aortic remodeling. l-NAME-treated rats showed reduced plasma NO levels and NOS activity and increased reactive oxygen species (ROS). Protein expression of eNOS, eNOS phosphorylated at Ser¹¹⁷⁷ (p-eNOS), Akt, and Akt phosphorylated at Ser⁴⁷³ (p-Akt) decreased, whereas that of Nox2, Nox4, and p22^phox increased in the aortas from l-NAME-treated rats. Nebivolol treatment reduced SBP and ameliorated aortic remodeling. The effects of nebivolol were accompanied by increasing NO levels, NOS activity, and expression of eNOS, p-eNOS, Akt, and p-Akt, as well as reduction of ROS generation and Nox2, Nox4, and p22^phox expression. These effects of nebivolol were not reproduced by atenolol. Conclusion: Our data indicate a protective role of nebivolol on the high blood pressure and vascular remodeling induced by l-NAME. The beneficial vascular effect of nebivolol is mediated by the upregulation of eNOS and inhibition of oxidative stress.     

Does the aromatic L-amino acid decarboxylase contribute to thyronamine biosynthesis?

Thyronamines (TAM), recently described endogenous signaling molecules, exert metabolic and pharmacological actions partly opposing those of the thyromimetic hormone T₃. TAM biosynthesis from thyroid hormone (TH) precursors requires decarboxylation of the l-alanine side chain and several deiodination steps to convert e.g. l-thyroxine (T₄) into the most potent 3-T₁AM. Aromatic l-amino acid decarboxylase (AADC) was proposed to mediate TAM biosynthesis via decarboxylation of TH. This hypothesis was tested by incubating recombinant human AADC, which actively catalyzes dopamine production from DOPA, with several TH. Under all reaction conditions tested, AADC failed to catalyze TH decarboxylation, thus challenging the initial hypothesis. These in vitro observations are supported by detection of 3-T₁AM in plasma of patients with AADC-deficiency at levels (46 ± 18 nM, n = 4) similar to those of healthy controls. Therefore, we propose that the enzymatic decarboxylation needed to form TAM from TH is catalyzed by another unique, perhaps TH-specific, decarboxylase.     

l-arginine supplementation reduces cardiac noradrenergic neurotransmission in spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) are known to have cardiac noradrenergic hyperactivity due to an impaired nitric oxide (NO)-cGMP pathway. We hypothesized that dietary l-arginine supplementation may correct this autonomic phenotype. Male SHR and Wistar Kyoto rats (WKY) aged 16-18 weeks were given l-arginine (10 g/L in drinking water) for 1 week. Separate control groups received no supplementation. The SHR control had a significantly lower plasma l-arginine than WKY control, but this was increased to a comparable level following l-arginine. Atrial cGMP was lower in the SHR control compared with the WKY control (2.4 ± 0.4 pmol/mg vs 3.9 ± 0.5 pmol/mg, p < 0.05), but increased to 4.1 ± 0.5 pmol/mg protein (n = 8, p < 0.05) with l-arginine. Evoked [³H]norepinephrine release in isolated spontaneously beating right atria from the SHR control (328 ± 19%, n = 19) was 28% higher than the WKY control (256 ± 20%, n = 14, p < 0.05), but was reduced to 258 ± 11% with l-arginine feeding (n = 24, p < 0.01). Soluble guanylyl cyclase (sGC) inhibition caused a greater increase of evoked norepinephrine release in the l-arginine fed SHR compared with the non-fed SHR. l-arginine feeding did not reduce evoked norepinephrine release in the WKY. In-vitro heart rate response to exogenous norepinephrine (0.1-5 μmol/L) was similar between l-arginine fed (n = 13) and non-fed SHR (n = 10), suggesting that l-arginine supplementation worked pre-synaptically. Myocardial tyrosine hydroxylase protein was decreased in SHR following l-arginine supplementation, providing a link to reduced synthesis of norepinephrine. In conclusion, l-arginine supplementation corrects local cardiac noradrenergic hyperactivity in the SHR, probably via increased pre-synaptic substrate availability of NOS-sGC-cGMP pathway and reduced tyrosine hydroxylase levels.     

Nitric oxide modulates pancreatic basal secretion and response to cerulein in the rat: Effects in acute pancreatitis

Nitric oxide synthase activity is detected in the pancreas, but the role of NO on pancreatic function has not been fully characterized. The aim of this study was to evaluate the role of NO in normal and diseased pancreatic function. Amylase and NO secretion were measured in vivo in rats and in vitro in dispersed acini, with and without NO synthesis blockade, by N^G-nitro-l-arginine methyl ester (l-NAME). Rats were subjected to cerulein-induced pancreatitis, and the effects of l-NAME or NO donors were assessed. l-NAME reduced amylase output to 60% of basal. This effect was reversed by l-arginine. The secretory response to optimal doses of cerulein induced a poor amylase secretion and a marked release of NO. High doses of cerulein in combination with l-NAME inhibited NO formation and amylase secretion. In dispersed acini, supramaximal cerulein concentrations induced NO release, but the amylase dose-response curve was not modified by NO inhibition. In acute pancreatitis, l-NAME increased amylasemia and tissue myeloperoxidase activities, whereas NO donors reduced amylasemia, lipasemia, and the histological damage score. The l-arginine/NO pathway facilitates basal and stimulated pancreatic secretion in vivo. NO donor drugs may improve the course of acute pancreatitis.     

The protective role of hydrogen sulfide in myocardial ischemia-reperfusion-induced injury in diabetic rats

Background

Hydrogen sulfide (H₂S) displays anti-inflammatory and cytoprotective activities to attenuate myocardial ischemia-reperfusion (MIR)-induced injury, but its role in MIR in diabetics is not known. This study was undertaken to investigate whether H₂S plays a protective role in MIR in diabetic rats.

Methods

Diabetes was induced by streptozocin in Wistar rats, which were subjected to myocardial ischemia by blocking the left circumflex artery for 30 min, followed by 2 h reperfusion. dl-propargylglycine (PAG) and sodium hydrosulfide (NaHS) were administered to the rats to investigate their effects on severity of MIR-induced injury.

Results

Diabetic rats had smaller myocardial infarct sizes and higher serum levels of H₂S (both P < 0.05) than non-diabetics when they underwent MIR. MIR significantly increased the serum level of H₂S (49.5 ± 7.1 μM), H₂S-synthesizing activity (7.4 ± 1.6 nmol/mg) and the myocardial infarct size (44.0 ± 7.2%), compared with sham-operated diabetic rats (21.7 ± 2.1 μM, 0.15 ± 0.4 nmol/mg and 1.2 ± 0.4%, respectively). Administration of NaHS increased the H₂S level (65.8 ± 6.9 μM) and had little effect on H₂S production activity (6.5 ± 2.2 nmol/mg), while PAG reduced both the H₂S level (29.2 ± 5.0 μM) and H₂S-synthesizing activity (2.2 ± 1.8 nmol/mg). NaHS significantly reduced the myocardial infarct size (31.2 ± 4.7%), inhibited the production of lipid peroxidation, MPO activity, and cell apoptosis, and downregulated expression of caspase-3, Fas, FasL, and TNF-α, which had been elevated by MIR, while PAG further increased the myocardial infarct size (58.3 ± 5.9%), and displayed opposite effects.

Conclusions

The study indicates that H₂S may play a protective role in MIR-induced myocardial injury in diabetics by its anti-apoptotic, anti-oxidative and anti-inflammatory activities.     

5-lipoxygenase inhibition reduces intrahepatic vascular resistance of cirrhotic rat livers: a possible role of cysteinyl-leukotrienes

BACKGROUND & AIMS: Cysteinyl-leukotrienes (Cys-LTs) increase intrahepatic vascular resistance in normal rat livers. CCl4 cirrhotic rat livers have increased Cys-LT production and 5-lipoxygenase messenger RNA (mRNA) expression. The aim of this study was to investigate the role of 5-lipoxygenase-derived eicosanoids regulating intrahepatic vascular tone in control and CCl4-induced cirrhotic rat livers. METHODS: In different groups of portally perfused control and cirrhotic rat livers, the following were analyzed: a portal perfusion pressure (PP) dose-response curve to LTD4; the effects on PP caused by either vehicle, the selective 5-lipoxygenase inhibitor AA-861, the selective Cys-LT1 receptor antagonist MK-571, or the dual Cys-LT1 and Cys-LT2 receptor antagonist BAY u9773; and immunohistochemistry for 5-lipoxygenase in liver sections of cirrhotic and control livers. RESULTS: Cirrhotic livers have a hyperesponse to LTD4. In control livers, AA-861 and MK-571 produced a moderate and similar reduction in PP. In cirrhotic livers, 5-lipoxygenase inhibition produced a marked and significantly greater reduction in PP than in controls. However, no effect on PP was observed after MK-571 or BAY u9773. 5-Lipoxygenase-positive cells were markedly increased in cirrhotic livers. CONCLUSIONS: Our results suggest that 5-lipoxygenase-derived eicosanoids may contribute to the increased intrahepatic vascular resistance of cirrhotic rat livers and therefore the pathogenesis of portal hypertension.     

Genipin prevents fulminant hepatic failure resulting in reduction of lethality through the suppression of TNF-alpha production.

Genipin is a metabolite derived from the herbal medicine Inchinko-to. Little is known about the mechanism of genipin action on acute liver injury through inflammatory cytokines. We examined the effects of genipin on production of TNF-alpha in vivo and in vitro. Mice were given GalN/LPS with or without genipin treatment. All mice not given genipin died within 12h. But in mice given genipin, 8 of 15 mice survived for 24h after GalN/LPS administration. Histologically, hepatic necrosis and inflammatory cells infiltration were significantly slight in mice given genipin. Serum AST and ALT activity were significantly lower in mice given genipin. Serum and liver homogenate TNF-alpha levels were significantly lower in mice given genipin. However, in IL-6 and IL-1beta, there were no significant differences in mice given and not given genipin. TNF-alpha, NF-kappaB activation and TNF-alpha mRNA expression in a cultured mouse macrophage-like cell line J774.1 were significantly suppressed by genipin administration. In conclusion, the present findings suggest that genipin, a metabolite derived form the herbal medicine Inchinko-to improved acute liver dysfunction by suppressive effect of TNF-alpha production.     

The development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-D-aspartate receptor

BACKGROUND & AIMS: Visceral hypersensitivity is a common feature of functional gastrointestinal disorders. One speculated mechanism is an activity-dependent increase in spinal cord neuronal excitability (central sensitization), which is dependent on activation of the N-methyl-D-aspartate (NMDA) receptor. Our aims were to determine whether the development and maintenance of human visceral hypersensitivity is NMDA receptor mediated. METHODS: Healthy subjects were studied using a randomized, double-blind, placebo-controlled, crossover design. Pain thresholds to electrical stimulation were determined both in the proximal esophagus and in the foot (control) before and after a 30-minute distal esophageal infusion of 0.15 mol/L HCl acid. Ketamine (NMDA receptor antagonist) or saline (vehicle) was given intravenously either prior to or following acid infusion, and pain thresholds were measured for the following 120 minutes. Protocol 1: In 6 subjects, the effect of ketamine in the esophagus was assessed without acid infusion. Protocol 2: In 14 subjects, ketamine was given prior to esophageal acid. Protocol 3: In 12 subjects, ketamine was given after esophageal acid. RESULTS: Protocol 1: In the absence of esophageal acid, ketamine had no effect on either esophageal or foot pain thresholds (area-under-the-curve, [AUC] P = 0.36 esophagus, P = 0.34 foot, ANOVA) within 30 minutes of cessation of the infusion. Protocol 2: Acid-induced esophageal hypersensitivity was prevented by ketamine (AUC, P < 0.0001, ANOVA) without affecting foot pain thresholds (AUC, P = 0.06, ANOVA). Protocol 3: Ketamine delivered after acid reversed the induction of esophageal hypersensitivity induced by acid (AUC, P < 0.0001, ANOVA). CONCLUSIONS: The induction and maintenance of acid-induced esophageal hypersensitivity is prevented and reversed by ketamine. This finding strongly indicates that central sensitization is a mechanism of visceral hypersensitivity.     

dl-3-n-butylphthalide inhibits platelet activation via inhibition of cPLA2-mediated TXA2 synthesis and phosphodiesterase

Aberrant platelet activation plays a critical role in the pathogenesis of heart attack and stroke. dl-3-n-butylphthalide (NBP) has been approved in China to treat stroke with multiple mechanisms. The anti-stroke effects of NBP may be related to its antiplatelet effects reported in rats in addition to its antioxidative, antiapoptotic, and angiogenic effects. However, the effects and the underlying mechanisms of NBP on human platelets are not yet clear. In this study, we found that NBP concentration-dependently inhibited human platelet aggregation and ATP release induced by ADP, thrombin, U46619, arachidonic acid, or collagen. NBP also inhibited PAC-1 binding induced by ADP or thrombin and platelet spreading on immobilized fibrinogen. NBP reduced TXA₂ synthesis induced by thrombin or collagen via inhibiting cPLA2 phosphorylation, concomitantly with a marked decrease in intracellular calcium mobilization. Moreover, NBP also inhibited human platelet phosphodiesterase (PDE) and elevated 3,5-cyclic adenosine monophosphate level in platelets. In conclusion, NBP significantly inhibits human platelet activation via inhibition of cPLA2-mediated TXA₂ synthesis and PDE, and may be effective as an antiplatelet drug to treat other arterial thrombotic diseases.     

Ischemic preconditioning protects hepatocytes via reactive oxygen species derived from Kupffer cells in rats

BACKGROUND AND AIMS: Hepatic ischemic preconditioning decreases sinusoidal endothelial cell injury and Kupffer cell activation after cold ischemia/reperfusion, leading to improved survival of liver transplant recipients in rats. Ischemic preconditioning also protects livers against warm ischemia/reperfusion injury, in which hepatocyte injury is remarkable. We aimed to determine whether ischemic preconditioning directly protects hepatocytes and to elucidate its mechanisms. METHODS: Rats were injected with gadolinium chloride to deplete Kupffer cells or with N -acetyl- l -cysteine, superoxide dismutase, or catalase to scavenge reactive oxygen species. Livers were then preconditioned by 10 minutes of ischemia and 10 minutes of reperfusion. Subsequently, livers were subjected to 40 minutes of warm ischemia and 60 minutes of reperfusion in vivo or in a liver perfusion system. In other rats, livers were preconditioned by H(2)O(2) perfusion instead of ischemia. In the other experiments, livers were perfused with nitro blue tetrazolium to detect reactive oxygen species formation. RESULTS: Ischemic preconditioning decreased injury in hepatocytes, but not in sinusoidal endothelial cells. Kupffer cell depletion itself did not change hepatocyte injury after ischemia/reperfusion, indicating no contribution of Kupffer cells to ischemia/reperfusion injury. However, Kupffer cell depletion reversed hepatoprotection by ischemic preconditioning. Reactive oxygen species formation occurred in Kupffer cells after ischemic preconditioning. Scavenging of reactive oxygen species reversed the effect of ischemic preconditioning, and H(2)O(2) preconditioning mimicked ischemic preconditioning. CONCLUSIONS: Ischemic preconditioning directly protected hepatocytes after warm ischemia/reperfusion, which is not via suppression of changes in sinusoidal cells as in cold ischemia/reperfusion injury. This hepatocyte protection was mediated by reactive oxygen species produced by Kupffer cells.     

Protective effect of nitric oxide on development of acute pancreatitis in rats

Nitric oxide (NO) has been implicated to regulate pancreatic circulation, promote capillary integrity, and inhibit leukocyte adhesion. We investigated the role of NO in the development of pancreatitis. Nitro-l-arginine, an inhibitor of NO synthase, in total dose of 35 mg/kg body wt was infused in the rats with edematous pancreatitis induced by two intraperitoneal injections of cerulein (20 g/kg).l-Arginine (125 or 250 mg/kg), a NO donor was intravenously administered twice in the rats with hemorrhagic pancreatitis induced by waterimmersion stress plus two intraperitoneal injections of cerulein (40 g/kg). The degree of pancreas edema, serum amylase levels, and histologic alterations were investigated. Nitro-l-arginine exacerbated cerulein-induced pancreatitis and caused a decrease in pancreatic blood flow.l-Arginine ameliorated the severity of hemorrhagic pancreatitis dose dependently and improved the pancreatic blood flow. These findings suggest that NO could confer protection against the development of hemorrhagic pancreatitis, probably through improvement of the pancreatic microcirculation.This study was supported by the research fund of the Research Committee on Intractable Diseases of the Pancreas of the Japanese Ministry of Health and Welfare, and by a Grant-in-Aid for General Scientific Research from the Ministry of Education, Science and Culture, Japan.