Gastric intramucosal acidosis in mechanically ventilated patients: role of mucosal blood flow

To examine the roles of Arg-vasopressin (AVP)- and vasoactive intestinal peptide (VIP)-containing neurons in the suprachiasmatic nucleus (SCN) in production of circadian rhythmicity of locomotor activity, variations in the contents of AVP and VIP in punched-out SCN tissue and locomotor activity were measured under a light-dark cycle as well as under conditions of constant light for up to 3 weeks. Under the light-dark cycle, contents of AVP and VIP, and locomotor activity showed marked circadian rhythmicity. Under constant light, AVP content showed circadian rhythmicity until 3 weeks, while VIP rhythm disappeared from the first week with decreases in its content. Locomotor activity showed a free-running circadian rhythm for more than 3 weeks under constant light conditions in most cases. These results suggest that AVP but not VIP in the SCN may be involved in the generation of locomotor activity rhythm under conditions of constant light.     

Regulation of distal esophageal mucosal blood flow: the roles of nitric oxide and substance P

BACKGROUND: An increase in esophageal mucosal blood flow (MBF) may be an important protective mechanism against mucosal injury from noxious agents that are ingested or refluxed. This study investigated the changes in MBF and the regulation thereof after intraluminal application of noxious chemical stimuli. The role, if any, of substance P (SP) and nitric oxide (NO), two potent vasodilatory substances, and the vascular distribution of SP in the distal esophagus were evaluated. METHODS: Esophageal MBF was measured in anesthetized dogs with a laser Doppler flow probe attached to manometry and pH probes. MBF was measured before and after topical application of HCl (2 ml; 1N) or capsaicin (2 ml; 0.5%) in the distal esophagus. The effects on MBF of intraarterial SP and bradykinin were also determined. Pharmacologic antagonists and denervation procedures were used to delineate the mechanisms that regulate MBF. RESULTS: Sequential luminal applications of hydrochloric acid (HCl) or a single application of capsaicin increased MBF (p < 0.01). Topical intraluminal lidocaine blocked the response to capsaicin (p > 0.2) but not to HCl (p < 0.05). Abrupt increases in MBF occurred with intraarterial SP or bradykinin (p < 0.01). Neither atropine nor truncal vagotomy blocked the increase in MBF from these peptides or noxious stimuli. The NO synthesis antagonist NG-nitro-L-arginine methyl ester (L-NAME) blocked the response to bradykinin and attenuated the response to HCl (p < 0.05). NG-nitro-L-arginine methyl ester did not affect the response to SP or capsaicin. A substance P antagonist blocked the effects of both capsaicin (p > 0.6) and SP (p > 0.1) but not that of HCl (p < 0.01) or bradykinin (p > 0.01). CONCLUSIONS: Intraluminal applications of HCl or capsaicin appear to stimulate increases in esophageal MBF by different mechanisms. HCl produces an adaptive response that appears dependent on the paracrine effect of NO. Capsaicin-sensitive neurons mediate vasodilation through SP neurotransmission, independent of extrinsic vagal or cholinergic innervation.     

Oxidative stress in diabetic rats induced by streptozotocin: protective effects of melatonin

Two years after Kurt Schneider had finalised his thesis qualifying him as a lecturer at Cologne University, he completed his doctorate dissertation in philosophy, also at Cologne University. His advisor was Max Scheler. Schneider published the results of his researches in a short monograph. It appears that at this time Scheler's phenomenology began to influence psychiatry. However, Kurt Schneider made only passing references to Max Scheler in this regard. Nevertheless, Scheler's influence on Schneider remained noticeable even in his most famous book "Clinical Psychopathology". Years after their academic contacts, Scheler, on several occasions, asked Schneider's advice concerning his psychically disturbed son Wolfgang. Schneider's diagnosis amounted to a case of a severely psychopathic personality. He informed Max Scheler on this and, subsequently, Wolfgang Scheler was interdicted, i.e. legally incapacitated.     

Role of nitric oxide in maintenance of basal anterior choroidal blood flow in rats

PURPOSE: The aim of this study was to use laser Doppler flowmetry to measure anterior choroidal blood flow in the anesthetized rat and to determine the role of nitric oxide (NO) in the maintenance of basal ocular blood flow in vivo. METHODS: By using laser Doppler flowmetry, blood flow from the anterior choroid in pentobarbital-anesthetized rats was measured continuously. Graded single doses (0.03-300 mg/kg) of the nonselective NO synthase inhibitor NG-nitro-L-arginine-methyl ester (L-NAME) were administered intravenously to establish dose-response relationships. Other groups of animals were tested with L-NAME after the prior administration of L-arginine, with D-NAME, or with the selective neural NO synthase inhibitor 7-nitroindazole. RESULTS: Intravenous administration of L-NAME produced a dose-related depression of anterior choroidal blood flow in the 0.3- to 30-mg/kg range. Maximal depression of approximately 60% occurred at the 30-mg/kg dose, peaked at approximately 30 minutes, and lasted throughout the 60-minute experimental period. At 10 mg/kg, L-NAME reduced ocular blood flow by approximately 50%, an effect that was abolished by pretreatment with intravenous L-arginine (300 mg/kg). Both D-NAME (10 mg/kg, intravenously) and 7-nitroindazole (50 mg/kg, intraperitoneally) were inactive with regard to ocular blood flow depression. CONCLUSIONS: Laser Doppler flowmetry appears to be a useful tool for continuous, online measurement of anterior choroidal blood flow in the rat eye. Results with L-NAME and 7-nitroindazole suggest that local tonic generation of endothelial NO plays an important role in the maintenance of basal anterior choroidal blood flow in this species.     

Forearm blood flow in response to stress.

Examined the relationship between stress, forearm blood flow, and subjective anxiety. In 26 normal male Ss, electric shocks applied to the opposite forearm led to a rapid rise in anxiety and forearm blood flow. With repeated regular shocks, habituation of the vasomotor response occurred and anxiety became less intense. Changes appeared to be related to S's ability to predict accurately the intensity and frequency of the stimulus. Mental arithmetic under harassment produced a more gradual but greater rise in blood flow without an equal rise in anxiety. 23 alcoholic Ss who were judged to have limited motivation and ego strength showed a significantly lower vasomotor response during mental arithmetic. It is concluded that changes in forearm blood flow observed during stress cannot be related only to an increase in anxiety. This response seems to depend also on the significance of the stimulus to S, his psychiatric status, and his level of motivation. (19 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Regional differences in the arterial response to vasopressin: role of endothelial nitric oxide

Two Epstein-Barr virus (EBV) gene products, latent infection membrane protein 1 (LMP1), expressed mainly in latent infection, and BHRF1, expressed in lytic infection, have the ability to promote cell survival. LMP1 protects human B cells from apoptosis by upregulating expression of Bcl-2 and A20. We have demonstrated that LMP1 transfectants of Jurkat T cells are resistant to apoptosis induced by serum depletion without affecting the Bcl-2/Bax system. Overexpression of LMP1 in epithelial cells inhibits apoptosis induced by TNF-alpha, but not by anti-Fas antibodies. These results indicate that the anti-apoptotic mechanism of LMP1 differs among different cell types. BHRF1 can prevent apoptosis induced by TNF-alpha and anti-Fas antibodies in epithelial cells. The implication of the anti-apoptotic function of LMP1 and BHRF1 is reviewed in relation to EBV infection.     

Long-term cardiovascular role of nitric oxide in conscious rats

Twenty-eight non-allergic subjects suffering from mono- and bilateral chronic nasal respiratory obstruction underwent investigation employing routine semeiological examination. The real cause of the obstruction, however, was not ascertained. The subjects underwent nasal endoscopy employing rigid fiberoptics and, on the grounds of the findings, a cat scan of the nasal fossae in coronal projection, was made. The results of the study revealed involvement of the middle meatal area in 63% of bilateral nasal obstructions (B.N.O.) and in 77.7% of the monolateral obstructions (M.N.O.). Choanal pathology was evident in 21% of the B.N.O., while isolated upper and posterior deviations of the septum were present in 23.6% of the B.N.O. and in 22.5% of the M.N.O. Meatal involvement was due to the presence of anatomic changes of the middle turbinate (m.t.) such as concha bullosa, paradoxical deviation of the m.t. and of the uncinate process. Moreover, small "mucosal polyps" were also noticed in this meatal area. Cat scans, performed on 18 of these 28 patients, confirmed and defined meatal alterations found with endoscopy in 16 cases. In the remaining 2 cases, cat scans showed a thickening of the mucosal+bony tissues of the m.t. The Authors did not consider CT necessary in 10 subjects in that endoscopy sufficed in explaining obstruction symptoms.     

Role of nitric oxide in pathogenesis of aspirin-induced gastric mucosal damage in rats

In 14 patients with stable angina pectoris we examined the effect of pentoxifyline (PTX) on oxidative metabolism of TNF-alpha-priming neutrophils. The control group consisted of 21 patients with stable angina pectoris without pentoxifylline administration. Blood samples for examination were taken from basilic vein (peripheral blood) and coronary sinus immediately before PTCA procedure. In PTX-group was found the significant decrease in spontaneous CL of TNF-alpha-priming neutrophils from coronary sinus blood (1231.0 +/- 119.4 mV x min), in comparison to the control group (1374 +/- 124.4 mV x min). In PTX-group was found the significant decrease in fMLP stimulated CL of TNF-alpha-priming neutrophils from peripheral blood (4219.0 +/- 707.2 mV x min) and coronary sinus blood (4322.0 +/- 664.4 mV x min), in comparison to the control group (5248.0 +/- 595.8 mV x min and 4973.0 +/- 536.5 mV x min; respectively). There were no differences between both groups in PMA stimulated CL of TNF-alpha-priming neutrophils.     

Role of nitric oxide in the vasodilator response to mental stress in normal subjects

Vascular production of nitric oxide (NO) plays an important role in a variety of physiologic processes. This study examines the contribution of NO to the vasodilator response to mental stress. The effects of mental arithmetic testing on forearm vascular dynamics were analyzed in 15 normal subjects (9 men; age 45 +/- 12 years) during intraarterial infusion of either saline or N(G)-monomethyl-L-arginine (L-NMMA; 4 micromol/min for 15 minutes), an inhibitor of NO synthesis. The effect of L-NMMA on endothelium-independent vasodilation induced by intraarterial infusion of sodium nitroprusside was also studied in 11 of the 15 subjects. Forearm blood flow was measured by plethysmography. Mental stress increased forearm blood flow from 2.35 +/- 0.84 to 5.06 +/- 2.66 ml/min/dl (115%) during saline and from 1.72 +/- 0.59 to 2.81 +/- 0.99 ml/min/dl (63%) during L-NMMA infusion. The vasodilator effect of mental stress was significantly lower during L-NMMA infusion than during saline (1.1 +/- 0.65 vs 2.71 +/- 2.15 ml/min/dl; p = 0.01). L-NMMA administration did not significantly change mean arterial pressure and heart rate responses to mental stress. In contrast, the vasodilator effect of sodium nitroprusside (1.6 microg/min) was similar during infusion of L-NMMA and during saline (3.75 +/- 1.55 vs 2.85 +/- 1.38 ml/min/dl; p = 0.16). These findings indicate that local release of NO is involved in the forearm vasodilator response to mental stress.     

Possible role for nitric oxide releasing nerves in the regulation of ocular blood flow in the rat

AIM: To investigate the role of nitrergic nerves in the regulation of ocular blood flow. METHODS: Conscious, lightly restrained rats were treated with either the neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI), or the nonselective inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), and ocular blood flow was measured ex vivo from tissue samples, using the fully quantitative [14C]-iodoantipyrine technique. RESULTS: In the peripheral circulation, L-NAME produced an increase in arterial blood pressure (+22%) while 7-NI had no effect. In contrast, both 7-NI and L-NAME produced significant decreases in ocular blood flow (-31% and -59% respectively). The ocular vascular resistance calculated from ocular blood flow and mean arterial blood pressure increased by 29% following 7-NI, but by 130% following L-NAME. CONCLUSIONS: Nitric oxide releasing neurons may play an important contributory role in regulating ocular blood flow.     

Renal ischemia-reperfusion injury: contribution of nitric oxide and renal blood flow

In nocturnal rodents, the c-fos gene is directly involved in the light mechanism of resetting of the suprachiasmatic nucleus (circadian clock). Light also induces c-fos expression in the retinal ganglion cell layer (GCL), but no attempt has been made to study the retinal responses to the phase-shifting effects of light. The expression of the Fos protein in each of the two populations of the GCL (displaced amacrine cells [DACs] and ganglion cells [GCs]) was analyzed in hamsters after light stimulation delivered early (circadian time [CT13]) and in the middle (CT18) of the subjective night. To evaluate as accurately as possible the number of GCs able to phase shift the locomotor activity rhythm (LAR), neonatal hamsters treated with monosodium glutamate (MSG) were also used, an in vivo model which displays retinal degeneration and LAR normally entrained by light. In nontreated hamsters, the number of Fos-immunoreactive (Fos-ir+) nuclei in the GCL was significantly higher at CT18 than at CT13. In MSG-treated hamsters, the number of Fos-ir+ nuclei was the same at both CTs and nonsignificantly different as those of nontreated hamsters at CT13. MSG treatment destroyed as many Fos-ir+ DACs as Fos-ir- DACs or Fos-ir+ GCs. Fos-ir+ GCs were less sensitive to neurotoxic than other GCs, as only 37% of them were destroyed by treatment versus 92% for Fos-ir- GCs. At CT18, a maximum of 3,500 GCs expressed Fos protein in nontreated hamsters versus only 2,200 in MSG-treated hamsters. This minor subgroup was sufficiently potent to normally synchronize the circadian rhythms to the Light/dark cycle in treated hamsters.     

Impaired vasoreactivity to nitric oxide in experimental diabetic neuropathy

Nerve blood flow (NBF) is reduced in experimental diabetic neuropathy (EDN), but the mechanism of its reduction is uncertain. We tested the hypothesis that reduced NBF might be due to alterations of nitric oxide synthase (NOS) and endothelin of microvascular endothelial cells of sciatic nerve. We evaluated epineurial arteriolar vasoreactivity in response to superfused test agents. NBF was measured using microelectrode H2 polarography. Vasoconstrictor responses to endothelin-1 (ET-1; 10(-6), 10(-7), 10(-8), 10(-9), 10(-10) M) showed dose-response curves with similar EC50 values, indicating no change in potency. We applied the NOS inhibitor NG-nitro-L-arginine and observed reduced inhibition of NBF in EDN, correctable with insulin treatment and also with infused L-arginine. We conclude that vasoreactivity is disturbed in EDN, and is due to a combination of an impairment of NOS activity with reduced NO and increased endothelin effect (normal receptor sensitivity and increased plasma values) in EDN. Hyperglycemia is likely to be the mechanism of NOS inhibition since insulin treatment reversed this abnormality.     

The role of inducible nitric oxide synthase in the host response to Coxsackievirus myocarditis

The host response to Coxsackievirus infection is complex, including T lymphocytes, B lymphocytes, natural killer cells, and macrophages. Although Coxsackievirus infection induces expression of inducible nitric oxide synthase (NOS2; EC 1.14.13.39) in macrophages, the precise role of NOS2 in the host response to Coxsackievirus myocarditis has been unclear. We show, by using mice homozygous for a disrupted NOS2 allele, that Coxsackievirus replicates to higher titers in NOS2(-/-) mice, that the host lacking NOS2 clears virus more slowly than the wild-type host, and that myocarditis is much more severe in infected NOS2(-/-) mice. These data show that NOS2 is crucial for the host response to Coxsackievirus in the mouse.     

Role of nitric oxide in angiotensin IV-induced increases in cerebral blood flow

Whether a rapid elevation of serum gliclazide concentration in human subjects can be achieved through an acceleration of dissolution of gliclazide from a formulation was examined. A soft gelatin capsule containing PEG 400, PEG 4000, Tween 20 and glycerin was prepared as a formulation that may accelerate dissolution of gliclazide. The in vitro dissolution of gliclazide at pH 7.2 was identical for the soft capsule and conventional tablets, Diamicron and Diberin. However, at pH 1, 2 and 4.0 the dissolution from the soft capsule was more rapid compared to the tablets. When bioavailability parameters were compared following oral administration of the soft capsule and Diamicron to 16 healthy Korean male subjects, the parameters representing the amount of adsorption (i.e. the area under the serum gliclazide concentration vs. time curve up to 24 h, AUC24, and the peak serum concentration Cmax) were not statistically different for both formulations. However, the time required to reach the peak (Tmax) was significantly shorter for the soft capsule than for the Diamicron. Our results, therefore, indicate that a rapid elevation of serum gliclazide concentration following oral administration of a formulation can be achieved by accelerating the in vitro dissolution of gliclazide from the formulation into the acidic buffers. Thus, the rate of gastrointestinal absorption of gliclazide appears to be dependent on its in vivo dissolution rate in gastric fluid. A soft capsule containing a PEG 400 suspension of gliclazide appears to be an appropriate formulation for accelerating the dissolution.     

Mechanisms of stroke in sickle cell disease: sickle erythrocytes decrease cerebral blood flow in rats after nitric oxide synthase inhibition

The etiology of stroke in sickle cell disease is unclear, but may involve abnormal red blood cell (RBC) adhesion to the vascular endothelium and altered vasomotor tone regulation. Therefore, we examined both the adhesion of sickle (SS)-RBCs to cerebral microvessels and the effect of SS-RBCs on cerebral blood flow when the nitric oxide (NO) pathway was inhibited. The effect of SS-RBCs was studied in the rat cerebral microcirculation using either a cranial window for direct visualization of infused RBCs or laser Doppler flowmetry (LDF) to measure RBC flow. When fluorescently labeled human RBCs were infused into rats, SS-RBCs had increased adhesion to rat cerebral microvessels compared with control AA-RBCs (P = .01). Next, washed SS-RBCs or AA-RBCs were infused into rats prepared with LDF probes after pretreatment (40 mg/kg intravenously) with the NO synthase inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME), or the control isomer, D-NAME. In 9 rats treated with systemic L-NAME and SS-RBCs, 5 of 9 experienced a significant decrease in LDF and died within 30 minutes after the RBC infusion (P = .0012). In contrast, all control groups completed the experiment with stable LDF and hemodynamics. Four rats received a localized superfusion of L-NAME (1 mmol/L) through the cranial window followed by infusion of SS-RBCs. Total cessation of flow in all observed cerebral microvessels occurred in 3 of 4 rats within 15 minutes after infusion of SS-RBCs. We conclude that the NO pathway is critical in maintaining cerebral blood flow in the presence of SS-RBCs in this rat model. In addition, the enhanced adhesion of SS-RBCs to rat brain microvessels may contribute to cerebral vaso-occlusion either directly, by disrupting blood flow, or indirectly, by disturbing the vascular endothelium.     

Hyperdynamic circulation of cirrhotic rats: role of substance P and its relationship to nitric oxide

BACKGROUND: It has been suggested that excessive formation of nitric oxide (NO) is responsible for the hyperdynamic circulation observed in portal hypertension. Substance P is a neuropeptide partly cleared by the liver and causes vasodilatation through the activation of the endothelial NO pathway. However, there are no previously published data concerning the plasma level of substance P in cirrhotic rats and its relationship to NO. METHODS: Plasma concentrations of substance P and nitrate/nitrite (an index of NO production) were determined in control rats and cirrhotic rats with or without ascites using an enzyme-linked immununosorbent assay and a colorimetric assay, respectively. In addition, systemic and portal hemodynamics were evaluated by a thermodilution technique and catheterization. RESULTS: Cirrhotic rats with and without ascites had a lower systemic vascular resistance (2.6 +/- 0.2 and 3.9 +/- 0.4 mmHg ml(-1) x min x 100 g body weight, respectively) and higher portal pressure (14.6 +/- 0.6 and 11.3 +/- 1.8 mmHg) than control rats (6.5 +/- 0.3 mmHg x ml(-1) x min x 100 g BW and 6.8 +/- 0.2 mmHg, respectively, P < 0.05), and cirrhotic rats with ascites had the lowest systemic vascular resistance. Plasma levels of nitrate/nitrite progressively increased in relation to the severity of liver dysfunction (control rats, 2.7 +/- 0.5 nmol/ml; cirrhotic rats without ascites, 5.6 +/- 1.3 nmol/ml; cirrhotic rats with ascites, 8.3 +/- 2.2 nmol/ml; P < 0.05). Cirrhotic rats with ascites displayed higher plasma values of substance P (57.7 +/- 5.9 pg/ml) than cirrhotic rats without ascites (37.9 +/- 3.1 pg/ml, P < 0.05) and control rats (30.1 +/- 1.0 pg/ml, P < 0.05). There was no significant difference in plasma substance P values between control rats and cirrhotic rats without ascites (P > 0.05). No correlation was found between plasma levels of substance P and nitrate/nitrite (r = 0.318, P > 0.05). CONCLUSIONS: Excessive formation of NO may be responsible, at least partly, for the hemodynamic derangements in cirrhosis. Although substance P may not participate in the initiation of a hyperdynamic circulation in cirrhosis, it may contribute to the maintenance of the hyperdynamic circulation observed in cirrhotic rats with ascites.     

Failure of L-NAME to cause inhibition of nitric oxide synthesis: role of inducible nitric oxide synthase

We addressed the hypothesis that administration of nitric oxide synthase inhibitor, NG -nitro-L-arginine methyl ester (L-NAME) does not result in a sustained suppression of nitric oxide (NO) synthesis, because of a compensatory expression of inducible nitric oxide synthase (iNOS). L-NAME was administered in the drinking water (0.1-1.0 mg/ml) for 7 days to guinea pigs and rats. Nitric oxide synthesis was assessed by [1] ex vivo formation of nitrite in blood vessels and intestine [2] tissue levels of cGMP [3] iNOS gene expression by RT-PCR [4] NADPH diaphorase staining [5] direct assessment of NO release in tissue explants using a microelectrode/electrochemical detection system. Chronic L-NAME administration elevated intestinal cGMP and nitrite levels in guinea pigs (p < 0.05). In rats, intestinal nitrite levels were comparable in control and L-NAME treatment groups, whereas direct assessment of NO release defined a marked increase in the L-NAME group. Chronic L-NAME resulted in an induction of iNOS gene expression in rats and guinea pigs and novel sites of NADPH diaphorase staining in the intestine. We conclude that iNOS expression is responsible for a compensatory increase or normalization of NO synthesis during sustained administration of L-NAME.     

Chronic 17beta-estradiol augments relaxant role of basal nitric oxide in blood vessels from rats with heart failure

It is estimated that approximately 27% of women have a history of childhood sexual abuse. Long-term effects of this abuse include physical and psychologic consequences that can affect the pregnant woman during the prenatal, antenatal, and postpartum periods. Careful screening of all pregnant women and specific interventions during examinations and procedures can help survivors of childhood sexual abuse experience childbearing as healing and empowering. Care providers who are survivors of such abuse can better serve their patients by working therapeutically on their own healing.