Histamine-2 Receptor Blockade Research Articles

Morphine is an arteriolar vasodilator in man

The mechanisms of action of morphine on the arterial system are not well understood. The aim was to report forearm vascular responses, and their mediation, to intra-arterial morphine in healthy subjects. Three separate protocols were performed: (i) dose ranging; (ii) acute tolerance; (iii) randomized crossover mechanistic study on forearm blood flow (FBF) responses to intrabrachial infusion of morphine using venous occlusion plethysmography. Morphine was infused either alone (study 1 and 2), or with an antagonist: naloxone, combined histamine-1 and histamine-2 receptor blockade or during a nitric oxide clamp. Morphine caused an increase in FBF at doses of 30 microg min(-1)[3.25 (0.26) ml min(-1) 100 ml(-1)][mean (SEM)] doubling at 100 microg min(-1) to 5.23 (0.53) ml min(-1) 100 ml(-1). Acute tolerance was not seen to 50 microg min(-1) morphine, with increased FBF [3.96 (0.35) ml min(-1) 100 ml(-1)] (P = 0.003), throughout the 30-min infusion period. Vasodilatation was abolished by pretreatment with antihistamines (P = 0.008) and the nitric oxide clamp (P < 0.001), but not affected by naloxone. The maximum FBF with pretreatment with combined H1/H2 blockade was 3.06 (0.48) and 2.90 (0.17) ml min(-1) 100 ml(-1) after 30 min, whereas with morphine alone it reached 4.3 (0.89) ml min(-1) 100 ml(-1). Intra-arterial infusion of morphine into the forearm circulation causes vasodilatation through local histamine-modulated nitric oxide release. Opioid receptor mechanisms need further exploration.

Post-transplant lymphoma of the pancreatic allograft in a kidney-pancreas transplant recipient: a misleading presentation

A 37-year-old male patient underwent combined kidney–pancreas transplantation with an immunosuppressive treatment consisting of tacrolimus, mycophenolate mofetil and steroids, after induction therapy with anti-thymocyte globulin. The pancreas graft had intestinal drainage. Twenty-seven days post transplantation, the patient developed an episode of acute graft pancreatitis, which responded well to conservative measures (i.v. fluids, nil per orally, histamine-2 receptor blockade). On day 45, renal function was stable with a serum creatinine of 1.28mg/dl, corresponding to a measured creatinine clearance of 57ml/min. Because of persistent postprandial hyperglycaemia, the addition of low-dose insulin therapy was necessary for a period of 6 weeks after transplantation. Two months post transplantation, the patient was admitted because of diarrhoea and a rise in serum creatinine to 2.49mg/dl. A renal biopsy showed acute cellular rejection grade Ib according to the revised Banff 2001 criteria [1]. The patient was treated with corticosteroids, resulting in a good clinical and biochemical response. However, renewed insulin therapy was temporally required during this rejection episode and was discontinued during further follow-up. Stool cultures at that time revealed Campylobacter jejuni, for which doxycylin was administered for 10 days. Four months later, the patient presented with acute pain and swelling over the pancreatic graft. Other complaints were anorexia, weight loss and low grade fever. On clinical examination, we saw a thin patient with normal vital signs. A firm mass in the right iliac area (10 10 cm), painful on palpation, was present. Laboratory results showed haemoglobin levels of 10.0 g/dl—normochromic, normocytic—a white cell count of 9600/mm—93% neutrophils—a serum creatinine of 1.4mg/dl, urea nitrogen levels of 41mg/dl, gglutamyl transferase 68U/l, and lipase 70U/l. C-reactive protein (CRP) levels were 65.4mg/l. Amylase, triglycerides and calcium levels were normal. Tacrolimus blood levels were within therapeutic range (8–12 ng/ml). Proteinuria was 0.27 g/l without haematuria or bacteriuria. Screening for viral and fungal disease revealed the presence of Epstein–Barr virus (EBV) DNA viraemia [log 4.16 (1⁄414.510) copies/ml)]. At the time of transplantation, the patient tested positive for EBV serology (status of immunity). Abdominal ultrasound showed a heterogeneous, multinodular mass (10 10 7 cm) that was partly solid and partly heterogeneous cystic. The mass could not be distinguished from the surrounding adipose tissue. Differentiation between an inflammatory process and a tumoural mass was impossible. Magnetic resonance imaging (MRI) scan of the abdomen showed a complex heterogeneous and nodular mass (9.4 cm) with compression on the pancreatic allograft and the surrounding small intestinal loops (Figure 1). The mass was isoto hypointense on T2-weighted images and isoto slightly hyperintense on T1-weighted images. Its vascularization originated from the right iliac vessels (Figure 2). The process could not be distinguished from the head of the pancreas nor from the transplanted afferent part of the small intestine. Reaching a conclusive diagnosis was still impossible, although an inflammatory mass with necrosis or a graft pancreatitis with pseudocyst Correspondence and offprint requests to: Dirk R. J. Kuypers, MD, PhD, Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium. Email: Dirk.Kuypers@uz.kuleuven.ac.be Nephrol Dial Transplant (2006) 21: 3306–3310

Outcomes of surgical fundoplication in children

Surgical fundoplication has been recommended for children with persistent GERD. The purpose of this study was to determine the frequency of postoperative symptoms requiring medical evaluation and/or treatment after fundoplication in children with or without associated medical disorders. In a retrospective cohort study, we reviewed the medical records of all children who underwent fundoplication during 1996-1999. Data were collected to analyze the following: (1) postoperative complications, (2) postoperative symptoms, (3) procedures performed to evaluate postoperative symptoms, (4) medical treatment, and (5) repeat surgery. A total of 198 children underwent fundoplication, and 176 (89%) came for follow-up evaluation within 2 months after surgery. The median age at the time of surgery was 2.1 y (range, 6 mo-18 y) and the median duration of follow-up was 2.0 y (range, 1.2-4.8 y). A total of 130 (74%) children had one or more associated medical disorders including neurodevelopmental delay (70%), cystic fibrosis (8%), tracheoesophageal anomalies (8%), bronchopulmonary dysplasia (8%), and reactive airway disease (35%). Postoperatively, children with associated medical disorders had a higher frequency of lung infections (52% vs. 22%, P = .03) and dumping syndrome (2% vs. 0%, P = .05). Most children (63%) received evaluation and treatment for symptoms suggestive of recurrent reflux despite fundoplication. Nearly two thirds of children who received fundoplication and were followed-up within 2 months after surgery either have symptoms or receive medical therapy for reflux. Fundoplication for the control of GERD in children needs further evaluation.

Altered influence of CCK-B/gastrin receptors on HDC expression in ECL cells after neoplastic transformation

Gastrin is one of the main factors controlling enterochromaffin-like (ECL) cell endocrine function and growth. Long-standing hypergastrinemia may give rise to ECL cell carcinoids in the gastric corpus in man and in experimental models . We have analysed the expression and function of CCK-B/gastrin receptors in normal ECL cells and in ECL cell tumours (gastric carcinoids) of the African rodent Mastomys natalensis. Hypergastrinemia induced by short-term (5 days) histamine 2-receptor blockade (loxtidine) resulted in increased histidine decarboxylase (HDC) mRNA expression in the gastric oxyntic mucosa. This increase was significantly and dose-dependently reversed by selective CCK-B/gastrin receptor blockade (YM022). Long-term (12 months) hypergastrinemia, induced by histamine 2-receptor blockade, gave rise to ECL cell carcinoids in the gastric oxyntic mucosa. CCK-B/gastrin receptor mRNA was only slightly elevated while HDC mRNA expression was eight-fold elevated in ECL cell carcinoids and was not influenced by CCK-B/gastrin receptor blockade. Thus CCK-B/gastrin receptor blockade of hypergastrinemic animals reduces the HDC mRNA expression in normal mucosa but not in ECL cell carcinoids. These results demonstrate that HDC mRNA expression in neoplastic ECL cells is not controlled by CCK-B/gastrin receptors.

Measurement of gastric mucosal carbon dioxide tension by saline and air tonometry

Purpose: This study compares the balloon air tonometry method of measuring gastric mucosal CO 2 to standard saline tonometry. Also, this study investigates the effect of histamine-2 receptor blockade on the precision of tonometric measures of gastric mucosal Pco 2 (P tco 2). Materials and Methods: We obtained hourly measurements of P tco 2 from two gastric tonometers inserted orally in 19 healthy volunteers. One tonometer measured P tco 2 by the intermittent saline method, whereas the other measured P tco 2 using a newer continuous air method. Subjects received intravenous 5% dextrose during the first 6 hours of the experiment followed by a continuous infusion of a solution of ranitidine in 5% dextrose for another 6 hours. The ranitidine infusion was titrated to maintain gastric fluid pH ≥ 4. Results: Comparison of air to saline tonometry yielded a bias of −1.3 mm Hg with a limit of agreement of 6.6 mm Hg under optimal conditions of optimal gastric fluid pH (gastric fluid pH ≥ 5.0). Measures of P tco 2 were lower with ranitidine for either group, 45.3 ± 1.3 mm Hg versus 39.7 ± 0.5 mm Hg for saline ( P < .01) and 45.9 ± 1.0 versus 41.3 ± 0.5 for air ( P < .01). The mean Pco 2 gap (P tco 2 - P arterialco 2) at gastric fluid pH ≥ 5.0 was 1.4 mm Hg, with a standard deviation of 2.7 mm Hg. A span of three standard deviations yields a normal limit for Pco 2 gap of 9.5 mm Hg. Conclusion: Measures of P tco 2 with the air tonometer method are similar to those obtained with saline tonometry. The reliability of P tco 2 measurements with either method improved with the use of ranitidine to maintain gastric fluid pH ≥5.

Histidine decarboxylase expression and histamine metabolism in gastric oxyntic mucosa during hypergastrinemia and carcinoid tumor formation.

Histamine is an important stimulator of gastric acid secretion. In experimental animals, inhibition of acid secretion by long term histamine2 receptor blockade causes hypergastrinemia, proliferation of enterochromaffin-like (ECL) cells, and formation of histamine-producing gastric carcinoids. The aim of this study was to examine the role of gastrin in histamine synthesis and metabolism of the oxyntic mucosa of normal, hyperplastic, and carcinoid-bearing Mastomys natalensis. Administration of exogenous gastrin to normal animals increased histidine decarboxylase (HDC) messenger RNA (mRNA) expression in the oxyntic mucosa within 30 min, indicating that gastrin stimulates histamine synthesis by regulating HDC mRNA abundance. Endogenous hypergastrinemia, induced by short term histamine2 receptor blockade (loxtidine) for 3-29 days, did not induce tumors, but enhanced the expression of HDC mRNA (2- to 4-fold elevated) and histamine contents (2-fold elevated) in the oxyntic mucosa. Long term histamine2 receptor blockade (7-21 months) resulted in sustained hypergastrinemia and ECL tumor formation. Tumor-bearing animals had a 4-fold increase in HDC mRNA expression and histamine contents of the oxyntic mucosa. Urinary excretion of the histamine metabolite methyl-imidazole-acetic acid was 2-fold elevated. Tumor-bearing animals recovering from histamine2 receptor blockade were normogastrinemic and had normal levels of HDC mRNA and histamine in the oxyntic mucosa as well as normal excretion of methyl-imidazole-acetic acid. The results indicate that ECL cell carcinoids developing during hypergastrinemia are well differentiated tumors that respond to high gastrin levels with increased histamine synthesis and secretion.

Regulation of Mastomys ECL Cell Function by Transforming Growth Factor Alpha

Little progress has been made in the understanding of the pathobiology of gastric neoplasia over the past 4 decades. This reflects the paucity of information available regarding the biology of gastric mucosal cell proliferation. More recently it has become apparent that growth factor regulation of cell proliferation is of considerable relevance in initiating mucosal mitogenesis. We have recently identified the histamine secreting enterochromaffin-like (ECL) cell as a pivotal cellular regulator of gastric acid secretion. In addition to its critical role in initiating acid secretion, we have proposed that the ECL cell may produce agents responsible for the regulation of mucosal cell proliferation. We have therefore hypothesized that such a function may be subserved by production of transforming growth factor alpha (TGFα). TGFα is known to play a significant role both in normal physiology and in the transformation of naive cells into a neoplastic form. We therefore proposed that increased levels of gastrin induced by low acid states might stimulate TGFα secretion and that this agent might be capable of regulating ECL cell DNA synthesis and cell proliferation. We used the mastomys rodent to generate anin vivohy- pergastrinemia model using long-term histamine-2 receptor blockade (loxtidine 1 mg/kg/day). In order to evaluate the cell-specific effects, we developed a pure isolated ECL cell system from the mastomys stomach. This utilized pronase digestion (1.0 mg/ml) and EDTA exposure (1 mM) of the mucosa followed by particle size separation with countercurrent elutriation and density purification on a Nycodenz step gradient. ECL cells were obtained with a purity of 90–95%. Histamine secretion from ECL cells was measured by radioimmunoassay (RIA). TGFα content was measured by RIA, and TGFα expression was measured by RNAse probe protection assay. DNA synthesis was quantified by measuring bromo-deoxyuridine (BrdU) incorporation into cultured cells. TGFα levels were increased in fundic mucosa after 16 weeks of hypergastrinemia (from 4.3 ± 0.6 to 32.6 ± 2.6 fmole/mg protein,P< 0.05). TGFα message was identified in the ECL cells by RNAse probe protection assay, and was fourfold amplified in ECL cell tumors after 16 weeks of exposure to hypergastrinemia. Gastrin stimulated (10 nM) histamine secretion in isolated naive ECL cells was inhibited by TGFα (IC502 × 10−10M). DNA synthesis was stimulated by gastrin (EC502 × 10−11M) and TGFα (EC505 × 10−9M). These data are consistent with the proposal that elevated gastrin levels are associated with ECL cell TGFα production and that TGFα stimulates ECL cell DNA synthesis.

Development of gastric carcinoids inmastomys during histamine2-receptor blockade

We have investigated the effect of histamine2-receptor blockade on gastric carcinoid formation inMastomys, a rodent prone to develop gastric carcinoids. During long-term treatment (8–24 weeks) with loxtidine, a 3–5 fold increase in plasma gastrin levels was observed. Oxyntic mucosal histamine and histidine decarboxylase activity were increased 2 times and 4–10 times respectively in loxitidine-treated animals, as compared to controls. An increase in oxyntic mucosal thickness was also noted in all treated animals, while gross tumors were only observed in animals treated for 24 weeks. Immunocytochemical analysis of treated animals revealed a marked proliferation of chromogranin-positive cells in the oxyntic mucosa. These cells were identified as ECL cells because they were labeled by histamine antibodies, but not by gastrin-, somatostatin-or serotonin-antibodies. Hyperplasia of endocrine cells was noted after 8 weeks of treatment, while dysplastic lesions were seen after 16 weeks and the first micro- or macrocarcinoids after 24 weeks of treatment. No tumors, or hyperplastic changes, were observed in control animals. The results demonstrate that histamine2-receptor blockade significantly enhances the development of gastric carcinoids inMastomys and suggest that hypergastrinemia may be important for the development of these tumors.

Growth Factors and Carcinoid Tumours

The presence of growth factors and their receptors in human midgut carcinoids and in gastric carcinoids of Mastomys have been investigated. Human midgut carcinoid tumours produce IGF-I as demonstrated by immunocytochemistry and radioimmunoassay. IGF-I receptors were detectable in half of the tumours and stimulation of cultured tumour cells with IGF-I enhanced DNA synthesis. IGF-I may therefore act as an autocrine stimulator of carcinoid tumour growth. Expression of TGF-alpha and EGF-receptors could also be demonstrated in midgut carcinoids by immunocytochemistry and Northern analysis, suggesting that TGF-alpha participates in the autocrine modulation of carcinoid growth. Co-culture of human midgut carcinoid tumours and rat fetal cholinergic neurons demonstrated secretion of a potent neuronotrophic factor by cultured tumour cells. IGF-I and TGF-alpha may account for these neuronotrophic effects, but carcinoid tumours may also secrete an as yet unidentified growth factor. Gastric (ECL cell) carcinoids developed rapidly in Mastomys during hypergastrinemia due to histamine2-receptor blockade, suggesting that gastrin is an essential growth factor for these carcinoids.

Induction and reversal of gastric endocrine cell proliferation during histamine2-receptor blockade

Induction and reversal of gastric endocrine cell proliferation during histamine2-receptor blockade

Influence of histamine receptors on basal left ventricular contractile tone in humans: Assessment using the H2receptor antagonist famotidine and the beta-adrenoceptor antagonist esmolol as pharmacologic probes

Histamine has a positive inotropic action in humans. Recent controversial data have suggested that histamine2(H2) receptor blockade depresses overall left ventricular systolic performance in healthy volunteers. To explore the possibility that H2receptors positively influence basal left ventricular contractile tone, 10 normal subjects were studied by using imaging and Doppler echocardiography and calibrated subclavian pulse data in a blinded, randomized, two-period crossover trial with measurements obtained at the end of each 7-day period.Oral drug administration consisted of either the potent H2antagonist famotidine (40 mg/day) or placebo. Left ventricular circumferential end-systolic wall stress-rate-corrected velocity of fiber shortening (Vcfc) relations were generated over a range of loads with methoxamine. Contractility was assessed by using Vcfcat a common end-systolic wall stress. During each study, data were obtained before and during high dose intravenous esmolol administration to determine the contributions, if any, of sympathetic reflex responses.Famotidine did not alter blood pressure, left ventricular percent fractional shortening, circumferential end-systolic wall stress, stroke volume index, cardiac index, total vascular resistance or ventricular contractile state in comparison with placebo but did decrease heart rate by 3 beats/min (p < 0.05). With beta-adrenergic blockade, no differences in contractility were evident between esmolol alone and famotidine plus esmolol.Thus, H2receptor blockade with famotidine does not alter myocardial mechanics or cardiac sympathetic tone, suggesting that in humans basal left ventricular contractile state is not physiologically dependent on the H2-mediated effects of histamine.

Effect of Histamine-2 Receptor Blockade by Cimetidine on Intraocular Pressure in Humans

The effect of an intravenous infusion of cimetidine (2 mg/kg of body weight/hr) on intraocular pressure and gastric acid secretion was determined in four healthy young adults and compared with the effect of a control infusion of normal saline. Cimetidine, a powerful histamine-2 receptor antagonist, abolished basal acid secretion, indicating that it was pharmacologically active, yet had no effect on intraocular pressure. Therefore, cimetidine may be given safely to patients with normal intraocular pressure. An additional observation was that intraocular pressure in all experiments declined linearly with repeated applanation tonometry for almost two hours before reaching a stable level.