"Shades of Gray" in pancreatic ductal adenocarcinoma: Reappraisals on resectability criteria: Debated indications for surgery in pancreatic cancer.

Pancreatic ductal adenocarcinoma is one of the leading causes of cancer-related deaths and, currently, surgery is the only curative treatment. Patients with borderline resectable pancreatic cancer (BRPC) can benefit from a multidisciplinary approach and R0 resection, and can achieve the same outcome as resectable patients treated with upfront surgery. However, the definition of BRPC changes according to different classifications with a heterogeneous distribution of patients, and it is thus difficult to compare clinical evidence. We performed a literature review to assess the most suitable classification of BRPC. Our review was conducted using the PubMed database. Only articles containing more than ten patients classified according to NCCN, MDACC or AHPBA/SSAT/SSO classifications were selected. A total of 16 studies were included in our analysis, and were grouped according to one of these three classifications. The total resection rate was 61.4%, with considerable differences between the groups (68.4% for NCCN, 54.9% for MDACC and 53.2% for AHPBA/SSO/SSAT). The total R0 resection rate was 90.1% (89.1% for NCCN, 92.5% for MDACC and 84% for AHPBA/SSO/SSAT). Of the three classifications, NCCN limits the use of confusing terms and uses restrictive criteria to define the most appropriate treatment for each subgroup. However, several reports have suggested that, even in the case of a limited disease, biological and clinical factors should be considered in order to classify patients as resectable. NCCN classification appears to be the classification that allows the highest percentage of patients with BRPC to achieve resection without reducing the R0 resection rate. The choice of therapy should not only be based on imaging results, but also on a wider clinical multidisciplinary evaluation.

Expanded Criteria Donor Kidney Transplantation: Comparative Outcome Evaluation Between Single Versus Double Kidney Transplantation at 8 Years: A Single Center Experience.

Transplantation of kidneys retrieved from expanded criteria donors is one of the options to expand the pool of available grafts, shorten the waiting time and increase the number of kidney transplant recipients. This study was a retrospective assessment of 99 patients who underwent renal transplantation during the period 2007-2015 with kidneys harvested from expanded criteria donors (ECD) as defined by the United Network for Organ Sharing (UNOS) following routine biopsy of all kidneys obtained by Karpinsky Score. They formed two groups: SKT (67 recipients that received a single kidney) and DKT (32 patients that received dual kidney transplant). An analysis of differences of two groups between graft and patient survival and graft function were performed after 8 years of observation. We observed between two groups the following statistical differences: Donor age (P < .001), basal high risk of recipients (P < .05), wait time before transplant (P < .05), recipient age (P < .001) delayed graft function (P < .005) while we observe similar values of donor renal function, outcome in graft and patient survival and graft function in recipients. The transplantation of kidneys obtained from expanded criteria donor, allows increase in the number of kidney transplants and in the respect of values of biopsy score and the donor renal function, showed in single or dual kidney transplantation with similar graft and patient survival.

The obesity gene and colorectal cancer risk: a population study in Northern Italy.

BACKGROUND: Representing the second cause of cancer-related death after lung cancer in men and breast cancer in women, colorectal cancer (CRC) is a major health problem in Italy. Obesity is reckoned to favor CRC; however, the underlying mechanisms are unclear. Recently, a single nucleotide polymorphism (SNP) in the fat mass and obesity associated (FTO) gene was found to be significantly associated with obesity. AIMS: To establish whether the FTO SNP rs9939609 may represent a risk factor for CRC and adenoma in the Italian population. PATIENTS AND METHODS: 1,037 subjects were enrolled in the study and divided in 3 groups: CRC (341 pts., M/F=197/144, mean age=65.17±11.16 years), colorectal adenoma (385 pts., M/F=247/138, mean age=62.49±13.01 years), healthy controls (311 pts., M/F=150/161, mean age=57.31±13.84 years). DNA was extracted from whole blood, and stored frozen for rs9939609 genotyping by real-time PCR. RESULTS: The frequency of the obesity-associated mutated A allele (AA+AT) on the FTO gene was 69.77% among controls, and 71.85% and 65.71% respectively among CRC and polyp patients. Compared to control subjects the AA+AT genotype had no significant effect on the risk for either CRC (OR=1.106; CI 95%=0.788-1.550; p=0.561) or colorectal adenomas (OR=0.830; CI 95%=0.602-1.144; p=0.255). We did not observe any association between the AA genotype and CRC/polyp localization and age at diagnosis. As measured in a patient subset, carriership of the risk alleles did not reflect in a significantly altered BMI. CONCLUSION: The obesity-linked FTO variants do not play a significant role in modulating the colorectal cancer risk in the Italian population.

"Immuknow" to measurement of cell-mediated immunity in renal transplant recipients undergoing short-term evaluation.

The aim of this preliminary, observational study was to evaluate the value of ImmuKnow (IK), a new tool to measure the net state of immunefunction among renal transplant recipients, in correlation with clinical and laboratory data among unselected renal transplant recipients. Forty-nine recipients of mean age of 51 years were enrolled and followed for 1 year after transplantation. All subjects received the same immunosuppressive strategy with basiliximab induction and tacrolimus, mycophenolate mofetil and steroid maintenance therapy. Samples for IK were collected before transplantation as well as at 7, 14, 21 and 42 days and after 3, 6, and 12 months. There were 54 samples with IK <225 ng/mL, 201 samples with normal IK values, and 135 samples with >525 ng/mL. We divided recipients into 3 groups with respect to their basal IK values: Group 1 (Gr1; IK <225 ng/mL); Group 2 (Gr2; normal values of IK between 226 and 524 ng/mL); and Group 3 (Gr3; IK >525 ng/mL). At 1 year, we observed a significant difference among IK values at the start and the end of the study: Gr1 vs Gr2, P<.0001; Gr2 vs Gr3, P<.06 and Gr 1 vs Gr 3, P<.01). We observed reduced IK values to predict an increased risk of infection, particularly with cytomegalovirus (CMV) replication while higher IK value did not correlate with an increased risk of acute rejection episodes. Reduction of serum creatine levels occurred within 1 year in all groups (P<.005), but there was a significant difference between Gr 2 versus Grs 1 and 3 (P<.0001 and P<.0005, respectively). There findings suggested that more stable IK values were associated with clinical quiescence and laboratory stability. In conclusion, our preliminary analysis showed a beneficial capacity of this assay to represent the global depression of the immune system. We noted that reduced IK values, as a sign of excessive immunosuppressive therapy, were associated with an increased risk of infection. We did not confirm the predictive value of higher IK values for an increased risk of an acute rejection episode.

Medial artery calcification of uremic patients: a histological, histochemical and ultrastructural study.

Recent findings suggest that vascular calcification (VC) is an active process similar to bone mineralization, the vascular smooth muscle cells (VSMCs) undergoing phenotypic differentiation into osteoblastic cells and synthesizing calcification-regulating proteins found in bone. This study has investigated the VC process of uremic patients, with a morphologic approach. Epigastric artery samples from 49 uremic, non-diabetic patients were taken during kidney transplantation. Sections from paraffin-embedded samples were stained with hematoxylin/eosin and von Kossa. CD68 was immunohistochemically detected, and sections from frozen samples were stained with Oil Red O. Deeply calcified samples were stained with Picrosirius Red, PAS, and Alcian blue. Specimens from one patient with moderate and one with severe VC were examined under the electron microscope. None of the samples had atherosclerosis. Calcifications were found in the media of 38 patients. In 23, dot-like calcifications were irregularly scattered near the adventitia (light VC); in 11, granular calcifications formed concentric rings near the adventitia (moderate-advanced VC); in 4, zones of consolidated calcifications were found (severe VC). These zones were poor in collagen, glycoproteins and proteoglycans. In cases with moderate or severe VC, VSCMs showed necrotic changes. Matrix vesicles could be recognized in the extracellular spaces. In cases with severe VC, uncalcified or partially calcified membranous bodies were found, together with Liesegang rings. Patches of fibrin were also found. These findings point to a mainly degenerative mechanism of VC, which proceeds from the outer portion of the media. An active mechanism, however, cannot be excluded. A unifying hypothesis is suggested.

Impact of preemptive reduction of immunosuppression with serial monitoring for BK virus replication in renal transplant recipients undergoing short-term evaluation.

The aim of this preliminary, prospective, longitudinal study was to evaluate the effects on graft function and viral loads of modulation of immunosuppressive therapy based upon serial noninvasive monitoring of urine and serum viral loads with real-time polymerase chain reaction among unselected renal transplant recipients. Thirty-nine renal transplant recipients with follow-up times of 7.8 +/- 4.3 months were monitored monthly with urine and serum samples to measure BK viral load. Interventions such as gradual reductions of mycophenolate mofetil and/or tacrolimus were performed when repeated urine and serum viral loads were >10(5) and >10(3) copies/mL, respectively. Among 271 samples, the patients were divided into 6 groups: negative urine (group = 1; n = 10) and negative serum (group 2; n = 25) versus BK viral loads that were intermittent (urine: group 3; n = 24 and serum: group 4; n = 11) versus persistent (urine: group 5; n = 5 and serum: group 6; n = 3). In groups 3-4 we observed the higher viral loads in the urine than in the serum (10(3): 21; 10(4): 1; 10(5): 1; 10(6): 1 vs 10(2): 8; 10(3): 2; 10(4): 1). The timing of resolution of viremia was more rapid than viruria. In groups 5-6 we observed the greatest viral load and greater number in urine. The overall incidences of viruria and viremia were 74.3% and 35.9%, respectively. The overall rates of clearance of viruria were 26/29 recipients (89%) and viremia, 11/14 recipients (78%). Only 10 patients (25.6%) needed extensive reduction of immunosuppression. No modifications of serum creatinine levels and no rejection episodes were observed. In conclusion this preliminary analysis suggested that serial, noninvasive monitoring of viral load allows gradual premptive reduction of immunosuppression with consequent strong reduction in viral load.

[Cytomegalovirus and BK polyomavirus infection after renal transplantation]. / Infezione da citomegalovirus (CMV) e da polioma BK virus (BKV) dopo trapianto di rene.

Cytomegalovirus (CMV) and BK polyomavirus (BKV) infections have been described in a high percentage of renal transplant patients and are known to cause various complications in renal transplantation. They are closely related to immunosuppressive therapy and implicated in the progression of graft failure. This review focuses on the clinical aspects of CMV and BKV infection after renal transplantation, optimal monitoring, and recent preventive measures and interventions to improve graft function and recipient survival.

Laparoscopic repair of Morgagni hernia and cholecystectomy in a 40-year-old male with Down's sindrome. Report of a case.

Morgagni-Larrey hernia (MH) is an unusual diaphragmatic hernia of the retrosternal region. Few cases of MH, treated laparoscopically, associated with Down's syndrome (DS) have been reported in literature. On October 2004, a DS 40-year-old male was admitted to our Department with mild abdominal pain and nausea. Hematochemical tests were within the normal range. Ultrasonography showed biliary sludge and multiple gallstones. Chest X-ray revealed a right-sided paracardiac mass that appeared as MH after a thoraco-abdominal computed tomography (CT). Four trocars were placed as a routinary cholecystectomy. Abdominal exploration confirmed the presence of a voluminous hernia through a wide diaphragmatic defect (12 cm) on the left side of the falciform ligament, containing the last 20 cm ileal loops and right colon with the third lateral of transverse. After retrograde cholecystectomy and reduction of the herniated ileo-colonic tract from multiple adherences, the defect was repaired with an interrupted 2/0 silk suture and then a running 2/0 polypropylene suture. Postoperative course was complicated by pulmonary edema but subsequently the patient was discharged without further complications and has no recurrence after 2 years. In conclusion, surgery is necessary for symptomatic MH and to prevent possible severe complications. We preferred laparoscopy for the reduced morbidity compared to laparotomy, even if in our case the postoperative course was not uneventful. There are still few comparative data about the modality of closure of the defect between primary repair with nonabsorbable suture material, in case of small defects, or continuous monofilament suture or prosthesis in case of large defects.

Emergency catheter probe endoscopic sonography (CP-EUS): an effective procedure in the assessment of a bleeding gangliocytic paraganglioma.

Catheter probe endoscopic sonography is a relatively rapid and safe procedure, carried out during standard endoscopy, capable of distinguishing solid from cystic lesions and vascular from avascular masses. Herein we discuss the role of catheter probe endoscopic sonography in the emergency assessment of a patient with recent and severe bleeding from an ulcerated polyp, arising from the papilla. During the endoscopy, catheter probe endoscopic sonography showed the solid and submucosal nature of the lesion, suggesting its localised and benign nature and, most importantly, demonstrating the high risk of rebleeding from vascular structures communicating with the ulcer. Because of this finding three metallic endoclips were positioned. The lesion was not removed endoscopically because of its difficult position and the high risk of haemorrhage. The mass, removed through a duodenotomy, was shown to be a gangliocytic paraganglioma, an uncommon tumour, frequently resulting in surgery because of abdominal pain and gastrointestinal bleeding.

Surgery for carcinoma of the gallbladder. Our experience.

BACKGROUND: Carcinoma of the gallbladder is a gastrointestinal malignancy with a very poor prognosis. The 5-year survival rate amounts to less than 5% in most series. In this study we reviewed the results of surgical treatment for gallbladder carcinoma with special reference to extended radical procedures. METHODS: Between 1995 and 2000 we enrolled 36 patients (17 males and 19 females), 24 of whom were treated with simple cholecystectomy and 12 with radical resection (partial hepatectomy, regional lymphadenectomy, and common bile duct resection). The tumours were classified by stage using the criteria of the American Joint Committee on Cancer (AJCC). Stages, operative procedures, results of pathologic examinations and the outcome of the resected cases were reviewed. RESULTS: There were 2 postoperative deaths (0.55%). The mean follow-up period was 19.1 months (range 1-60). For stage I and II disease extended cholecystectomy had a better result than simple cholecystectomy: the 5-year survival rates were 38.4 versus 19%, respectively. For the patients with advanced stage III or IV gallbladder carcinoma, a significant advantage of survival resulted in case of liver resection as compared to surgical treatment without liver resection: the 5-year survival rates were 20 and 0%, respectively. CONCLUSIONS: The survival of stage I-II patients was good. For the patients in higher stages the prognosis was significantly worse. In these cases more aggressive surgery may be needed.

[Management of sepsis of the biliary tract: indications to surgical treatment]. / Trattamento delle sepsi delle vie biliari. Indicazioni alla terapia chirurgica.

Sepsis of the biliary tract is a severe disease, due to its course and its significant association with relevant diseases, either benign or malignant, of the biliary tract, pancreas, hepatic hilus. In many cases it remains difficult to set the limit between medical therapy, percutaneous or endoscopic therapy and surgical treatment. Through a thorough review of the last 20 years' literature, we have studied this topic and classified cholangitis according to its etiology: Iithiasis, benign stenosis or Klatskin tumor as malignant diseases. The sequential approach, endoscopy-surgery, seems to provide the best results in lithiasic cholangitis. In patients with benign stenosis of the biliary tract, a percutaneous drainage is indicated as a first choice, meanwhile surgery is limited to unsuccessful bilioplasty and to segmental extrahepatic localization of sclerosing cholangitis. On the contrary, in Klatskin tumours preoperative percutaneous drainages are useful to obtain an accurate map, which is indispensable to perform an aggressive radical hepatic resection.

Laparoscopic cholecystectomy in cirrhotic patients.

BACKGROUND/AIMS: Laparoscopic cholecystectomy has become the procedure of choice for symptomatic cholelithiasis. A study to evaluate the benefits and risks of laparoscopic cholecystectomy in cirrhotic patients was performed. METHODS: Between January 1994 and December 2000, 1,100 laparoscopic cholecystectomies for symptomatic gallbladder diseases were performed. There were 24 cirrhotic patients (group A) and 72 age- and sex-matched controls (group B). All patients had well-compensated cirrhosis (Child's class A or B). RESULTS: There was no operative mortality in either group and the postoperative complication rates were 20.8 and 9.72% in groups A and B, respectively (p < 0.000001). Operative time in group A was 89.16 vs. 68.41 min in group B (p < 0.000001). The estimated intraoperative blood loss in group A was 106.25 vs. 37.08 ml in group B (p < 0.000001). The average transfusion requirement was 0.155 and 0.0 units in groups A and B, respectively (p < 0.025). The hospital stay in groups A and B was 4.7 and 3.61 days, respectively (p < 0.0500). CONCLUSION: Laparoscopic cholecystectomy in patients with compensated cirrhosis is safe and should be the treatment of choice for these patients. Laparotomy should be applied only if the surgeon considers the operation inadequate to be continued laparoscopically.

[Sufentanil vs morphine combined with ropivacaine for thoracic epidural analgesia in major abdominal surgery]. / Sufentanil vs morgina in associazione alla ropivacaina per l'analgesia epidurale toracica in chirurgia addominale maggiore.

BACKGROUND: Pain, postoperative ileus, nausea, vomiting are the universal complications after major abdominal surgery. The aim of this study was to assess pain relief, side effects and recovery of gastrointestinal function during epidural analgesia with ropivacaine plus sufentanil and ropivacaine plus morphine after major abdominal surgery. METHODS: In this prospective study, sixty patients (median age 62+/-12 years) undergoing major abdominal surgery, after informed consent, were randomized into two groups, during a period of 3 months. Patients who were not considered suitable candidates for epidural anaesthesia were excluded. Epidural catheters were inserted at T8-T9 (upper abdominal surgery) or T9-T11 (lower abdominal surgery) and ropivacaine 0,5% 7-9 ml (upper abdominal surgery) or 10-12 ml (lower abdominal surgery) combined with sufentanil 30 mcg (group S, n=30) or with morphine 2 mg (group M, n=30) was injected. General anaesthesia was induced and a continuous epidural infusion of ropivacaine 0.5% 5-10 ml/h was begun. Postoperatively, continuous epidural administration of ropivacaine 0.2% plus sufentanil 0.5 mcg/ml (group S) or ropivacaine 0.2 plus morphine 0.02 mg/ml (group M) was continued. Data on the quality of analgesia, recovery of gastrointestinal function and all side effects were recorded for 48 hours. RESULTS: Incident and resting pain scores were not significantly different among group; although sufentanil provided better resting pain scores at 16th, 20th, 24th hours, and incident pain score at 24th hour. The incidence of nausea, vomiting and pruritus was more in morphine group (p<0,0001). Time to the first flatus was significantly shorter for patients in the sufentanil group (p<0,0001). The quality of pain relief assessed by the patients was rated as good in all patients. CONCLUSIONS: Continuous administration of epidural ropivacaine combined with sufentanil or with morphine resulted in good analgesia. Epidural analgesia with ropivacaine plus sufentanil provided the best balance of analgesia, side effects and recovery of gastrointestinal function.

[Intestinal fistulas in Crohn disease]. / Le fistole enteriche nel morbo di Crohn.

BACKGROUND: Only a part of patients suffering from Crohn's disease has enteric fistulae and a different behaviour of Crohn's disease with fistulae is reported in the literature. Aim of this paper is to evaluate if enteric fistulae are a factor conditioning mortality, morbidity and overall postoperative course, in patients with Crohn's disease. METHODS: Data on the postoperative course of 126 laparotomies for Crohn's disease, performed between November 1993 and July 1998, have been prospectively examined. Moreover, the presence of enteric fistula has been evaluated during surgery. RESULTS: Out of 126 interventions, in 58 (46%) enteric fistulae were present. Mortality (5.2% vs 0), morbidity (14.5% vs 7.3%), necessity for a temporary ostomy (20.4% vs 3.5%) were greater in those patients with fistula, as compared as those without fistula. CONCLUSIONS: In conclusion, it is suggested that Crohn's disease with fistulae is a different type of disease, with higher mortality and morbidity rates.

Primary leiomyosarcoma of the diaphragm in a 23-year-old male: a case report.

Primary neoplasms of the diaphragm are extremely rare and their diagnosis is often difficult. We present a case of leiomyosarcoma of the diaphragm in a 23-year-old male presenting with aspecific abdominal discomfort. The final diagnosis was achieved on the basis of histopathological findings after surgery. The role of different imaging techniques as diagnostic tools is also discussed.

Hepatocellular carcinoma in a non-cirrhotic liver. Two case reports and literature review.

Hepatocellular carcinoma (HCC) is closely associated with cirrhosis, but it also develops, although much less frequently, in a non-cirrhotic liver. It is suspected that hepatocellular carcinoma has a different etiology when associated and not associated with chronic liver disease. We report two cases of patients with hepatocellular carcinoma that developed in a non-cirrhotic liver. In the first case we describe an incidental liver nodular lesion containing multiple foci of HCC including pseudogland or trabecular formation and areas of sclerosis. The non-cancerous parenchyma of the liver was histologically unremarkable except for mild fatty changes of hepatocytes and minimal dysplasia. The second case describes a combined hepatocellular carcinoma and cholangiocellular carcinoma (CCC) (mixed carcinoma) in a patient who was serologically negative for both hepatitis B and C viruses. The adjacent liver parenchyma showed mild piecemeal necrosis and mild lobular activity compatible with chronic viral hepatitis, but cirrhosis was not established. This case appears to indicate that mixed type carcinoma can develop in a non-cirrhotic liver, with CCC being far more dominant than HCC; such a finding is extremely unusual, based on previously published reports.

Defective suppression of the aldosterone biosynthesis during stroke permissive diet in the stroke-prone phenotype of the spontaneously hypertensive rat.

Previous studies have shown that short-term high salt intake unmasks blunted plasma aldosterone suppression in stroke-prone spontaneously hypertensive rats (SHRsp). The aim of this study was to evaluate the response of aldosterone biosynthesis and production to a sustained exposure to the stroke-permissive Japanese-style diet (JD) in young stroke-prone and stroke-resistant SHRs. For this purpose, 6-week old male rats from both strains were divided into 2 dietary groups and received regular diet (SHR = 37, SHRsp = 32) or the JD and 1% saline to drink (SHR = 34, SHRsp = 30) for 4 weeks. All measurements were carried out at the end of the dietary periods. After JD, plasma aldosterone levels were significantly decreased in SHR (from 357.8 +/- 57 to 163.3 +/- 31.5 pg/ml, p < 0.05) but markedly increased in SHRsp (from 442 +/- 56.5 to 739 +/- 125.7 pg/ml, p < 0.05). Consistently, the adrenal aldosterone synthase expression was reduced by JD in SHR (p < 0.05), whereas it was even slightly raised by JD in SHRsp so that, at the end of JD, aldosterone synthase mRNA was 5-fold higher in SHRsp than in SHR. Urinary sodium excretion (mEq/24h) achieved lower levels in SHRsp, so that fractional excretion of sodium was 80.2 +/- 9% in SHR and 40.3 +/- 8% in SHRsp (p < 0.05) in balance studies performed at the end of JD. These different responses of mineralocorticoid biosynthesis and urinary sodium excretion to JD were not accounted for by different adaptations of the renin-angiotensin and atrial natriuretic peptide systems, of serum potassium levels, or of adrenal 11beta-hydroxylase expression in the two strains. Systolic blood pressure was comparable in both strains throughout the experiment. These results demonstrate enhanced aldosterone biosynthesis, associated with reduced urinary excretion of sodium in response to JD in SHRsp before the onset of stroke. This abnormality may play a role in the higher susceptibility to stroke of this model.

Characterization of caveolae from rat heart: localization of postreceptor signal transduction molecules and their rearrangement after norepinephrine stimulation.

Caveolae are plasma membrane subcompartments that have been implicated in signal transduction. In many cellular systems, caveolae are rich in signal transduction molecules such as G proteins and receptor-associated tyrosine kinases. An important structural component of the caveolae is caveolin. Recent evidence show that among the caveolin gene family, caveolin-3 is expressed in skeletal and cardiac muscle and caveolae are present in cardiac myocyte cells. Both the ANP receptor as well as the muscarinic receptor have been localized to the caveolae of cardiac myocytes in culture. These findings prompted us to conduct a further analysis of cardiac caveolae. In order to improve our understanding of the mechanisms of signal transduction regulation in cardiac myocytes, we isolated cardiac caveolae by discontinuous sucrose density gradient centrifugation from rat ventricles and rat neonatal cardiocytes. Our analysis of caveolar content demonstrates that heterotrimeric G proteins, p21ras and receptor-associated tyrosine kinases are concentrated within these structures. We also show that adrenergic stimulation induces an increase in the amount of diverse alpha- and beta-subunits of G proteins, as well as p21ras, in both in vivo and in vitro experimental settings. Our data show that cardiac caveolae are an important site of signal transduction regulation. This finding suggests a potential role for these structures in physiological and pathological states.

Role of angiotensin II AT1 and AT2 subtype receptors in the regulation of atrial natriuretic peptide expression in salt-restricted rats.

Previous studies have suggested that angiotensin II modulates ANP secretion and this action appears to be largely independent from its hemodynamic effects. In order to explore the contribution of angiotensin II AT1 (AT1r) and AT2 (AT2r) receptor subtypes in the regulation of cardiac ANP, we studied the effects of selective antagonists of these receptors on ANP mRNA levels in the cardiac chambers of salt-restricted rats. Thirty-one Sprague-Dawley rats (12 weeks-old) weighing 250-350 g were studied during a low salt regimen and randomly assigned to the following treatment groups: AT1r-blockade (losartan) (10 mg/kg/day) (n = 18), AT2r-blockade (PD123319) (50 microg/kg/min) (n = 6), Control (salt-restriction) (n = 7). Treatments were maintained for 7 days; subsequently, 12 rats from the AT1r-blockade group were subdivided in to two groups: AT1r/AT2r-blockade (losartan +PD123319) (n = 6) and AT1r-blockade/vehicle (losartan+vehible) (n = 6), and treated for 7 additional days. Systolic blood pressure was significantly reduced by AT1r-blockade (p < 0.001), while it was not affected by AT2r-blockade. Concomitant treatment with both antagonists (AT1r/AT2r-blockade) restored blood pressure values to baseline (p < 0.001 vs. AT1r-blockade, p = n.s. vs Control). Atrial ANP mRNA was reduced by AT1r-blockade (-42%, p < 0.05) and did not change during AT1r-blockade alone. On the contrary, concomitant treatment with both antagonists resulted in a further significant inhibition of ANP expression (-65% and -36% vs Control and AT1r-blockade, respectively, both p < 0.05). ANP expression in ventricles was not affected by any of these treatments. Our results demonstrate that angiotensin II tonically modulates cardiac ANP expression in our experimental model. In particular, angiotensin II receptor subtypes AT1r and AT2r regulate atrial ANP mRNA levels through a synergic action and independently from blood pressure changes.