Acute diverticulitis with extraluminal air: is conservative treatment sufficient? A single-center retrospective study.

BACKGROUND: Acute diverticulitis with extraluminal air constitutes a heterogeneous condition whose management is controversial. The aims of this study are to report the failure rate of conservative treatment for diverticulitis with extraluminal air and to report risk factors of conservative treatment failure. METHODS: A retrospective study was performed from an institutional review board-approved database of patients admitted with acute diverticulitis with extraluminal air from 2015 to 2021 at a tertiary referral center. All patients managed for acute diverticulitis with covered perforation (without intraabdominal abscess) were included. The primary endpoint was failure of medical treatment, defined as a need for unplanned surgery or percutaneous drainage within 30 days after admission. RESULTS: Ninety-three patients (61% male, mean age 57 ± 17 years) were retrospectively included. Ten patients had failure of conservative treatment (11%). These patients were significantly older than 50 years (n = 9/10, 90% versus n = 47/83, 57%, p = 0.007), associated with cardiovascular disease (n = 6/10, 60% versus n = 10/83, 12%, p = 0.002), American Society of Anesthesiologists (ASA) score of 3-4 (n = 4/7, 57% versus 6/33, 18%, p = 0.05), under anticoagulant and antiplatelet (n = 6/10, 60% versus n = 11/83, 13%, p = 0.04) and steroid or immunosuppressive therapy (n = 3/10, 30% versus 5/83, 6%, p = 0.04), and with distant pneumoperitoneum location (n = 7/10, 70% versus n = 14/83, 17%, p = 0.001) compared with those with successful conservative treatment. On multivariate analysis, only distant pneumoperitoneum was an independent risk factor of failure (odds ratio (OR) 6.5, 95% confidence interval (CI) [2-21], p = 0.002). CONCLUSIONS: Conservative treatment with antibiotics for acute diverticulitis with extraluminal air is safe with a success rate of 89%. Patients with distant pneumoperitoneum should be carefully monitored.

Prognosis of poorly cohesive gastric cancer after complete cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (CYTO-CHIP study).

BACKGROUND: The incidence of gastric poorly cohesive carcinoma (PCC) is increasing. The prognosis for patients with peritoneal metastases remains poor and the role of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is controversial. The aim was to clarify the impact of gastric PCC with peritoneal metastases treated by CRS with or without HIPEC. METHODS: All patients with peritoneal metastases from gastric cancer treated with CRS with or without HIPEC, in 19 French centres, between 1989 and 2014, were identified from institutional databases. Clinicopathological characteristics and outcomes were compared between PCC and non-PCC subtypes, and the possible benefit of HIPEC was assessed. RESULTS: In total, 277 patients were included (188 PCC, 89 non-PCC). HIPEC was performed in 180 of 277 patients (65 per cent), including 124 of 188 with PCC (66 per cent). Median overall survival (OS) was 14.7 (95 per cent c.i. 12.7 to 17.3) months in the PCC group versus 21.2 (14.7 to 36.4) months in the non-PCC group (P < 0.001). In multivariable analyses, PCC (hazard ratio (HR) 1.51, 95 per cent c.i. 1.01 to 2.25; P = 0.044) was associated with poorer OS, as were pN3, Peritoneal Cancer Index (PCI), and resection with a completeness of cytoreduction score of 1, whereas HIPEC was associated with improved OS (HR 0.52; P < 0.001). The benefit of CRS-HIPEC over CRS alone was consistent, irrespective of histology, with a median OS of 16.7 versus 11.3 months (HR 0.60, 0.39 to 0.92; P = 0.018) in the PCC group, and 34.5 versus 14.3 months (HR 0.43, 0.25 to 0.75; P = 0.003) in the non-PCC group. Non-PCC and HIPEC were independently associated with improved recurrence-free survival and fewer peritoneal recurrences. In patients who underwent HIPEC, PCI values of below 7 and less than 13 were predictive of OS in PCC and non-PCC populations respectively. CONCLUSION: In selected patients, CRS-HIPEC offers acceptable outcomes among those with gastric PCC and long survival for patients without PCC.

Impact of obesity after cytoreductive surgery and intraperitoneal hyperthermic chemotherapy for rare peritoneal malignancies: Paradox of obesity or poor prognostic factor?

BACKGROUND: Obesity is a public health concern with an increasing occurrence worldwide. Literature regarding impact of obesity on results after management of peritoneal carcinomatosis is poor. Our aim was to compare postoperative and oncological outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for rare peritoneal malignancies according to the body mass index. METHODS: All the patients managed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for rare peritoneal malignancies (including mainly pseudomyxoma peritonei and peritoneal mesothelioma), between 1995 and 2020, were retrospectively included from the French national registry of rare peritoneal tumors. RESULTS: 1450 patients were retrospectively included (63.5 % female, mean age 54 ± 13 years). Patients were divided into two groups according to their body mass index: non-obese (n = 1248, 86 %) and obese (n = 202, 14 %). Overall morbidity was significantly lower in non-obese patients in comparison with obese patients (n = 532/1248, 43 % vs n = 106/202, 53 %, p = 0.009). Medical and surgical morbidities were significantly lower in non-obese patients in comparison with obese patients (423/1258, 34 % vs n = 86/202, 43 %, p = 0.02 and n = 321/1248, 26 % vs n = 67/202, 33 %, p = 0.003, respectively). One-, 5- and 10-year overall survivals were similar between non-obese and obese patients (95 %, 82 % and 70 % vs 94 %, 76 % and 63 %; p = 0.1). One-, 5- and 10-year disease free survivals were similar between non-obese and obese patients (84 %, 67 % and 61 % vs 79 %, 62 % and 56 %, p = 0.1). CONCLUSION: Obese patients have to be carefully managed after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for rare peritoneal malignancies. Some perioperative prophylactic treatments could be specifically implemented to reduce thromboembolic events, metabolic and wound complications.

Mucosal advancement flap anoplasty for chronic anal fissure resistant to conservative therapy.

BACKGROUND: Sphincter-sparing procedures are increasingly advocated in the treatment of chronic anal fissures (CAF) resistant to conservative management. Herein, we report about our results with sphincter-sparing transanal mucosal advancement flap anoplasty (MAAP) to treat CAF. PATIENTS AND METHODS: The present study was a retrospective single-center analysis of patients in whom conservative management of CAF failed and who subsequently underwent MAAP between January 2003 and December 2008. RESULTS: A total of 26 patients with a median age of 46.5 years (range: 17-79 years) had undergone MAAP after suffering with CAF for a median period of 9 months (range: 4-36 months). Surgery was well tolerated in all patients. One patient developed a perianal abscess at the operative site 3 weeks after MAAP, which required excision. At 2, 12, and 24 months follow-up, all patients were free of pain with no fissure recurrence or any worsening of incontinence. CONCLUSIONS: Mucosal advancement flap anoplasty might be another sphincter-sparing treatment option in patients suffering from CAF. To draw final conclusions about the value of MAAP in the treatment of CAF, more solid data are required.

[The lymph node of Mondor: myth or reality?]. / Le ganglion de Mondor : mythe ou réalité ?

AIM OF THE STUDY: Lymph node involvement is one of the most significant prognostic factors of patients with rectal cancer. Despite major advances in our understanding of the propagation of the rectal cancer, the lymphatic drainage of the rectum remains unclear. This study was designed to assess the number of lymph nodes located around the superior rectal artery and to assess the frequency of Mondor's lymph nodes. PATIENTS AND METHODS: Twenty-five anatomic subjects were studied. All resections were performed using total mesorectal excision. Lymph nodes were sought in the tissue surrounding the superior rectal artery up to 2 cm under the ending of the superior rectal artery by manual dissection and were submitted for histological examination. The correlation between the number of lymph nodes, and the volume and weight of the tissue surrounding the superior rectal artery was evaluated by non-parametric Spearman test. RESULTS: The mean number of lymph nodes per specimen was 2.7 +/- 1.4. The size of the lymph nodes varied between 1 and 7 mm. The lymph nodes were mostly smaller than 3 mm (56%). The number of lymph nodes in the superior rectal mesentery was independent of its volume and its weight. Seven subjects had a Mondor's lymph node. The mean size of Mondor's lymph node was 3.4 +/- 2.1 cm. CONCLUSIONS: The number of NL located around the superior rectal artery is small, varying between 1 and 5. The Mondor's lymph node is an inconstant rectal NL. Its only characteristic is its location in the bifurcation or trifurcation of the superior rectal artery.

[What do we know about the lymphatic drainage of the rectum?]. / Que savons-nous du drainage lymphatique du rectum ?

Lymph node (LN) involvement is one of the most significant prognostic factors of patients with rectal cancer. However, the distribution of rectal LN is not well known. The rectal LN are mainly located around the rectal arteries. In the mesorectum, the LN are mainly located posteriorly. The number of LN by patient varies considerably. Many reasons can explain this variability. Acquired factors such as infection, inflammation or metastatic involvement facilitate the detection of LN. In contrast, preoperative radiotherapy reduces the number and size of lymph nodes. The procedure of resection affects the number of LN harvested. Extensive lymphadenectomies increase the number of LN harvested. The technique used by pathologist has equally a major influence. The fat clearing method allows detection of a greater number of LN than manual dissection particularly for small LN. Toxicity of these solutions and a time-consuming process explain that fat clearing method is rarely used in clinical practice. Detection of rectal lymph nodes is difficult and tedious but is necessary for an accurate staging of patients with rectal cancer.

[Hand distal interphalangeal joints: sonographic anatomy]. / Echoanatomie des articulations interphalangiennes distales de la main.

PURPOSE: To determine normal anatomy of hand distal interphalangeal joints at ultrasonography, and to compare sonographic and anatomic findings. MATERIALS AND METHODS: Right hands of three embalmed cadavers and dominant hands of 10 asymptomatic volunteers were evaluated. Distal interphalangeal joints were scanned longitudinally and transversely with a high-frequency linear-array transducer. Sonographic appearances of intra-articular and periarticular structures were analysed in consensus by two musculoskeletal radiologists. Cadaveric dissection provided anatomic comparisons. RESULTS: Sagittal and transverse sonographic images enabled good analysis of the extensor tendon, the deep flexor tendon, and the palmar plate. The radial and ulnar collateral ligaments were identified on all coronal scans. Direct visualization of the dorsal triangular structure and of the middle phalanx head's cartilage was possible on longitudinal scans. The dorsal and palmar synovial recesses were better recognized when a small amount of fluid was present. CONCLUSION: Ultrasonography with a high-frequency linear-array transducer provides detailed anatomical information about intra-articular and periarticular structures of the hand distal interphalangeal joints.

Risk factors of exocrine and endocrine pancreatic insufficiency after pancreatic resection: A multi-center prospective study.

Management of functional consequences after pancreatic resection has become a new therapeutic challenge. The goal of our study is to evaluate the risk factors for exocrine (ExoPI) and endocrine (EndoPI) pancreatic insufficiency after pancreatic surgery and to establish a predictive model for their onset. PATIENTS AND METHODS: Between January 1, 2014 and June 19, 2015, 91 consecutive patients undergoing pancreatoduodenectomy (PD) or left pancreatectomy (LP) (72% and 28%, respectively) were followed prospectively. ExoPI was defined as fecal elastase content<200µg per gram of feces while EndoPI was defined as fasting glucose>126mg/dL or aggravation of preexisting diabetes. The volume of residual pancreas was measured according to the same principles as liver volumetry. RESULTS: The ExoPI and EndoPI rates at 6 months were 75.9% and 30.8%, respectively. The rate of ExoPI after PD was statistically significantly higher than after LP (98% vs. 21%; P<0.001), while the rate of EndoPI was lower after PD vs. LP, but this difference did not reach statistical significance (28% vs. 38.5%; P=0.412). There was no statistically significant difference in ExoPI found between pancreatico-gastrostomy (PG) and pancreatico-jejunostomy (PJ) (100% vs. 98%; P=1.000). Remnant pancreatic volume less than 39.5% was predictive of ExoPI. CONCLUSION: ExoPI occurs quasi-systematically after PD irrespective of the reconstruction scheme. The rate of EndoPI did not differ between PD and LP.

[What are the risk factors of anal incontinence after vaginal delivery?]. / Quels sont les facteurs de risque de l'incontinence anale du post-partum?

Fecal incontinence is one of the most feared complications of vaginal delivery. It may be the consequence of sphincter tears, of pudendal neuropathy, or of a combination of the two. Fecal incontinence occurs immediately following 13-54% of vaginal deliveries but its persistence in the mid and long term is poorly known. The incidence of perineal tear with anal sphincteric defect varies from 1-9% and the incidence of unrecognized sphincter injury may be as high as 18-35%. Half the women who undergo primary anal sphincter repair have short or long term continence problems. Pudendal neuropathy is caused by nerve stretch during pushing in the second stage of labor and descent of the fetal head; it may occur even with the first delivery. Risk factors for sphincter injury and pudendal neuropathy include forceps delivery, large neonatal size, and prolonged second stage of labor. The risk of fecal incontinence must be considered even during the first pregnancy. Routine episiotomy does not prevent sphincter injury and may even predispose to it. Pudendal neuropathy following delivery may lead to delayed fecal incontinence abetted by postmenopausal hormonal deficiency and tissue senescence. The possible benefit of early episiotomy for women at high risk of sphincter injury must be evaluated by prospective studies.

[Feasibility of colorectal surgery without colonic preparation. A prospective study]. / Faisabilité de la chirurgie colorectale sans préparation colique. Etude prospective.

INTRODUCTION: Mechanical bowel preparation (MBP), aimed at reducing the infectious complications of colorectal surgery, was considered as indispensable. This benefit is actually disputed. The aim of this study was to report an experience of colorectal surgery without MBP. MATERIALS AND METHODS: Hundred ninety patients without MBP and without low residue diet, who underwent colorectal surgery with primary anastomosis not requiring a diverting stoma were included. The main outcome were the rate of mortality, anastomotic leak, wound infection and intra-abdominal abscess. Secondary outcomes were duration of intravenous perfusion, nasogastric aspiration, total hospitalisation stay and time to realimentation. RESULTS: The procedure was performed by laparotomy (n=142) or laparoscopy (n=48). Forty-eight patients underwent emergency surgery. Ninety-two patients were operated for malignancy. The rate of mortality was 6.3% in correlation with the scale of AFC. The rate of anastomotic leak was 3.7%. The rate of specific morbidity was independent of scale of AFC on the contrary to the frequency of non-specific complications. The mean duration of intravenous perfusion and nasogastric suction were 6 days and 0.3 day. The patient had normal diet to the 4th day (4+/-3 days). The mean hospital stay was 13.4 days. CONCLUSION: The colorectal surgery without MBP may be safely performed and could improve the quality of life of patients in the perioperatory period.

[Long term outcome following 26 surgical ampullectomies]. / Résultat à long terme de 26 ampullectomies chirurgicales.

BACKGROUND: Pancreaticoduodenectomy (PD) is the standard surgical treatment for malignant ampullomas but is still associated with a mortality and morbidity still ranging from 0 to 10% and from 15 to 40%, respectively. Ampullectomy is an alternative to PD for benign ampulloma or, in high-risk patients, for invasive carcinoma. The aim of this study was to report early and long term results of surgical ampullectomy for presumed benign ampullomas. PATIENTS AND METHODS: From 1981 to 2004, 26 patients from two institutions underwent surgical ampullectomy. Of the 26 patients, 8 had familial adenomatous polyposis (FAP). Surgical ampullectomy was indicated on a multisciplinary basis. RESULTS: Final pathological examination revealed 15 adenomas, 4 in situ adenocarcinomas, 2 endocrine tumors, and 5 other benign lesions. There was no postoperative mortality. Specific morbidity was 8% (N=2). Mean follow-up was 86+/-70 months (range: 3-204). Actuarial overall 5-year survival was 92%. There were 4 local recurrences (none in patients with FAP). Four patients died during follow-up (including 3 from initial disease). CONCLUSION: Ampullectomy is a good alternative to PD in case of benign or non-invasive malignant ampullary lesion, including in selected cases of FAP.

[Study of 3 white matter fiber trackings using MRI diffusion]. / Etude de 3 faisceaux de substance blanche en IRM de diffusion.

UNLABELLED: The aim of this study is to evaluate the interest of diffusion weighted MRI for the study of white matter fiber tracking. METHODS: Fifteen subjects having undergone diffusion weighted MRI have been included. Three white matter fiber trackings have been studied for each subject: interhemispheric transcallosum, optic radiations and pyramidal tracts. The results were compared to an atlas of human anatomy. RESULTS: All the white matter tracts studied have been visualized. The morphology of the three white matter tracts was similar to standard anatomy. The orientation of the three white matter tracts was determined in 100% of the cases. CONCLUSION: diffusion weighted MRI allowed the morphological study of all the analyzed white matter tracts. This technique might, therefore, help to evaluate nerve fiber tracts and guide neurosurgical interventions.

Assessment of the main pancreatic duct using computed tomography with multiplanar reconstructions.

UNLABELLED: The aim of this study was to assess the morphology of the main pancreatic duct (MPD) using multiplanar reconstructions and to compare this with the morphology of the MPD of anatomic subjects. MATERIALS AND METHODS: The morphology of the MPD was studied by means of multiplanar reconstructions obtained on the one hand from thin tomodensitometric slices and on the other hand from the dissection of anatomic subjects. This study involved 15 subjects in each group. RESULTS: Full multiplanar reconstruction was obtained in 13 cases. In 2 cases, the isthmus did not appear in the reconstructions. The morphology of the MPD was similar in both groups. The length of the MPD was identical at the head and isthmus of the pancreas in both groups but was greater in the dissection group than in the reconstruction group in the body and tail areas of the pancreas. The diameter of the MPD was greater at the head of the pancreas in the dissection group and was identical in both groups for the other segments of the MPD. CONCLUSIONS: Multiplanar tomodensitometric reconstruction of the main pancreatic duct is feasible. This new technique, currently under evaluation, could allow the study of canalar pathologies of the pancreas through tomodensitometry.

[Cecal volvulus: anatomical bases and physiopathology]. / Volvulus du caecum: bases anatomiques et physiopathologie.

UNLABELLED: The aim of this study was to report on 7 cases of cecal volvulus and to evaluate anatomical variations allowing this pathology. METHODS: 7 consecutive patients (4 women) treated for cecal volvulus were included. The clinical and paraclinical parameters, the management of patients, were studied through an analysis of medical histories. Contributing factors for cecal volvulus were analysed by an anatomical study and literature analysis. RESULTS: all patients complained about abdominal pain associating or not to acute intestinal obstruction. The diagnosis was radiographically carried out for 3 patients. All patients were treated by surgical procedures (right colectomy: n = 6, cecopexy: n = 1). The mortality and morbidity rates were 0 percent and 28 percent. Fifteen anatomical subjects had complete dorsal fixation (75 percent). Seven out of them had retrocecal recessus. Five subjects (25%) had a non fixed cecum, according to the literature relating a non-fixation of ascending colon to parietal peritoneum in 11 to 25 percent of the cases. The main factor of risk is the female gender. CONCLUSION: cecal volvulus can be advocated for patients having abdominal pain. The diagnosis is rarely based on an only clinical examination or abdominal radiographs alone. Tomodensitometry is most performing examination for diagnosis. An early and appropriate management of patients is necessary to avoid significant morbidity and mortality rates.

[Appendicitis: yes or no to laparoscopic approach?]. / Appendicites: coelioscopie ou non?

Whether or not there is a benefit to laparoscopy versus open surgery in the management of acute appendicitis remains a subject of controversy despite the publication of numerous randomized studies. Operative time is longer for the laparoscopic approach. The incidence of abdominal wall abscess is decreased for laparoscopy but the incidence of deep intra-abdominal abscess may be increased, especially in the case of complicated appendicitis. Post-operative pain is diminished and resumption of normal activity is quicker with the laparoscopic approach. Hospitalization is shorter but the cost of hospital care is higher; nevertheless, the global cost may be less - particularly for patients whose return to work is hastened by a laparoscopic approach. Laparoscopy diminishes the number of normal appendectomies, particularly in women of reproductive age where the diagnosis may be unclear. Laparoscopic appendectomy is practicable and has advantages over open appendectomy under certain circumstances. These advantages are most evident in the young female, the working patient, and the obese patient. Overall, the advantages of laparoscopy are, at best, modest and clinical benefit is not always demonstrable. The risk of deep abscess, particularly in patients with perforated or gangrenous appendicitis, remains an unknown and should be evaluated by further studies.

[Pancreaticoduodenectomy in the era of evidence based medicine]. / La duodénopancréatectomie céphalique à l'ère de la médecine factuelle.

The aim of this comprehensive literature review was to analyse evidence based data in the field of pancreaticoduodenectomy. Pylorus preserving does reduce mortality or morbidity of the standard procedure and could increase the risk of delayed gastric emptying. Pancreaticogastrostomy does not decrease the rate of postoperative pancreatic fistula and is not superior to the pancreaticojejunal anastomosis which is more physiological. No other procedure (chemical occlusion, octreotide, stenting) has been demonstrated to prevent pancreatic fistula. Octreotide injection could be advocated in centres where there is a high rate of pancreatic fistula, when pancreatic parenchyma is soft and the main pancreatic duct thin. Intra-abdominal drainage is not beneficial and could be associated with some morbidity. Its use needs to be further evaluated. When a resection is done for pancreatic cancer, less than 5% of patients are a live five years after surgery with postoperative mortality rate of 5% in expert centres and a high morbidity rate (25-50%). Extended lymphadenectomy does not increase survival. The first trials showed that adjuvant therapies could be beneficial for pancreatic cancers, but further trials did not confirm these findings. Adjuvant therapy is not validated for pancreatic cancers and needs to be considered only in the settings of clinical trials.

Professional risks when carrying out cytoreductive surgery for peritoneal malignancy with hyperthermic intraperitoneal chemotherapy (HIPEC): A French multicentric survey.

BACKGROUND: Over the last two decades, many surgical teams have developed programs to treat peritoneal carcinomatosis with extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Currently, there are no specific recommendations for HIPEC procedures concerning environmental contamination risk management, personal protective equipment (PPE), or occupational health supervision. METHODS: A survey of the institutional practices among all French teams currently performing HIPEC procedures was carried out via the French network for the treatment of rare peritoneal malignancies (RENAPE). RESULTS: Thirty three surgical teams responded, 14 (42.4%) which reported more than 10 years of HIPEC experience. Some practices were widespread, such as using HIPEC machine approved by the European Community (100%), individualized or centralized smoke evacuation (81.8%), "open" abdominal coverage during perfusion (75.8%), and maintaining the same surgeon throughout the procedure (69.7%). Others were more heterogeneous, including laminar flow air circulation (54.5%) and the provision of safety protocols in the event of perfusate spills (51.5%). The use of specialized personal protective equipment is ubiquitous (93.9%) but widely variable between programs. CONCLUSION: Protocols regarding cytoreductive surgery/HIPEC and the associated professional risks in France lack standardization and should be established.

Differential actions of angiotensin II and angiotensin-(1-7) on transmitter release.

The central cardiovascular and dipsogenic effects of angiotensin II involve interactions with norepinephrine, dopamine, and serotonin. Our findings that angiotensin II receptors and substance P immunoreactivity show a parallel distribution in the dorsal medulla and that angiotensin II releases substance P from perfused rat medulla slices revealed the potential for a functional relation between these peptidergic systems as well. Additional evidence suggests that the heptapeptide angiotensin-(1-7) exerts its biological activities via selective angiotensin receptor subtypes. Thus, we compared the effects of these two peptides on release of substance P and monoamines in perfused slices of medulla and hypothalamus from 77 male Sprague-Dawley rats. Transmitter levels were determined in 6-minute collections of perfusate before (basal), during (experimental), and after (recovery) perfusion with either angiotensin-(1-7), angiotensin II, or Krebs' solution alone (control). Substance P was measured by radioimmunoassay and monoamines and their metabolites by high-performance liquid chromatography with electrochemical detection. In the medulla, 2 microM angiotensin II but not angiotensin-(1-7) significantly increased efflux of substance P (221 +/- 87% of basal) and norepinephrine (130 +/- 17% of basal) during the experimental period. The effect of angiotensin II on substance P was sustained into the recovery period. Dopamine and its metabolite 3,4-dihydroxyphenylacetic acid were not detected in this brain region. In the hypothalamus, both angiotensin-(1-7) and angiotensin II increased substance P (169 +/- 30% and 141 +/- 35% of basal, respectively); the effect of angiotensin II was sustained throughout the recovery period.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolism of angiotensin-(1-7) by angiotensin-converting enzyme.

Angiotensin converting enzyme (ACE) inhibitors augment circulating levels of the vasodilator peptide angiotensin-(1-7) [Ang-(1-7)] in man and animals. Increased concentrations of the peptide may contribute to the antihypertensive effects associated with ACE inhibitors. The rise in Ang-(1-7) following ACE inhibition may result from increased production of the peptide or inhibition of the metabolism of Ang-(1-7)-similar to that observed for bradykinin. To address the latter possibility, we determined whether Ang-(1-7) is a substrate for ACE in vitro. In a pulmonary membrane preparation, the ACE inhibitor lisinopril attenuated the metabolism of low concentrations of 125I-Ang-(1-7). The primary product of 125I-Ang-(1-7) metabolism was identified as Ang-(1-5). Using affinity-purified ACE from canine lung, HPLC separation and amino acid analysis revealed that ACE functioned as a dipeptidyl carboxypeptidase cleaving Ang-(1-7) to the pentapeptide Ang-(1-5). The ACE inhibitors lisinopril and enalaprilat (1 micromol/L), as well as the chelating agents EDTA, o-phenanthroline, and DTT (0.1-1 mmol/L) abolished the generation of Ang-(1-5) and did not yield other metabolic products. Ang-(1-5) was not further hydrolyzed by ACE. Kinetic analysis of the hydrolysis of Ang-(1-7) by ACE revealed a substrate affinity of 0.81 micromol/L and maximal velocity of 0.65 micromols min(-1) mg(-1). The calculated turnover constant for the peptide was 1.8 sec(-1) with a catalytic efficiency (Kcat/Km) of 2200 sec(-1) mmol/L(-1). These findings suggest that increased levels of Ang-(1-7) following ACE inhibition may be due, in part, to decreased metabolism of the peptide.

Release of angiotensin-(1-7) from the rat hindlimb: influence of angiotensin-converting enzyme inhibition.

The results of recent studies have demonstrated that angiotensin (Ang)-(1-7) contributes to the antihypertensive actions of either combined ACE/Ang II type 1 receptor blockade or ACE inhibition alone. The vasculature is a key site of action for either drug regimen, and evidence favors a local Ang system within these tissues. Because ACE may degrade Ang-(1-7), we determined whether ACE inhibition alters Ang-(1-7) release from the rat hindlimb perfused with Krebs-Ringer buffer containing Ficoll. Ang-(1-7) release averaged 36+/-13 fmol (period 1, 15-minute collection) and 44+/-11 fmol (period 2) in the control buffer. The addition of the ACE inhibitor lisinopril to the perfusion buffer augmented levels of Ang-(1-7) in periods 3 (144+/-39 fmol) and 4 (163+/-35 fmol; P<0.05 versus 1 or 2, n=8). HPLC and radioimmunoassay of effluent from control or lisinopril treatment demonstrated a single immunoreactive peak with a retention time identical to that of Ang-(1-7). The addition of the neprilysin inhibitor SCH 39370 reduced Ang-(1-7) release in the lisinopril buffer from 177+/-32 (period 1) and 173+/-39 (period 2) fmol to 112+/-24 (period 3) and 87+/-23 fmol (period 4; P<0.05 versus 1 or 2, n=6). Ang I metabolism in the collected perfusate revealed the formation of Ang-(1-7) that was sensitive only to thimet oligopeptidase inhibition; Ang II generation was not detected. The present study demonstrates the recovery of endogenous Ang-(1-7) from the perfused hindlimb. The release of Ang-(1-7) is significantly influenced by inhibition of ACE, which may reflect both increased substrate (Ang I) levels and reduced metabolism of the peptide. Neprilysin inhibition reduced but did not abolish Ang-(1-7) release, which suggests that other endopeptidases may contribute to the release of the peptide.