Age adjusted Charlson Co-morbidity Index is an independent predictor of mortality over long-term follow-up in infective endocarditis.

BACKGROUND: Infective endocarditis (IE) is associated with high morbidity and mortality. The epidemiology of IE is changing, affecting more elderly patients with increased medical comorbidities. We aimed to assess the ability of the age adjusted Charlson Co-morbidity Index (ACCI) to predict early and late outcomes. METHODS: Between 1998 and 2010, adult patients with definite IE according to the modified Duke criteria were identified. The primary outcome was in-hospital and all-cause mortality. The secondary outcome was predictors of the primary outcome incorporating ACCI. RESULTS: 148 patients with IE were followed up for a mean of 3.8 ± 3 years. The mean age was 57 ± 17 years and 66% were male. In-hospital mortality and all-cause mortality were 24 and 47% respectively. Comorbid conditions included diabetes mellitus (DM) (21%); ischaemic heart disease (16%); heart failure (HF) (14%); renal failure (eGFR <60 ml/min/1.73 m(2)) (19%); and anaemia (64%). The most common causative organism was Staphylococcus aureus (53%). ACCI was >3 in 59% of patients. Cardiac surgery was performed in 45% of patients. On Cox regression analysis, ACCI >3 (HR=3.0 [1.5-6.0], p<0.002), new onset HF (HR=2.2 [1.3-3.6], p<0.003), anaemia (HR=1.8 [1.1-3.2], p=0.04) and age-per decade (HR=1.4 [1.1-1.7]. p=0.004) were independently associated with all-cause mortality. ACCI >3 was the strongest predictor of in-hospital mortality (OR=8.4 [2.8-24], p<0.001). Of the individual ACCI components, prior HF, DM with complications and metastatic disease were independent predictors of all-cause mortality. CONCLUSION: In-hospital and all-cause mortality of IE remain high. An ACCI >3 was a strong predictor of mortality, in addition to age, new HF and anaemia.

Review article: the pathophysiological roles of the renin-angiotensin system in the gastrointestinal tract.

BACKGROUND: The renin-angiotensin system (RAS) is a homeostatic pathway widely known to regulate cardiovascular and renal physiology; however, little is known about its influence in gastrointestinal tissues. AIM: To elicit the anatomical distribution and physiological significance of the components of the RAS in the gastrointestinal tract. METHODS: An extensive online literature review including Pubmed and Medline. RESULTS: There is evidence for RAS involvement in gastrointestinal physiology and pathophysiology, with all the components required for autonomous regulation identified throughout the gastrointestinal tract. The RAS is implicated in the regulation of glucose, amino acid, fluid and electrolyte absorption and secretion, motility, inflammation, blood flow and possibly malignant disease within the gastrointestinal tract. Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. Given the ready availability of drugs that modify the RAS and their excellent safety profile, an opportunity exists for investigation of their possible therapeutic role in a variety of human gastrointestinal diseases. CONCLUSIONS: The gastrointestinal renin-angiotensin system appears to be intricately involved in a number of physiological processes, and provides a possible target for novel investigative and therapeutic approaches.

Chronic kidney disease: cardiac and renal angiotensin-converting enzyme (ACE) 2 expression in rats after subtotal nephrectomy and the effect of ACE inhibition.

Renin-angiotensin system blockade slows but does not prevent the cardiovascular complications of chronic kidney disease (CKD). Angiotensin-converting enzyme (ACE) 2 is differentially regulated in acute kidney injury, with increased cardiac ACE2 but decreased kidney ACE2 levels. This study investigated the effect of long-term ACE inhibition on cardiac and renal ACE2 in rats with CKD induced by subtotal nephrectomy (STNx). Sprague-Dawley rats had sham (control) or STNx surgery. Control rats received vehicle (n = 9) and STNx rats ramipril (1 mg kg(-1) day(-1); n = 10) or vehicle (n = 10) for 28 days. Subtotal nephrectomy resulted in impaired creatinine clearance (P < 0.05), proteinuria (P < 0.05), renal fibrosis (P < 0.05) and reduced renal cortical ACE2 mRNA (P < 0.05) and activity (P < 0.05). In rats with CKD, ramipril improved creatinine clearance (P < 0.05) and was associated with an increase in cortical but not medullary ACE2 activity (P < 0.05). Compared with control rats, STNx rats were hypertensive (P < 0.01), with increased left ventricular end-diastolic pressure (LVEDP; P < 0.01), left ventricular hypertrophy (LVH; P < 0.05) and interstitial (P < 0.05) and perivascular fibrosis (P < 0.01). In rats with CKD, ramipril decreased blood pressure (P < 0.001) and reduced LVEDP (P < 0.01), LVH (P < 0.01) and perivascular fibrosis (P < 0.05) but did not significantly reduce interstitial fibrosis. There was no change in cardiac ACE2 in rats with CKD compared with control rats. In rats with CKD, ACE inhibition had major benefits to reduce blood pressure and cardiac hypertrophy and to improve creatinine clearance, but did not significantly impact on cardiac ACE2, cardiac interstitial fibrosis, renal fibrosis or proteinuria. Thus, in rats with CKD, renal ACE2 deficiency and lack of activation of cardiac ACE2 may contribute to the progression of cardiac and renal tissue injury. As long-term ACE inhibition only partly ameliorated the adverse cardio-renal effects of CKD, adjunctive therapies that lead to further increases in ACE2 activity may be needed to combat the cardio-renal complications of CKD.

Angiotensin II mediates epithelial-to-mesenchymal transformation in tubular cells by ANG 1-7/MAS-1-dependent pathways.

Epithelial-to-mesenchymal transformation (EMT) of tubular cells into a myofibroblastic phenotype is an important mediator of renal scarring in chronic nephropathy. This study examines the role of the renin-angiotensin system (RAS) in this process. NRK-52E cells were exposed to angiotensin (ANG) II and ANG 1-7 in the presence or absence of inhibitors and agonists of RAS signaling. EMT was assessed at 3 days by expression of alpha-smooth muscle actin (alpha-SMA) and E-cadherin and the induction of a myofibroblastic phenotype. Expression of fibrogenic growth factors and matrix proteins was assessed by RT-PCR and immunofluorescence microscopy. To confirm findings in vivo, rats were also infused with ANG 1-7 (24 microg*kg(-1)*h(-1)) or saline via an osmotic minipump for 10 days, and renal fibrogenesis was then assessed. Treatment of NRK-52E cells with ANG II induced characteristic changes of EMT. Selective blockade of the AT(1) receptor or the AT(2) receptor failed to inhibit ANG II-induced EMT. However, blockade of the ANG 1-7 receptor, Mas-1, was able to prevent ANG II-dependent EMT. To confirm these findings, both ANG 1-7 and the selective Mas receptor agonist, AVE-0991, were able to induce NRK-52E cells in a dose-dependent manner. Exposing cells to recombinant ACE2 was also able to induce EMT. In addition, an infusion of ANG 1-7 induced the tubular expression of alpha-SMA and the expression of matrix proteins in the kidney. ANG II is a potent stimulus for EMT, but not through conventional pathways. This study points to the possible limitations of conventional RAS blockade, which not only fails to antagonize this pathway, but also may enhance it via augmenting the synthesis of ANG 1-7.

ACE2 and AT4R are present in diseased human blood vessels.

A growing body of evidence suggests that the angiotensin II fragments, Ang(1-7) and Ang(3-8), have a vasoactive role, however ACE2, the enzyme that produces Ang(1-7), or AT4R, the receptor that binds Ang (3-8), have yet been simultaneously localised in both normal and diseased human conduit blood vessels. We sought to determine the immunohistochemical distribution of ACE2 and the AT4R in human internal mammary and radial arteries from patients undergoing coronary artery bypass surgery. We found that ACE2 positive cells were abundant in both normal and diseased vessels, being present in neo-intima and in media. ACE2 positive immunoreactivity was not present in the endothelial layer of the conduit vessels, but was clearly evident in small newly formed angiogenic vessels as well as the vaso vasorum. Endothelial AT4R immunoreactivity were rarely observed in either normal and diseased arteries, but AT4R positive cells were observed adjacent to the internal elastic lamine in the internal mammary artery, in the neo-intima of radial arteries, as well as in the media of both internal mammary artery and radial artery. AT4R was abundant in vaso vasorum and within small angiogenic vessels. Both AT4R and ACE2 co-localised with smooth muscle cell alpha actin. This study identifies smooth muscle cell alpha actin positive ACE2 and AT4R in human blood vessels as well as in angiogenic vessels, indicating a possible role for these enzymes in pathological disease.

Acute kidney injury in the rat causes cardiac remodelling and increases angiotensin-converting enzyme 2 expression.

Patients with kidney failure are at high risk of a cardiac death and frequently develop left ventricular hypertrophy (LVH). The mechanisms involved in the cardiac structural changes that occur in kidney failure are yet to be fully delineated. Angiotensin-converting enzyme (ACE) 2 is a newly described enzyme that is expressed in the heart and plays an important role in cardiac function. This study assessed whether ACE2 plays a role in the cardiac remodelling that occurs in experimental acute kidney injury (AKI). Sprague-Dawley rats had sham (control) or subtotal nephrectomy surgery (STNx). Control rats received vehicle (n = 10), and STNx rats received the ACE inhibitor (ACEi) ramipril, 1 mg kg(-1) day(-1) (n = 15) or vehicle (n = 13) orally for 10 days after surgery. Rats with AKI had polyuria (P < 0.001), proteinuria (P < 0.001) and hypertension (P < 0.001). Cardiac structural changes were present and characterized by LVH (P < 0.001), fibrosis (P < 0.001) and increased cardiac brain natriuretic peptide (BNP) mRNA (P < 0.01). These changes occurred in association with a significant increase in cardiac ACE2 gene expression (P < 0.01) and ACE2 activity (P < 0.05). Ramipril decreased blood pressure (P < 0.001), LVH (P < 0.001), fibrosis (P < 0.01) and BNP mRNA (P < 0.01). These changes occurred in association with inhibition of cardiac ACE (P < 0.05) and a reduction in cardiac ACE2 activity (P < 0.01). These data suggest that AKI, even at 10 days, promotes cardiac injury that is characterized by hypertrophy, fibrosis and increased cardiac ACE2. Angiotensin-converting enzyme 2, by promoting the production of the antifibrotic peptide angiotensin(1-7), may have a cardioprotective role in AKI, particularly since amelioration of adverse cardiac effects with ACE inhibition was associated with normalization of cardiac ACE2 activity.

Evidence for cardioprotective, renoprotective, and vasculoprotective effects of vasopeptidase inhibitors in disease.

In both the natriuretic peptide and renin-angiotensin systems, peptidases play an important role in the inactivation or activation of the system. Angiotensin-converting enzyme is responsible for the conversion of angiotensin I to angiotensin II, while neutral endopeptidase is one of the pathways involved in the degradation of the natriuretic peptides. The vasopeptidase inhibitors, which simultaneously inhibit neutral endopeptidase and angiotensin-converting enzyme, appear to offer distinct therapeutic advantages in treating hypertension, heart failure, and endothelial dysfunction.

Vasopeptidase inhibition attenuates the progression of renal injury in subtotal nephrectomized rats.

BACKGROUND: Vasopeptidase inhibitors are a new class of cardiovascular compounds that inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The aim of the present study was to explore the effects of omapatrilat, a vasopeptidase inhibitor, on renal function and pathology in subtotally nephrectomized (STNx) rats. METHODS: STNx rats were randomized to four groups and treated for 12 weeks: no treatment (N = 14); omapatrilat at a low dose of 10 mg/kg (L, N = 12) and at a high dose of 40 mg/kg (H, N = 10); or an ACE inhibitor, fosinopril, at a dose of 10 mg/kg (N = 12). Sham-operated rats were used as control animals (N = 12). RESULTS: Elevated blood pressure in STNx rats (174 +/- 9 mm Hg) was reduced by omapatrilat in a dose-dependent manner (L, 121 +/- 3 mm Hg; H, 110 +/- 3 mm Hg) and by fosinopril (149 +/- 5 mm Hg). Proteinuria in STNx rats (246 +/- 73 mg/day) was reduced by treatment with fosinopril (88 +/- 21 mg/day) and was normalized by treatment with omapatrilat (L, 30 +/- 4 mg/day; H, 20 +/- 2 mg/day vs. control 25 +/- 1 mg/day). Decreased glomerular filtration rates, elevated plasma urea and creatinine and glomerulosclerosis, and tubulointerstitial fibrosis were ameliorated by omapatrilat and fosinopril to a similar degree. Compared with fosinopril, omapatrilat treatment was associated with increased plasma renin activity and decreased renal ACE and NEP binding in a dose-dependent manner. CONCLUSION: These findings suggest that vasopeptidase inhibition may provide a useful strategy for the treatment of progressive renal disease.

In-vitro and in-vivo inhibition of rat neutral endopeptidase and angiotensin converting enzyme with the vasopeptidase inhibitor gemopatrilat.

OBJECTIVES: Vasopeptidase inhibitors are single molecules that simultaneously inhibit neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). The aim of this study was to characterize in-vitro and in-vivo inhibition of NEP and ACE in the rat with the vasopeptidase inhibitor gemopatrilat. DESIGN AND METHODS: In-vitro NEP and ACE inhibition was studied by radioinhibitory binding assay using rat renal membranes and the specific NEP inhibitor radioligand 125I-RB104 and the specific ACE inhibitor radioligand 125I-MK351A, respectively (n = 3 per curve). In-vivo NEP and ACE inhibition was studied using in-vitro autoradiography in rats that received oral gemopatrilat (1, 3, 10 mg/kg; n = 4 per dose) and were killed 1 h later, or received oral gemopatrilat (3, 10 mg/kg) and were killed at time points 1, 2, 4, 8, 18, 24 and 48 h (n = 4 per time point). RESULTS: Gemopatrilat caused a concentration-dependent displacement of specific radioligands from renal membrane NEP (IC50 305 +/- 5.4 nmol/I) and ACE (IC50 3.6 +/- 0.02 nmol/). In the dose-response study gemopatrilat (1, 3 and 10 mg/kg) caused significant inhibition of plasma ACE (P< 0.01), and renal ACE and NEP (3, 10 mg/kg, P < 0.01). In the time course experiment, gemopatrilat (10 mg/kg) increased plasma renin activity for 8 h (P< 0.01) and inhibited plasma ACE (P< 0.05), renal NEP (P< 0.01) and renal ACE (P< 0.05) for 48 h. CONCLUSIONS: Gemopatrilat is a potent in-vitro vasopeptidase inhibitor that also causes prolonged inhibition of circulating and renal ACE and renal NEP after a single oral dose. The data suggest that gemopatrilat may be a useful addition to existing vasopeptidase inhibitors in the treatment of cardiovascular disease.

Antihypertensive and antihypertrophic effects of omapatrilat in SHR.

Vasopeptidase inhibitors, such as omapatrilat are single molecules that simultaneously inhibit neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). In normotensive rats, a single dose of oral omapatrilat (10 mg/kg) and 1 mg/kg inhibited plasma ACE (P < .01) for 24 h and increased plasma renin activity for 8 h (P < .01). In vitro autoradiography using the specific NEP inhibitor radioligand 125I-RB104 and the specific ACE inhibitor radioligand 125I-MK351A showed omapatrilat (10 mg/kg) caused rapid and potent inhibition of renal NEP and ACE, respectively, for 24 h (P < .01). In spontaneously hypertensive rats, 10 days of oral omapatrilat (40 mg/kg/day) reduced blood pressure (vehicle 237 +/- 4 mm Hg; omapatrilat, 10 mg/kg, 212 +/- 4 mm Hg; omapatrilat 40 mg/kg, 197 +/- 4 mm Hg, P < .01) in a dose-dependent manner (10 v 40 mg/kg, P < .01). Left ventricular hypertrophy was significantly reduced by high-dose omapatrilat (vehicle 2.76 +/- 0.03 mg/g body weight; omapatrilat, 10 mg/kg, 2.71 +/- 0.02 mg/g; omapatrilat 40 mg/kg, 2.55 +/- 0.02 mg/g, P < .01) and omapatrilat also increased kidney weight compared to vehicle (both doses, P < .01). Omapatrilat caused significant inhibition of plasma ACE and increased plasma renin activity (both doses, P < .01), and in vitro autoradiographic studies indicated sustained inhibition of renal ACE and NEP (both doses, P < .01). Omapatrilat is a potent vasopeptidase inhibitor, and its antihypertensive effects are associated with inhibition of NEP and ACE at the tissue level and beneficial effects on cardiovascular structure. Relating the degree of tissue inhibition to physiologic responses may allow further definition of the role of local renin angiotensin and natriuretic peptide systems in the beneficial effects of vasopeptidase inhibitors.

Reversal of cardiac hypertrophy and fibrosis by S21402, a dual inhibitor of neutral endopeptidase and angiotensin converting enzyme in SHRs.

OBJECTIVE: The major advantage of dual inhibitors of neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE) is their ability to lower blood pressure irrespective of renin or volume status. The aim of this study was to determine whether dual NEP/ACE inhibition produces different effects on cardiovascular structure and fibrosis, hormonal parameters and inhibition of tissue enzymes compared with selective inhibition of ACE and NEP in the spontaneously hypertensive rat (SHR). METHODS: Male SHRs received the dual NEP/ACE inhibitor (S21402, 100 mg/kg per day), the ACE inhibitor (captopril, 50 mg/kg per day), the NEP inhibitor (SCH42495, 60 mg/kg per day) or vehicle for 2 weeks. RESULTS: S21402 produced equivalent blood pressure lowering effects to captopril (vehicle, 220 +/- 1 mmHg; S21402, 189 +/- 2 mmHg; captopril, 187 +/- 3 mmHg), but was a more effective antihypertensive agent than SCH42495 (214 +/- 2 mmHg, P< 0.01). All treatments reduced left ventricular mass (P< 0.05) and cardiac fibrosis (P< 0.01). S21402 inhibited renal NEP and ACE (P< 0.01), SCH42495 inhibited renal NEP (P < 0.01), and captopril inhibited renal ACE (P< 0.01). Captopril and S21402 increased plasma renin activity (P< 0.05), but the rise with S21402 was attenuated compared with that caused by captopril (P< 0.01). All treatments reduced plasma aldosterone levels (P< 0.01), and NEP inhibition with SCH42495 and S21402 increased plasma atrial natriuretic peptide (ANP; P< 0.05). CONCLUSIONS: These results indicate that selective NEP inhibition has major benefits in the regression of cardiac hypertrophy and reduction of fibrosis but has limited antihypertensive effects. The dual NEP/ACE inhibitor S21402 offered no advantage over the selective ACE inhibitor in terms of blood pressure reduction, or attenuation of cardiac hypertrophy and fibrosis, but did increase plasma ANP and blunted the reactive rise in renin with ACE inhibition. Further studies are needed to determine whether more complete blockade of the renin-angiotensin system with dual NEP/ACE inhibition results in additional benefits in terms of morbidity and mortality in cardiovascular disease.

Beneficial renal and cardiac effects of vasopeptidase inhibition with S21402 in heart failure.

S21402 is a vasopeptidase inhibitor that simultaneously inhibits neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE). This study determined whether chronic treatment with S21402 produced different effects on sodium and water excretion, hormonal parameters, and cardiovascular structure compared with selective inhibition of ACE and NEP in a rat model of myocardial infarction-induced congestive heart failure (CHF). CHF rats received the vasopeptidase inhibitor (S21402, 100 mg. kg(-1). d(-1)), an ACE inhibitor (captopril, 50 mg. kg(-1). d(-1)), a NEP inhibitor (SCH42495, 60 mg. kg(-1). d(-1)), or vehicle for 4 weeks. S21402 alone caused a diuresis and natriuresis (P<0.01) in CHF. After 4 weeks, blood pressure was lowered by captopril but not other treatments (P<0.01). Both S21402 and captopril increased plasma renin activity (P<0.01), all treatment lowered plasma aldosterone (P<0.05) and plasma natriuretic peptide levels were unchanged. In the kidney, S21402 inhibited NEP and ACE (P<0.01), SCH42495 inhibited NEP (P<0.01), and captopril inhibited ACE (P<0.01). Heart mass was reduced by all active treatments; captopril reduced left ventricular mass (P<0.01), SCH42495 reduced right ventricular mass (P<0.01), and S21402 decreased left (P<0.05) and right ventricular mass (P<0.01), atrial mass (P<0.05), and lung mass (P<0.01). In CHF, vasopeptidase inhibition with S21402 produces effects that differ from those of selective NEP or ACE inhibition. S21402 improved sodium and water excretion, reduced pulmonary congestion, and attenuated both right and left ventricular remodeling. These effects, which occurred in the absence of any hypotensive action, suggest that S21402 may offer several advantages over ACE inhibition alone in the treatment of heart failure.

Localization of the insulin-like growth factor system in a rat model of heart failure induced by myocardial infarction.

Although cardiac effects of growth hormone (GH) and insulin-like growth factor (IGF)-I have been reported in experimental models of heart failure and in human dilated cardiomyopathy, the IGF system has not been comprehensively assessed in the failing heart. We therefore localized the IGF system in the left ventricle during congestive heart failure after myocardial infarction (MI) in the rat. The left anterior descending coronary artery was ligated in adult female Sprague-Dawley rats and hearts were examined after 6 months when congestive heart failure had developed. In situ hybridization histochemistry was used to localize mRNA for the components of the IGF system in the left ventricle of sham and congestive heart failure animals. We were able to detect changes in the spatial distribution of mRNA for IGF-I and IGF binding proteins 3, 4, 5, and 6 in the left ventricle during congestive heart failure after MI. IGF-I and the binding proteins were predominantly increased in the infarct/peri-infarct area of the left ventricle. Other components of the IGF system were indistinguishable from the low to undetectable levels in sham-operated rats. These results demonstrate that the IGF system is altered in the failing heart and suggest that the IGF system plays an important role in the response of the heart to MI and consequent failure.

Clinical management of carpal tunnel syndrome: a 12-year review of outcomes.

Carpal tunnel syndrome (CTS) is a disorder frequently encountered by occupational health care specialists. The health care management of this disorder has involved a diverse set of clinical procedures. The present article is a review of the literature related to CTS with an emphasis on occupational-related CTS. MEDLINE, Cumulative Index to Nursing and Allied Health Literature, PsycLIT, and NIOSHTIC databases from 1985-1997 were searched for treatment outcome studies related to CTS. Treatments of interest included surgery, physical therapy, drug therapy, chiropractic treatment, biobehavioral interventions, and occupational rehabilitation. A systematic review of the effects of these interventions on symptoms, medical status, function, return to work, psychological well-being, and patient satisfaction was completed. Compared to other treatments, the majority of studies assessed the effects of surgical interventions. Endoscopic release was associated with higher levels of physical functioning and fewer days to return to work when compared to open release. Limited evidence indicated: 1) steroid injections and oral use of B6 were associated with pain reduction; 2) in comparison to splinting, range of motion exercises appeared to be associated with less pain and fewer days to return to work; 3) cognitive behavior therapy yielded reductions in pain, anxiety, and depression; and, 4) multidisciplinary occupational rehabilitation was associated with a higher percentage of chronic cases returning to work than usual care. Workers' compensation status was associated with increased time to return to work following surgery. Conclusions are preliminary due to the small number of well-controlled studies, variability in duration of symptoms and disability, and the broad range of reported outcome measures. While there are several opinions regarding effective treatment, there is very little scientific support for the range of options currently used in practice. Despite the emerging evidence of the multivariate nature of CTS, the majority of outcome studies have focused on single interventions directed at individual etiological factors or symptoms and functional limitations secondary to CTS.

Dual inhibition of neutral endopeptidase and angiotensin-converting enzyme in rats with hypertension and diabetes mellitus.

It has been suggested that combined inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may lower blood pressure more effectively than either treatment alone, independent of the degree of salt and volume status or the activity of the renin-angiotensin system. The effects of NEP inhibition in hypertension associated with diabetes mellitus are largely unknown. We therefore compared ACE inhibition, NEP inhibition, and dual NEP/ACE inhibition in diabetic hypertensive rats. Spontaneously hypertensive rats (SHR) aged 9 to 10 weeks were injected with either streptozotocin (45 mg/kg) or citrate buffer and randomized to receive either the ACE inhibitor captopril (25 mg/kg BID), the NEP inhibitor SCH 42495 (30 mg/kg BID), the dual NEP/ACE inhibitor S 21402 (25 or 50 mg/kg BID), or vehicle by gavage for 4 weeks. A group of diabetic SHR was also allocated to receive the combination of SCH 42495 (30 mg/kg BID) and captopril (25 mg/kg BID). The degree of renal NEP inhibition was determined by autoradiography, and plasma renin activity (PRA) was determined by radioimmunoassay. In diabetic SHR, the dual NEP/ACE inhibitor (50 mg/kg BID), as well as the combination of the NEP inhibitor and the ACE inhibitor, reduced systolic blood pressure more effectively than the ACE inhibitor (P<0.001) or the NEP inhibitor (P<0.001) alone. In nondiabetic SHR, the dual NEP/ACE inhibitor and the ACE inhibitor were equally effective, while the NEP inhibitor had only slight blood pressure lowering effects. Relative heart weight decreased in parallel to the changes in blood pressure. Renal NEP was clearly inhibited (70% to 92%; P<0.001) by both the NEP inhibitor and the dual NEP/ACE inhibitor. Both the ACE inhibitor and the dual NEP/ACE inhibitor increased PRA, but the stimulating effect of dual NEP/ACE inhibition on PRA was less than that observed with ACE inhibition alone (P<0.05). Albuminuria in diabetic SHR was lower during treatment with both the dual NEP/ACE inhibitor (50 mg/kg BID) and the combination of NEP inhibition and ACE inhibition compared with vehicle treatment (P<0.05). In conclusion, the present study shows that hypertension in SHR with streptozotocin-induced diabetes is modulated by natriuretic peptides and thus is sensitive to NEP inhibition. The increased efficacy of dual NEP/ACE inhibition on blood pressure in diabetic SHR, compared with ACE or NEP inhibition alone, suggests that this therapeutic approach may prove beneficial in the treatment of hypertension associated with diabetes mellitus and other forms of volume-dependent hypertension.

High-dose cyclophosphamide, etoposide and carboplatin with autologous bone marrow support for metastatic breast cancer: long-term results.

We report long-term results of high-dose cyclophosphamide, etoposide and carboplatin with ABMT in 20 patients with metastatic breast cancer. Median age of the group was 41 years, ECOG performance status = 0 in 18 patients and 1 in two patients. Twelve patients had received adjuvant chemotherapy. Predominant sites of metastases were lung (eight), chest wall (four), liver (four), bone (three) and lymph nodes (three). Response to pretransplant chemotherapy was complete (CR) in four patients, partial (PR) in 10 patients and stable (SD) in five patients. After high-dose chemotherapy eight patients were in CR, six PR, four SD and one progressive disease. Two patients died of regimen-related toxicities (candidal sepsis and alveolar hemorrhage). With a median follow-up period of 55 months (minimum 48 months), 12 patients have died of recurrent breast cancer, one died of toxicity of salvage chemotherapy, two are alive with disease, two are alive and free of progressive disease. One patient with relapsed disease was lost to follow-up. Median event-free survival is 6 months and median overall survival is 17 months. All three of the long-term disease-free survivors had predominantly nodal disease. Two of these three patients presented with metastatic disease and received high-dose chemotherapy with ABMT as part of initial therapy for breast cancer; two of three attained CR to standard-dose cytoreductive therapy; none received doxorubicin-containing adjuvant chemotherapy.

New hormonal blockade strategies in cardiovascular disease.

The circulation is controlled by overlapping haemodynamic, structural and neurohumoral mechanisms. Many hormonal vasoactive substances, mostly derived from endothelial cells, are also growth regulators. Although neurohormonal systems are involved in normal physiological compensatory responses they often become maladaptive in conditions such as congestive heart failure. The success of blocking the renin angiotensin system by angiotensin converting enzyme (ACE) inhibitors has led to efforts to block other hormonal systems. Neutral endopeptidase (NEP), the major enzymatic pathway for degradation of natriuretic peptides, has a similar catalytic site to ACE. This has led to compounds that simultaneously inhibit both enzymes. Such dual ACE/NEP inhibitors show promise in experimental hypertension and heart failure. Similar dual NEP/ECE (endothelin converting enzyme) inhibitors are becoming available. The hormone vasopressin has dual actions on the vasculature and the kidney via specific membrane receptors. Specific orally active vasopressin receptor antagonists have been developed and their therapeutic potential in hypertension, heart failure and oedematous states are being explored.

Effects of neutral endopeptidase inhibition in the rat remnant kidney model.

The orally active neutral metalloendopeptidase (NEP) inhibitor SCH34826 was given by oral gavage in a dose of 90 mg/kg twice daily for 3 days to rats with subtotal nephrectomy (n = 7) and effects were compared to a placebo group receiving phosphate buffer (n = 5). Inhibition of neutral endopeptidase in the remnant kidney was measured by in vitro autoradiography using the specific radioligand [125I]-SCH 47896. Treatment with the NEP inhibitor SCH34826 caused a 60% reduction in the neutral endopeptidase radioligand-binding site density in the kidneys of the SCH34826-treated animals compared to the placebo group (81.6+/-3.7 versus 214.5+/-4.2 dpm/mm2, p<0.01). This was associated with a marked increase in urinary atrial natriuretic peptide (ANP) from 3,930+/-295 to 9,094+/-1,089 pg/24 h in the SCH34826-treated group (p<0.01). Concomitantly there was a transient increase in natriuresis in the SCH34826-treated group [baseline 2.03+/-0.55 to 3.77+/-0.58 mmol/24 h on treatment day 1 (p = 0.02) and 2.58+/-0.19 mmol/24 h on treatment day 3 (p = 0.09)] which was not observed in the placebo group. Urinary protein excretion, glomerular filtration rate (determined by 99mTc-DTPA clearance), systemic blood pressure, plasma ANP concentration and urinary cyclic GMP excretion were not changed by SCH34826 treatment. These results suggest that oral administration of the NEP inhibitor SCH34826 inhibits renal neutral endopeptidase, increases urinary ANP and modulates natriuresis without alteration of systemic blood pressure, plasma ANP and renin level, glomerular filtration or protein excretion.

Chronic vasopressin antagonism in two-kidney, one-clip renovascular hypertension.

The role of vasopressin (AVP) in the maintenance of hypertension in the rat model of two-kidney, one-clip (2K1C) Goldblatt hypertension was assessed using the nonpeptide orally effective V1a receptor antagonist, OPC-21268. Rats were studied eight weeks after surgery when mean arterial pressure (MAP) was significantly increased in 2K1C rats compared to SHAM operated controls (2K1C 139 +/- 6, SHAM 106 +/- 3, P < 0.01). Neither acute (OPC-21268, 30 mg/kg) nor chronic (OPC-21268, 30 mg/kg twice daily) V1a receptor blockade reduced blood pressure in either 2K1C or SHAM rats. The results of binding kinetic studies confirmed that OPC-21268 was effective at its putative site of action, the V1a receptor in both 2K1C and SHAM rats. These results indicate AVP is not involved in the maintenance of blood pressure in the 2K1C model of renovascular hypertension.