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BACKGROUND: Patients with diabetes mellitus have a high incidence of coronary heart disease and congestive heart failure (CHF). Thiazolidinediones (TZD) are a new class of pharmacological agents for the treatment of Type 2 diabetes mellitus, which have many beneficial cardiovascular effects. Peripheral oedema and weight gain have been reported in 4.8% of subjects on TZDs alone, with a higher incidence noted in those receiving combination insulin therapy (up to 15%), but there is limited data on the occurrence of CHF. METHODS AND RESULTS: In this paper, we report on six cases of TZD-induced fluid retention with symptoms and signs of peripheral oedema and/or CHF that occurred in subjects attending our diabetic clinic. The predominant finding in all cases was of diastolic dysfunction. All subjects were obese and hypertensive, with 5/6 having the additional risk factor of LVH, 5/6 subjects had microvascular complications, whilst 3/6 were also on insulin therapy. CONCLUSION: We suggest that obese, hypertensive diabetics may benefit from echocardiographic screening prior to commencement of TZDs, as these agents may exacerbate underlying undiagnosed left ventricular diastolic dysfunction. Copyright 2004 Diabetes UK [ABSTRACT FROM AUTHOR]

Background Left ventricular non-compaction remains a poorly described entity, which has led to challenges of overdiagnosis. We aimed to evaluate if the presence of a thin compacted myocardial layer portends poorer outcomes in individuals meeting cardiac magnetic resonance criteria for left ventricular non-compaction . Methods and Results This was an observational, retrospective cohort study involving individuals selected from the Cleveland Clinic Foundation cardiac magnetic resonance database (N=26 531). Between 2000 and 2018, 328 individuals ≥12 years, with left ventricular non-compaction or excessive trabeculations based on the cardiac magnetic resonance Petersen criteria were included. The cohort comprised 42% women, mean age 43 years. We assessed the predictive ability of myocardial thinning for the primary composite end point of major adverse cardiac events (composite of all-cause mortality, heart failure hospitalization, left ventricular assist device implantation/heart transplant, ventricular tachycardia, or ischemic stroke). At mean follow-up of 3.1 years, major adverse cardiac events occurred in 102 (31%) patients. After adjusting for comorbidities, the risk of major adverse cardiac events was nearly doubled in the presence of significant compacted myocardial thinning (hazard ratio [HR], 1.88 [95% CI, 1.18‒3.00]; P =0.016), tripled in the presence of elevated plasma B-type natriuretic peptide (HR, 3.29 [95% CI, 1.52‒7.11]; P =0.006), and increased by 5% for every 10-unit increase in left ventricular end-systolic volume (HR, 1.01 [95% CI, 1.00‒1.01]; P =0.041). Conclusions The risk of adverse clinical events is increased in the presence of significant compacted myocardial thinning, an elevated B-type natriuretic peptide or increased left ventricular dimensions. The combination of these markers may enhance risk assessment to minimize left ventricular non-compaction overdiagnosis whilst facilitating appropriate diagnoses in those with true disease.

Background: Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants., Methods and Results: We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2 -knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2 -knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis -eQTL for LCN2 expression., Conclusions: Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

The renin-angiotensin system plays a major role in the pathophysiology of cardiovascular disease (CVD). The enzyme angiotensin-converting enzyme (ACE) converts angiotensin (Ang) I into the vasoconstrictor AngII and was thought, until recently, to be the main effector of the system. The enzyme ACE2, discovered in 2000, can counterbalance the effects of ACE through degradation of AngII and generation of Ang-(1-7). Angiotensin-converting enzyme 2 is abundantly expressed in the heart and localized to the endothelial cells of coronary vessels and smooth muscle cells. Its catalytically active ectodomain undergoes shedding, resulting in ACE2 in the circulation. There are 10 studies to date that have measured circulating ACE2 activity in humans, including in healthy subjects and those with heart failure, Type 1 diabetes, implantable cardioverter/defibrillator, elderly subjects undergoing emergency orthopaedic surgery and kidney transplant patients. The results suggest that circulating ACE2 activity may be a marker of CVD, with low levels in healthy individuals and increased levels in those with cardiovascular risk factors or disease. Whether increased plasma ACE2 activity reflects increased synthesis from tissue ACE2 mRNA or increased shedding of tissue ACE2 remains to be determined. Angiotensin-converting enzyme 2 is located on the X-chromosome and circulating ACE2 levels are higher in men than in women. Large clinical studies in CVD are needed to more precisely clarify the role of ACE2 as a biomarker of CVD, determine the prognostic significance of circulating ACE2 activity and assess whether the measurement of ACE2 will improve CVD risk prediction., (© 2013 The Authors Clinical and Experimental Pharmacology and Physiology © 2013 Wiley Publishing Asia Pty Ltd.)

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.

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., (© 2012 Blackwell Publishing Ltd.)

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.

Angiotensin-converting enzyme 2 (ACE2) is a novel enzyme with possible implications in the treatment of blood pressure disorders. Recent evidence suggests that an upregulation of ACE2 can be stimulated by all-trans retinoic acid (at-RA); however, at-RA also affects regulation of the stem-cell marker octomer-4 (Oct-4) and thus cellular differentiation. We have previously shown that smooth muscle cells and macrophages present within rabbit atherosclerotic plaques are positive for ACE2, Oct-4 and the haematopoietic stem-cell marker CD34. Thus, to provide evidence that possible at-RA treatment could affect both plaque cellular biology (via effects on cellular differentiation) and blood pressure (via ACE2), it is vital to show that cells with atherosclerotic plaques co-express all three markers. Thus, we sought to provide evidence that a subset of cells within atherosclerotic plaques is positive for ACE2, Oct-4 and CD34. We used New Zealand White rabbits that were fed a control diet supplemented with 0.5% cholesterol plus 1% methionine for 4 weeks and then allowed to consume a normal diet for 10 weeks. Immunohistochemistry was performed by standard techniques. We report that ACE2, Oct-4 and CD34 were all present within atherosclerotic plaques. Although macrophages were positive for all three markers, spindle-shaped cells in the media did not show all three markers. The endothelium overlying normal arterial wall showed positive Oct-4 and ACE2 immunoreactivity, but CD34 immunoreactivity was patchy, indicating that such cells might not have fully differentiated. It is concluded that cells in atherosclerotic plaques express co-express ACE2, Oct-4 and CD34. Further studies aimed at establishing the effects of all-trans retinoic acid on blood pressure and atherosclerotic cell differentiation are warranted.

Angiotensin-converting enzyme 2 (ACE2) is thought to act in an opposing manner to its homologue, angiotensin-converting enzyme (ACE), by inactivating the vasoconstrictor peptide angiotensin II and generating the vasodilatory fragment, angiotensin(1-7). Both ACE and ACE2 are membrane-bound ectoenzymes and may circulate in plasma as a consequence of a proteolytic shedding event. In this study, we show that ACE2 circulates in human plasma, but its activity is suppressed by the presence of an endogenous inhibitor. Partial purification of this inhibitor indicated that the inhibitor is small, hydrophilic and cationic, but not a divalent metal cation. These observations led us to develop a method for removal of the inhibitor, thus allowing detection of plasma ACE2 levels using a sensitive quenched fluorescent substrate-based assay. Using this technique, ACE2 activity measured in plasma from healthy volunteers (n = 18) ranged from 1.31 to 8.69 pmol substrate cleaved min-1 ml-1 (mean +/- s.e.m., 4.44 +/- 0.56 pmol min-1 ml-1). Future studies of patients with cardiovascular, renal and liver disease will determine whether plasma ACE2 is elevated in parallel with increased tissue levels observed in these conditions.

1. The role of arginine vasopressin (AVP) was examined in adrenocorticotrophin (ACTH)-induced hypertension in Sprague-Dawley rats using the non-peptide AVP V1a receptor antagonist OPC 21268. 2. In an acute study, six rats were pretreated with ACTH for 11 days and direct arterial blood pressure (4 h), plasma osmolality and electrolyte concentrations were measured after OPC 21268 gavage. In a chronic study, 40 rats were randomly divided into four groups: (i) sham injection + sham gavage; (ii) ACTH + sham gavage; (iii) sham injection + OPC 21268; or (iv) ACTH + OPC-21268 for 16 days. Systolic blood pressure (SBP), water intake, urine volume (UV), urine osmolality and electrolytes, food intake, bodyweight and plasma osmolality and electrolyte concentrations were measured. 3. In the acute study, direct mean arterial blood pressure did not change with OPC 21268 (122+/-2 and 120+/-3 mmHg at 0 and 240 min, respectively). 4. In the chronic study, OPC 21268 did not affect ACTH-induced rises in blood pressure (from 125+/-2 (control) to 145+/-5 mmHg (group 4) compared with 122+/-3 (control) to 149+/-5 mmHg (group2)). Water intake and UV increased (from 29+/-2 to 83+/-6 mL/day; and from 5+/-1 to 36+/-5 mL/day, respectively) and the change in bodyweight decreased from 0+/-2 to -107+/-7 g. 5. These results suggest that AVP (at the V1a receptor) does not play a significant role in the maintenance of ACTH-induced hypertension.

The precise role of vasopressin in the pathophysiology of cardiovascular disease is controversial, but this peptide hormone is important for several reasons. Firstly, circulating concentrations of vasopressin are elevated in heart failure and some forms of hypertension. Secondly, there is evidence that vasopressin is synthesized not only in the hypophysial-pituitary axis but also in peripheral tissues including the heart where it acts as a paracrine hormone. Thirdly, vasopressin has vasoconstrictor, mitogenic, hyperplastic and renal fluid retaining properties which, by analogy with angiotensin II, may have deleterious effects when present in chronic excess. Finally, the availability of orally active non-peptide vasopressin receptor antagonists allows vasopressin receptor antagonism to be considered as a therapeutic option in cardiovascular disease.

A case of pustular vasculitis of the hands with evidence of systemic involvement is described. A 64-year-old woman presented with a 2-day history of large, tense bullae arranged symmetrically over the dorsum of the three radial digits and extending on to the radial aspect of the dorsum of each hand. The bullae caused some discomfort and prevented normal use of her hands. There was no response to antibiotic therapy initiated prior to referral to hospital. Initial investigations revealed a raised white cell count with a neutrophilia, a raised erythrocyte sedimentation rate and a raised C-reactive protein. Abnormalities of liver function were detected. Aspirates from the bullae and blood cultures were sterile. The histology of debrided tissue demonstrated a florid neutrophilic dermal infiltrate with many blood vessels associated with prominent fibrin. A diagnosis of pustular vasculitis of the hands was made. The bullae were surgically debrided and treatment with oral corticosteroids was started. Two days after commencement of oral prednisolone, a crusted pustule appeared on her upper cutaneous lip. There was rapid resolution of both the vasculitis of the hands and the pustule on her upper lip following an increase in the dose of oral prednisolone. The patient was discharged on the seventeenth day following admission.

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.

1. The present study determined whether two dimensional guided M-mode echocardiography could assess left ventricular (LV) geometry and function following a moderate size myocardial infarction in the rat. 2. Myocardial infarction (MI) was induced by left coronary artery ligation and rats were studied 4 weeks later. Infarct rats showed increased LV internal diastolic diameter (7.33 +/- 0.8 vs 5.91 +/- 0.6 mm; P < 0.001), LV systolic diameter (3.73 +/- 1.2 vs 1.87 +/- 0.6 mm; P < 0.001) and thickening of the noninfarcted posterior wall compared with sham operated rats (1.81 +/- 0.2 vs 1.47 +/- 0.3; P < 0.001; n = 10/group; mean +/- s.d.). Systolic function was impaired in infarct rats who showed reduced fractional shortening (50 +/- 12 vs 68 +/- 9%; P < 0.001) and fractional area change (41 +/- 14 vs 78 +/- 5%; P < 0.001). Infarct size measured echocardiographically was comparable to that measured by quantitative histological examination (29 +/- 10 vs 28 +/- 5%; NS). 3. The present study indicates that postinfarction remodelling leading to LV cavity dilation, hypertrophy of surviving myocardium and impaired systolic function is apparent 4 weeks following moderate size MI in the rat. 4. Transthoracic echocardiography is a noninvasive technique that may be used to assess serially the efficacy of therapeutic interventions designed to prevent remodelling in moderate size MI in the rat.

Acquired pure red cell aplasia (PRCA) has been associated with various lymphoproliferative conditions but its occurrence with Hodgkin's disease is rare. We report a case of PRCA occurring immediately following the completion of induction chemotherapy in a patient with Stage IIIB nodular sclerosing Hodgkin's disease. In vitro erythroid colony studies documented evidence for T cell mediated suppression of erythropoiesis and lack of a serum inhibitor. Addition of cyclosporin to the in vitro cultures stimulated erythroid colony growth. Following in vivo treatment with cyclosporin peripheral blood CD4/CD8 ratios returned to normal. However, serum erythropoietin levels were inappropriately low. Subsequent treatment with erythropoietin induced a reticulocytosis and transfusion independence. Since discontinuing the erythropoietin, the patient has been able to maintain a hemoglobin of 100 g/L. This case illustrates that red cell aplasia occurring in the setting of Hodgkin's disease may be due to T cell mediated suppression of erythropoiesis. A response to cyclosporin may be masked by inappropriately low erythropoietin levels.

1. The aim of these studies was to determine the role of endothelin in cyclosporin A ([CsA], 10 mg/kg per day, s.c., for 30 days) hypertension in the rat. 2. There were no significant differences in plasma endothelin concentrations, in vitro mesenteric vascular membrane [125I]-endothelin-1 (ET-1) binding characteristics or myographic vascular responses to endothelin-1 between the CsA and control groups (systolic blood pressure 135 +/- 1 vs 127 +/- 1 mmHg, respectively, P < 0.001). 3. Twenty-four hours after selective endothelin type A receptor blockade in vivo with BQ123, blood pressure in CsA hypertensive rats was lowered to levels of normotensive controls. 4. These results suggest that changes in endothelin synthesis rather than changes in vascular sensitivity and/or ET-1 receptor characteristics may contribute to CsA-induced hypertension.

1. OPC-21268 and OPC-31260 are newly developed orally active non-peptide vasopressin (AVP) V1 and V2 receptor antagonists, respectively. The effects of the two compounds on human vessels have not been studied. 2. The effects of the two compounds on AVP-induced contraction of human internal mammary arteries (IMA) were investigated. Their effects were compared with the peptide V1 and V2 antagonists d(CH2)5Sar7AVP (SAVP) and d(CH2)5D-Ileu2Ileu4AVP (Ileu2Ileu4AVP), respectively. 3. The V1 antagonist OPC-21268 failed to antagonize AVP-induced contraction at low concentrations and potentiated the contraction at higher concentration (3 x 10(-7) mol/L, P < 0.05). It also caused a mild direct contractile effect on IMA. In contrast, the peptide V1 antagonist SAVP potently inhibited the AVP-induced contraction, indicating that functionally constrictor V1 receptors exist in IMA. Both the nonpeptide and peptide V2 antagonists OPC-31260 (3 x 10(-6) mol/L) and Ileu2Ileu4AVP significantly antagonized the AVP-induced contraction (P < 0.01). 4. The AVP-induced contraction was reversed by high concentrations of OPC-31260 (10(-6) mol/L-3 x 10(-5) mol/L) but not by OPC-21268 (up to 3 x 10(-5) mol/L). 5. These studies indicate that, in human IMA, OPC-21268 is a partial V1 receptor agonist with no V1 receptor antagonist activity, while OPC-31260 is a V1 receptor antagonist. The results also indicate that Ileu2Ileu4AVP may be a V1 receptor antagonist in humans.

1. The anti-emetic drug metoclopramide has been shown to stimulate secretion of the antidiuretic hormone arginine vasopressin. Since metoclopramide is used to treat nausea, which is another potent stimulus to vasopressin secretion, the aim of this study was to determine whether metoclopramide might limit free water excretion and so cause hyponatraemia. 2. Metoclopramide 20 mg (0.2-0.3 mg/kg), prochlorperazine 12.5 mg (0.1-0.2 mg/kg) and placebo were administered intravenously in a double blind randomized crossover way at 2 week intervals and the effects on urine flow rate, plasma osmolality, thirst ratings and plasma sodium and atrial natriuretic peptide concentrations determined in water-loaded (10 mL/kg) healthy young men. 3. There were no differential effects on any variable of either drug versus placebo. 4. These results indicate that metoclopramide is unlikely to cause any significant water retention in a clinical setting or precipitate hyponatraemia.

1. This paper reports on the in vitro and in vivo characteristics of a non-peptide vasopressin V1 receptor antagonist 1-(1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl)-3,4-dihydro-2( 1H)- quinolinone (OPC-21268). 2. OPC-21268 caused a concentration-dependent displacement of the selective V1 receptor antagonist radioligand, [125I]-[d(CH2)5, sarcosine7]AVP from vasopressin V1 receptors in rat liver and kidney membranes, inhibitory concentration of 50% (IC50) 4 x 10(-8), 0.3 mol/L liver and 1.5 x 10(-8), 0.2 mol/L kidney. OPC-21268 had little effect on the selective V2 antagonist radioligand [3H]desGly-NH2(9)-d(CH2)5[D-Ileu2, Ileu4]AVP binding to V2 receptors in renal membranes (IC50 > 10(-4) mol/L). 3. After oral administration to rats, OPC-21268 was an effective V1 antagonist to both liver and kidney V1 receptors, in a dose-dependent manner. 4. These studies confirm that OPC-21268 is a potent non-peptide, orally effective V1 vasopressin receptor antagonist.