Self-reported beta-lactam allergy in government and private hospitals in Cape Town, South Africa.

BACKGROUND: Up to a quarter of inpatients in high-income countries (HICs) self-report beta-lactam allergy (BLA), which if incorrect,increases the use of alternative antibiotics, worsening individual health outcomes and driving bacterial resistance. In HICs, up to 95% ofself-reported BLAs are incorrect. The epidemiology of BLA in low- and middle-income African countries is unknown. OBJECTIVES: To describe the epidemiology and de-labelling outcomes of self-reported BLA in hospitalised South African (SA) patients. METHODS: Point-prevalence surveys were conducted at seven hospitals (adult, paediatric, government and privately funded, district andtertiary level) in Cape Town, SA, between April 2019 and June 2021. Ward prescription records and in-person interviews were conductedto identify and risk-stratify BLA patients using the validated PEN-FAST tool. De-labelling was attempted at the tertiary allergy clinic atGroote Schuur Hospital. RESULTS: A total of 1 486 hospital inpatients were surveyed (1 166 adults and 320 children). Only 48 patients (3.2%) self-reported a BLA,with a higher rate in private than in government-funded hospitals (6.3% v. 2.8%; p=0.014). Using the PEN-FAST tool, only 10.4% (n=5/48)of self-reported BLA patients were classified as high risk for true penicillin hypersensitivity. Antibiotics were prescribed to 70.8% (n=34/48)of self-reported BLA patients, with 64.7% (n=22/34) receiving a beta-lactam. Despite three attempts to contact patients for de-labelling atthe allergy clinic, only 3/36 underwent in vivo testing, with no positive results, and 1 patient proceeded to a negative oral challenge. CONCLUSION: Unlike HICs, self-reported BLA is low among inpatients in SA. The majority of those who self-reported BLA were low risk fortype 1 hypersensitivity, but outpatient de-labelling efforts were largely unsuccessful.

Proximal translation of > 1 mm within the first two years of revision total hip arthroplasty correctly predicts whether or not an acetabular component is loose in 80% of cases: a case-control study with confirmed intra-operative outcomes.

AIMS: The purpose of this study was to determine the sensitivity, specificity and predictive values of previously reported thresholds of proximal translation and sagittal rotation of cementless acetabular components used for revision total hip arthroplasty (THA) at various times during early follow-up. PATIENTS AND METHODS: Migration of cementless acetabular components was measured retrospectively in 84 patients (94 components) using Ein-Bild-Rontgen-Analyse (EBRA-Cup) in two groups of patients. In Group A, components were recorded as not being loose intra-operatively at re-revision THA (52 components/48 patients) and Group B components were recorded to be loose at re-revision (42 components/36 patients). RESULTS: The mean proximal translation and sagittal rotation were significantly higher in Group B than in Group A from three months onwards (p < 0.02). Proximal translation > 1.0 mm within 24 months had a positive predictive value (PPV) of 90% and a specificity of 94%, but a sensitivity of 64%. Proximal translation > 1.0 mm within the first 24 months correctly identified 76 of 94 (81%) of components to be either loose or not loose. However, ten components in Group B (24%) did not migrate proximally above 1.0 mm within the first 60 months. CONCLUSION: The high PPV of EBRA-Cup measurements of proximal translation (90%) shows that this can be used in early follow-up to identify patients at risk of aseptic loosening. The absence of proximal translation within the first 60 months indicates a component is not likely to be loose at re-revision THA although it does not exclude late aseptic loosening as a cause of failure. Cite this article: Bone Joint J 2017;99-B:465-74.

The diagnostic performance of radiographic criteria to detect aseptic acetabular component loosening after revision total hip arthroplasty.

AIMS: This study aimed to determine the diagnostic performance of radiographic criteria to detect aseptic acetabular loosening after revision total hip arthroplasty (THA). Secondary aims were to determine the predictive values of different thresholds of migration and to determine the predictive values of radiolucency criteria. PATIENTS AND METHODS: Acetabular component migration to re-revision was measured retrospectively using Ein-Bild-Rontgen-Analyse (EBRA-Cup) and manual measurements (Sutherland method) in two groups: Group A, 52 components (48 patients) found not loose at re-revision and Group B, 42 components (36 patients) found loose at re-revision between 1980 and 2015. The presence and extent of radiolucent lines was also assessed. RESULTS: Using EBRA, both proximal translation and sagittal rotation were excellent diagnostic tests for detecting aseptic loosening. The area under the receiver operating characteristic (ROC) curves was 0.94 and 0.93, respectively. The thresholds of 2.5 mm proximal translation or 2° sagittal rotation (EBRA) in combination with radiolucency criteria had a sensitivity of 93% and specificity of 88% to detect aseptic loosening. The sensitivity, specificity, positive predictive value and negative predictive value (NPV) of radiolucency criteria were 41%, 100%, 100% and 68% respectively. Manual measurements of both proximal translation and sagittal rotation were very good diagnostic tests. The area under the ROC curve was 0.86 and 0.92 respectively. However, manual measurements had a decreased specificity compared with EBRA. Radiolucency criteria had a poor sensitivity and NPV of 41% and 68% respectively. CONCLUSION: This study shows that EBRA and manual migration measurements can be used as accurate diagnostic tools to detect aseptic loosening of cementless acetabular components used at revision THA. Radiolucency criteria should not be used in isolation to exclude loosening of cementless acetabular components used at revision THA given their poor sensitivity and NPV. Cite this article: Bone Joint J 2017;99-B:458-64.

Risk factors affecting survival after brain metastases from non-small cell lung carcinoma: a follow-up study of 70 patients.

OBJECT: The authors present their experience with the treatment of brain metastases from non-small cell lung carcinoma (NSCLC). METHODS: A retrospective review was conducted in which records from 74 patients treated at the authors' institution between 1994 and 1999 were assessed. Survival and functional outcome were reviewed relative to individual patient variables. The median survival time was 12.9 months, with 1-, 2-, and 5-year survival milestones reached by 52.2%, 30.7%. and 18.1% of patients, respectively. Patients were stratified into groups composed of those with synchronous brain metastases (tumors diagnosed within 3 months of NSCLC) and metachronous brain metastases (tumors diagnosed 3 months after NSCLC). The median survival time and 5-year survival rate were 18 months and 28.9% for metachronous, compared with 9.9 months and 0% for synchronous brain metastases. In univariate analyses, the stage of brain metastases, an initial Karnofsky Performance Scale (KPS) score of 90 or less, and conservative therapy for NSCLC were associated with worse outcomes (p < 0.05). In analyses in which tumors were stratified by synchronous compared with metachronous brain metastases, a preoperative KPS score of 90 or less and radiation therapy (RT) alone for brain metastases were associated with worse outcomes in patients with metachronous brain metastases but not with synchronous tumors (p < 0.05). When stratified by preoperative KPS score, the synchronous brain metastases stage or treatment of brain metastases with RT alone were associated with worse outcome in patients with KPS scores of 100, but had no discernible effect on patients with KPS scores of 90 or less (p < 0.05). CONCLUSIONS: The tumor stage and preoperative KPS score were significantly associated with survival. Craniotomy plus RT significantly improved the prognosis in patients with metachronous brain metastases or those with a preoperative KPS score of 100.

Delivery of human vascular endothelial growth factor with platinum coils enhances wall thickening and coil impregnation in a rat aneurysm model.

BACKGROUND AND PURPOSE: Histopathologic studies indicate that aneurysms treated with Guglielmi detachable coils (GDCs) have avascular centers with fibrosis mostly at the aneurysm periphery. We hypothesized that vascular endothelial growth factor (VEGF) released from a coil promotes clot organization, hyperplasia, and endothelial proliferation to facilitate closure of the aneurysm neck. METHODS: GDC segments were inserted into ligated common carotid arteries (CCAs) of adult male rats for 14 days. Coil segments (4-mm) were unmodified, modified with type I collagen (2.4 mg/mL), or modified with type I collagen and recombinant human VEGF-165 (rhVEGF; 500 microg/mL). CCA segments were harvested and coils removed for scanning electron microscopy (SEM). RESULTS: Collagen/rhVEGF coils (n = 11) resulted in marked reductions in CCA lumen area (0.03 mm(2)) compared with coils (n = 9, 0.21 mm(2), P <.001) and collagen coils (n = 5, 0.13 mm(2), P <.001). Collagen/rhVEGF coils (n = 11) also resulted in marked reductions in CCA diameter (0.19 mm) compared with coils (n = 9, 0.50 mm, P <.001) and collagen coils (n = 5, 0.40 mm, P <.001). Wall thickness was greater for the collagen/rhVEGF coil segments (0.22 mm) compared with coils (0.09 mm, P <.001), and the collagen coils (0.15 mm, P =.06). CCA segments containing collagen/rhVEGF coils also displayed Factor VIII positivity and were completely encapsulated in fibrotic tissue, while the unmodified and collagen coils were essentially smooth, as seen by SEM. CONCLUSION: These results suggest that rhVEGF may be beneficial in promoting endothelialization, clot organization, and tissue integration of the coils. This is the first study to hypothesize that rhVEGF may be useful as a surface modification to GDCs for enhancing their therapeutic effects in the treatment of cerebral aneurysms.

Biodegradable polyglycolide endovascular coils promote wall thickening and drug delivery in a rat aneurysm model.

OBJECTIVE: We designed biodegradable polyglycolide coils (BPCs) and compared the histopathological response to the coils with that to platinum Guglielmi detachable coils (GDCs), after insertion into ligated common carotid arteries (CCAs) of adult rats. BPCs were also tested for use in local drug delivery. METHODS: Segments (4-mm) of unmodified BPCs, unmodified GDCs, or BPCs coated with Type I bovine collagen and recombinant human vascular endothelial growth factor-165 (500 microg/ml) were inserted into ligated CCAs of adult rats for 14 days, and specimens were compared with contralateral CCA control specimens. RESULTS: Arterial segments with BPCs exhibited substantially increased wall thickening, compared with GDCs (0.33 mm versus 0.10 mm, P < 0.005), which reduced the luminal diameter by 40%, relative to untreated contralateral control specimens (P < 0.05, n = 6). Arterial segments with BPCs also exhibited a marked reduction (P < 0.05, n = 6) in luminal area (0.72 +/- 0.93 mm(2)), with marked cellular proliferation within the coil diameter, indicating coil integration. Arterial segments with collagen/recombinant human vascular endothelial growth factor-coated BPCs also exhibited a marked 2.9-fold increase (P < 0.005, n = 5) in wall thickness (0.29 +/- 0.11 mm) and a 34% reduction in luminal diameter, compared with contralateral control vessels. There was marked proliferation of cells within the coil lumen of vessels treated with BPCs with collagen/recombinant human vascular endothelial growth factor. CONCLUSION: In this feasibility study, BPCs enhanced the vascular response of CCA segments, compared with GDCs, and were also suitable for local protein delivery to the vessel lumen, under conditions of stasis and arterial pressurization of vascular cells.

Extracranial aneurysms of the posterior inferior cerebellar artery.

OBJECTIVE: Extracranial aneurysms of the distal posterior inferior cerebellar artery (PICA) are extremely rare and sometimes difficult to diagnose without an adequate angiogram. We present the first series of 3 patients who were evaluated by the senior author and treated surgically. METHODS AND RESULTS: All 3 patients presented with subarachnoid hemorrhage (SAH). Clincial symptoms, included occipital headache, nuchal rigidity, abducens nerve palsy and rapid neurologic deterioration. A unilateral injection of the vertebral artery failed to show the distal contralateral PICA and the aneurysm in 1 patient. All patients underwent aneurysm clipping through a posterior fossa craniectomy and C-1 laminectomy. The aneurysms were located on the tonsillomedullary segment of the PICA, 10-12 mm below the level of the foramen magnum. CONCLUSIONS: It is important to adequately visualize the distal extent of both PICAs or these aneurysms may not be seen. Patients who present with SAH must have the entirety of both vertebral arteries evaluated to avoid missing these aneurysms. The aneurysms were located adjacent to the atlas necessitating an upper cervical laminectomy for adequate surgical exposure. In general, the patients did well postoperatively and none of the patients developed cerebral vasospasm.

Topic review: surface modifications enhancing biological activity of guglielmi detachable coils in treating intracranial aneurysms.

BACKGROUND: Endovascular therapy with Guglielmi detachable coils is an accepted treatment option for patients with intracranial aneurysms. However, an emerging technology in the realm of endovascular tools is the use of traditional Guglielmi detachable coils with biologically active substances complexed to the coil surface to enhance aneurysm occlusion. METHODS: We review the literature and current trends in modified Guglielmi detachable coils. Surface modifications with extracellular matrix proteins, growth factors, ion impregnation, and genetically altered cells have been used in animal studies to improve the cellular response of Guglielmi detachable coils. Similarly, coronary artery stents have been modified in several different ways to maintain vessel patency, contrary to the goal of endovascular therapy. We comparatively reviewed this literature to add insight into the evolution of the research on modified Guglielmi detachable coils. CONCLUSIONS: Guglielmi detachable coil modifications have the potential to enhance aneurysm obliteration with directed cellular responses. This may allow aneurysm occlusion with coils in less time than untreated coils, thus decreasing the risks of aneurysm enlargement and hemorrhage.

Extrarenal nephroblastic proliferation in spinal dysraphism. A report of 4 cases.

Four cases of extrarenal nephrogenic proliferation in the sacrococcygeal region with spinal dysraphism are presented. In two of the cases, features of Wilm's or incipient Wilm's tumor were present. The previous literature on sacrococcygeal nephrogenic tissue is reviewed, and the impact of these findings on the histogenesis of extrarenal sacrococcygeal Wilm's tumor is discussed.

Hemangiopericytoma of the third ventricle. Case report.

The authors present the first reported case of a hemangiopericytoma (HPC) occurring in the third ventricle. Most of these lesions are based in the meninges. There is only one other reported case of an intraventricular HPC; in that case the lesion was found in the lateral ventricle. A 40-year-old right-handed man presented with a 3-month history of headaches. Clinical evaluation, including computerized tomography and magnetic resonance imaging studies, revealed a 1-cm enhancing lesion in the third ventricle. Given the findings on the preoperative imaging studies, the lesion was not consistent with some of the more commonly occurring tumors of the third ventricle, namely colloid cysts. A transcortical approach and resection of the lesion was performed without complication. The final pathological findings were consistent with those of an HPC. Hemangiopericytomas rarely occur in the ventricles and may pose a difficult diagnostic dilemma based on their radiographic and gross appearances, as shown in this case. Because of this difficulty, histological confirmation is required to make a definitive diagnosis. These lesions have a propensity to recur and metastasize in the central nervous system and periphery, thus making the goal of treatment a complete surgical resection followed by postoperative radiation therapy in most cases.

Localization of vasopressin binding sites in rat tissues using specific V1 and V2 selective ligands.

Arginine vasopressin (AVP) acts on at least two receptor types, classified on the basis of their second messengers. The V1 receptor acts via mobilization of intracellular calcium through phosphatidylinositol hydrolysis and influences blood pressure and hepatic glycogenolysis. The V2 receptor acts via cAMP through activation of adenylate cyclase and causes antidiuresis. Previous studies of the different AVP receptors have been hampered by the use of nonselective radioligands, such as [3H]AVP (which binds to all types of V1 and V2 receptors, certain oxytocin receptors, and neurophysins) as well as the difficulty of measurement of second messengers. This paper describes the use of selective V1 and V2 radioligands with in vitro autoradiography to study V1 and V2 binding sites in rat tissues. [125I][1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 7-sarcosine] arginine vasopressin ([125I][d(CH2)5,Sarcosine7]AVP), a selective V1 antagonist radioligand, bound to regions of the brain, testis, superior cervical ganglion, liver, blood vessels, and renal medulla. Pharmacological characterization of [125I][d(CH2)5,Sarcosine7]AVP binding was consistent with that expected for binding to V1 receptors. There was no specific binding demonstrable to pituitary, renal glomeruli, gut, heart, spinal cord, ovary, adrenal medulla, or adrenal cortex. [3H]1-deamino [8-D-arginine] vasopressin [( 3H]DDAVP), a potent V2 receptor agonist radioligand, was used to study V2 receptors. Specific binding was only identified in the kidney consistent with the known distribution of antidiuretic V2 receptors on renal collecting tubules. No binding was demonstrated on endothelium or liver where DDAVP might influence clotting factor release, nor in the brain, spinal cord, sympathetic ganglia, heart or vascular smooth muscle, regions where DDAVP might cause vasodilatation. These studies demonstrate the use of these radioligands to study V1 and V2 receptors in a variety of tissues. Also, since these ligands are selective they are of particular use to study the different receptor subtypes in tissues where V1 and V2 receptors coexist, such as in the kidney.

mu- and K-opiate receptor agonists reduce plasma neurohypophysial hormone concentrations in water-deprived and normally hydrated rats.

1. The effects of mu- and K-opiate receptor agonists on plasma concentrations of immunoreactive (ir) oxytocin (OXY) and arginine vasopressin (AVP) in normally hydrated and water-deprived rats were studied. 2. Water-deprivation for 36 h elevated both plasma ir-OXY and ir-AVP concentrations of Long-Evans rats. These elevated levels were lowered in a dose-dependent manner after subcutaneous administration of bremazocine (3-10 micrograms/kg), M320 (10-100 micrograms/kg) or morphine (0.1-10 mg/kg). Comparable reductions of plasma concentrations of ir-AVP and ir-OXY were observed. 3. Plasma concentrations of ir-OXY and ir-AVP of normally hydrated Long-Evans rats were lower after subcutaneous administration of bremazocine (10 micrograms/kg), M320 (10 micrograms/kg) and morphine (1.0 mg/kg). 4. These data suggest that both mu- and K-opiate receptor agonists inhibit both OXY and AVP release from the neurohypophysis of rats.

Effects of subacute opioid administration during late pregnancy in the rat on the initiation, duration and outcome of parturition and maternal levels of oxytocin and arginine vasopressin.

1. The effects, on parturition in the rat, of subacute and acute opioid administration were studied. Further experiments investigated the role of modulation of maternal plasma and pituitary oxytocin (OXY) and arginine vasopressin (AVP) levels in these effects. 2. Subacute opioid (M320, buprenorphine or bremazocine) administration prolonged the gestation of rats. This was accompanied by toxic effects on the offspring. Acute subcutaneous (s.c.) M320 (10 micrograms/kg) administration was accompanied by prolonged gestation without toxic effects. 3. Subacute M320 (10 micrograms/kg, s.c., twice daily) treatment was accompanied by increased interbirth intervals in parturient rats. 4. Maternal OXY but not AVP release, as assessed by measurement of plasma and pituitary immunoreactivity, was elevated during and up to 1 h after the completion of parturition. Subacute M320 treatment did not inhibit this elevated OXY release.

[125I]-[d(CH2)5, Sar7]AVP: a selective radioligand for V1 vasopressin receptors.

Arginine8-vasopressin (AVP) acts on vascular and hepatic V1 receptors to influence blood pressure and glycogenolysis respectively. We have radioiodinated the AVP V1 receptor antagonist, [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic-acid), 7-sarcosine, 8-arginine] vasopressin ([d(CH2)5, Sar7]AVP) and determined its receptor-binding properties in rat liver and kidney plasma membranes. The binding was of high affinity to single classes of receptors (liver: Kd = 3.0 nM and Bmax = 530 +/- 10 fmol/mg protein, kidney: Kd = 0.5 +/- 0.9 nM and Bmax = 11 +/- 8 fmol/mg protein). Competition of [125I]-[d(CH2)5, Sar7]AVP binding by unlabelled AVP analogues gave the following order of potency in both tissues, consistent with that expected for binding to a V1 receptor: [d(CH2)5, Tyr(Me)2]AVP greater than AVP greater than [d(CH2)5, D-Ile2, Ile4] AVP greater than DDAVP. No degradation of [125I]-[d(CH2)5, Sar7]AVP during incubation or storage was detected by HPLC analysis. We have used [125I]-[d(CH2)5, Sar7]AVP and in vitro autoradiography to demonstrate its use in localizing brain AVP receptors. These studies suggest that [125I]-[d(CH2)5, Sar7]AVP is a suitable selective radioligand for labelling V1 receptors and will provide a valuable tool for the study of the localization and regulation of AVP V1 receptors in tissues and in receptor isolation.

Localization of vasopressin binding sites in rat brain by in vitro autoradiography using a radioiodinated V1 receptor antagonist.

Vasopressin may act in the brain as a neurotransmitter or neuromodulator to influence blood pressure, memory, body temperature and brain development. In order to localize probable central nervous system sites for these actions, we have used 125I-labelled 1-d(CH2)5, 7-sarcosine-8-arginine vasopressin, a specific V1-receptor antagonist, and in vitro autoradiography to map brain vasopressin binding sites. High levels of binding were found in the choroid plexus, blood vessels, lateral septum, bed nucleus of stria terminalis, accumbens nucleus, central nucleus of amygdala, stigmoid hypothalamic nucleus, suprachiasmatic nucleus, arcuate nucleus, nucleus of the solitary tract, area postrema and parts of the hippocampus, thalamus, superior colliculus, and inferior olivary nuclei. Many of these regions are known to be vasopressin-sensitive and to contain vasopressin fibres. Significantly there was no binding to the paraventricular nor the supraoptic nuclei. Displacement of the radioligand from the lateral septum with unlabelled vasopressin analogues gave a rank order of potencies: d(CH2)5-D-Tyr2(Et)Val4-desGly9-arginine-vasopressin approximately equal to d(CH2)5-Tyr2-(Me)arginine-vasopressin approximately equal to arginine-vasopressin approximately equal to d(CH2)5-Sar7-arginine-vasopressin greater than [1-deamino, 8-D-arginine]-vasopressin approximately equal to oxytocin much greater than vasopressin4-9, consistent with binding to V1 receptor subtype. These studies confirm and extend previous findings of V1 receptors in the rat brain. In particular, several new regions of vasopressin receptor binding have been identified, possibly due to the advantages of a radioiodinated ligand with high receptor affinity without binding to neurophysins. Future study of these regions may prove fruitful in elucidating the central actions of vasopressin.

Vasopressin receptors in rat brain and kidney: studies using a radio-iodinated V1 receptor antagonist.

Arginine8-vasopressin (AVP) acts via V1 receptors (blood vessels, liver and brain) and V2 receptors (renal collecting duct). To study brain and kidney V1 receptors selectively, a specific V1 receptor antagonist [d(CH2)5,Sar7]AVP was radio-iodinated and purified by high performance liquid chromatography. Iodine-125[d(CH2)5,Sar7]AVP bound to single classes of rat liver and kidney V1 receptors with high affinity (liver: Kd = 3.0 +/- 0.9 mol/l and Bmax = 530 +/- 10 fmol/mg protein; kidney: Kd = 0.5 +/- 0.9 nmol/l and Bmax = 11 +/- 8 fmol/mg protein) in a time-dependent and saturable manner. Displacement of the radioligand from liver and renal medulla membranes and sections of the brain and kidneys by unlabelled AVP analogues was consistent with that expected for binding to V1 receptors. In vitro autoradiography of rat brain revealed areas of specific receptor binding in many regions, including regions involved in central cardiovascular regulation, such as the nucleus of the solitary tract and area postrema, as well as choroid plexus and large blood vessels. Binding was observed in several regions not previously observed to contain AVP receptors. In the kidney [3H]AVP bound to the inner and outer medulla, probably to vascular V1 and collecting duct V2 receptors. In contrast, [125I][d(CH2)5,Sar7]AVP binding was only in the inner medulla, possibly to vasa recta. These findings support a functional role for V1 receptors in the brain and kidney.

Properties of [3H]1-desamino-8-D-arginine vasopressin as a radioligand for vasopressin V2-receptors in rat kidney.

[3H]1-Desamino-8-D-arginine vasopressin [3H] DDAVP was assessed as a radioligand for vasopressin V2-receptors by studying its membrane-binding characteristics and in vitro autoradiographic localization in rat kidney, a rich source of V2-receptors. [3H]DDAVP bound specifically to a single class of high affinity, low capacity sites in rat medullopapillary membranes. Specific [3H]DDAVP binding at 25 C reached equilibrium after 2 h of incubation and was saturable and linear with protein concentration up to 2.2 mg/ml protein. Saturation analysis gave an equilibrium dissociation constant (Kd) of 0.76 nM. Displacement of [3H]DDAVP binding by unlabeled arginine vasopressin (AVP) and related analogs gave the following order of potency, consistent with that expected for a V2-receptor: DDAVP approximately equal to AVP approximately equal to 1-desamino-AVP greater than lysine vasopressin greater than oxytocin greater than [1-(beta-mercapto-beta, beta-cyclopentamethylene-propionic acid, 2-(O-methyl)tyrosine]AVP. The C-terminal metabolites of AVP, (pGlu4Cyt6)AVP-(4-9), and (pGlu4Cyt6)AVP-(4-8) did not displace [3H]DDAVP binding. No degradation of [3H] DDAVP during incubation could be detected by HPLC analysis. In vitro autoradiography of [3H]DDAVP binding to rat kidney sections showed a very dense localization of displaceable binding over inner and outer medulla, with a much lower density in cortex, consistent with the known major localization of V2-receptors on renal collecting tubules. These studies suggest that [3H]DDAVP is a suitable radioligand for labeling V2-receptors and may be useful in the characterization of vasopressin receptor subtypes in a variety of tissues and in purification of the V2-receptor.

The effects of N-(cyclopropylmethyl)-19-isopentylnororvinol (M320), a potent agonist at kappa- and mu-opiate receptors, on urine excretion of rats.

The effects of N-(cyclopropylmethyl)-19-isopentylnororvinol hydrochloride (M320) on urine excretion by rats were investigated. Further studies, using rabbit isolated vas deferens, investigated its interactions with kappa-opiate receptors. The output of urine for a 2 h period after M320, administered subcutaneously to normally hydrated Long Evans rats, showed a bell-shaped dose-response relationship, the maximum effect occurring after 10 micrograms kg-1. Urinary retention contributed to but did not fully account for the weaker diuresis after high doses. Attenuation of the ascending portion of the dose-response curve to M320 occurred after 1 and 10 mg kg-1 but not 0.1 mg kg-1 of naltrexone intraperitoneally. M320 in low doses (3-10 micrograms kg-1) caused a small but significant increase in sodium excretion. M320 (30 micrograms kg-1) reduced both sodium and potassium excretion. M320 (10 micrograms kg-1 s.c.) did not increase the volume of urine voided in 2 h by Brattleboro rats showing diabetes insipidus, even when urine excretion was reduced to normal by 1 week of vasopressin replacement. The volume of urine voided in 4 h by Brattleboro rats was progressively reduced to zero by M320 (10-100 micrograms kg-1 s.c.). Urinary retention contributed to but did not account for this reduction. Plasma levels of immunoreactive arginine vasopressin (ir-AVP) were reduced in both normal and dehydrated Long Evans rats after doses greater than 1 microgram kg-1 M320 s.c. In vitro, M320 caused persistent inhibition of twitches of the electrically stimulated rabbit vas deferens (IC50 1.7 nM). 8 These data suggest that M320 has potent opioid agonist activity at K-receptors and at higher concentrations stimulates mu- receptors. In the rat, its activity on K-receptors is associated with diuresis and suppression of plasma vasopressin levels. The antidiuresis seen after high doses may be due to its activity on mu-receptors, possibly at a central site.

Contribution of vasopressin to the maintenance of blood pressure in deoxycorticosterone-salt induced malignant hypertension in spontaneously hypertensive rats.

In the present study, deoxycorticosterone (DOC) and salt was administered to Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) by using silicone-rubber implants (DOC acetate, 100 mg/kg) and 0.9% NaCl as drinking water. SHR treated with DOC-salt for 4 weeks showed the characteristics of malignant hypertension including marked increases in blood pressure and left ventricular weight with typical histological changes in the kidney. DOC-salt treatment increased plasma vasopressin levels in WKY (from 6.1 +/- 0.5 to 8.9 +/- 0.8 pmol/l) but significantly more in SHR (from 5.0 +/- 0.6 to 15.8 +/- 1.2 pmol/l). Intravenous administration of the specific antagonist to the pressor effect of vasopressin, d(CH2)5Tyr(Me)AVP (10 micrograms/kg), decreased mean arterial pressure of DOC-salt treated WKY and SHR by 6.6 +/- 0.9 mmHg (P less than 0.05) and 9.7 +/- 1.7 mmHg (P less than 0.05) respectively. DOC-water treatment also increased plasma AVP levels in SHR to 10.5 +/- 0.8 pmol/l, but the vasopressin antagonist had little effect on blood pressure in these rats. Plasma levels of vasopressin were significantly correlated with both mean arterial pressure (r = 0.64) and left ventricular weight (r = 0.74). This suggests a close relationship between plasma AVP and severity of hypertension. The results of the present experiment demonstrate that vasopressin is part of the overall pressor mechanism which contributes to the maintenance of blood pressure in DOC-salt induced malignant hypertension in SHR, but the small fall in pressure produced by the AVP antagonists suggests that the contribution is of only minor importance.

Malignant hypertension in Brattleboro (vasopressin-deficient) rats.

The role of arginine vasopressin (AVP) in malignant renal hypertension was investigated using the homozygous Brattleboro (vasopressin-deficient) rat. Brattleboro rats with complete aortic-ligature between the renal arteries developed malignant hypertension with the same frequency and severity as normal Long-Evans rats subjected to the same procedure. The Long-Evans hypertensive rats had significantly elevated plasma AVP levels. Plasma renin activity and plasma angiotensin II levels were significantly elevated in both Brattleboro and Long-Evans rats with malignant hypertension and the levels reached were equivalent in both groups. Thus, the renin-angiotensin system did not compensate for the lack of AVP in malignant hypertensive Brattleboro rats. Specific vascular lesions of fibrinoid necrosis were observed in a high percentage of rats with malignant hypertension, in both the Brattleboro and Long-Evans strains. We conclude that AVP does not play a primary role in the pathogenesis of malignant renal hypertension and, in particular, in the development of the vascular lesions of fibrinoid necrosis.