Positive Smooth Muscle Research Articles

Chronic Rejection in Non-human Primates: Sirolimus (Rapamycin), but not Cyclosporin, Prevents Graft Vascular Disease (GVD) in Aortic Allografts after Acute Rejection.

981 We have developed the first technique, which allows GVD to be serially quantified in monkeys. Aortic allografts but not autografts develop GVD that is histologically indistinguishable from human allograft vasculopathy. Initially, we used serial intravascular ultrasound (IVUS) studies to show that sirolimus (SRL) halts and reverses progression of pre-existing GVD. The aim of the present study was to analyze the efficacy of SRL and cyclosporine (CsA) for prevention of GVD after acute alloimmune injury. Methods. Aortic allografts were exchanged between MLR mismatched, blood group compatible cynomolgus monkeys. 6 control animals received no immunosuppression, 6 animals were treated with SRL (mean trough level ±SEM, 43±2 μg/l), and 6 animals with CsA (mean trough level ±SEM, 562±74 ng/ml). Both treatments were started on day 45 after transplantation. The progression of GVD was quantified by IVUS as changes in intimal area (IA) and intimal index (II=intimal area/vessel area) in the middle 6 segments of all grafts every 3 weeks until day 105. Results. Elevated anti-donor IgG and IgM levels occurred in all animals before initiation of treatment due to unimpeded acute rejection. IA and II did not increase significantly from day 21 to 42 in any of the 3 groups in the middle 6 segments. In untreated controls, IA (Figure) and II increased significantly from day 63 to 105 (p=0.003, p=0.008, respectively). IA and II also increased in CsA treated monkeys (p=0.033, p=0.006), whereas SRL treatment prevented increases in II and IA (p=0.988, p=0.313). Histochemical analyses of the vessels suggested that SRL prevented migration of alpha-actin positive smooth muscle cells from the media to the intima. Conclusion. We show for the first time that SRL, but not CsA, prevents GVD after acute alloimmune injury in non-human primates. SRL's efficacy may be due to its ability to inhibit both the migration and proliferation of smooth muscle cells. Our data support the conduct of clinical trials of SRL in the patients whose grafts have been injured by acute rejection and who are at high risk for GVD.Figure

Hemodialysis Graft Mechanical Thrombolysis with Use of the Amplatz Thrombectomy Device: Histopathologic Evaluation of Extracted Myointimal Tissue

To histopathologically evaluate material extracted from thrombosed hemodialysis access grafts by the Amplatz Thrombectomy Device (ATD). Thrombosed hemodialysis access grafts were recanalized with use of crossed catheter technique with introduction of the ATD through 8-F sheaths. After removal of the ATD from the introducer sheath, the tip of the device was visually inspected. Discernible tissue in the impeller/housing mechanism was gently extracted with a hemostat and preserved in formalin. Specimens were evaluated histologically with hematoxylin-eosin and smooth muscle immunoperoxidase stains. The ATD was utilized in 18 patients with acutely thrombosed grafts. Sufficient tissue for pathologic evaluation was extracted from 10 devices. Histopathologic analysis yielded findings of fibrotic myointima in all 10 cases with positive smooth muscle stains. The unexpected, although consistent, finding of intimal and myointimal tissue fragments in the impeller/housing mechanism of the ATD raises questions with respect to the mechanism of tissue extraction and concerns regarding the use of the device in native vessels. Further studies are indicated to determine whether this apparent intimal injury will have a deleterious effect on vessel patency.

EMBRYONIC DEVELOPMENT OF THE URETER AND BLADDER: ACQUISITION OF SMOOTH MUSCLE

To delineate the temporal and spatial acquisition of the smooth muscle of the ureter, Sprague-Dawley rat embryos and newborn pups were immunostained with alpha-smooth muscle actin (alpha-SM actin) antibody. alpha-SM actin expression was first detected in the urinary tract at 16 days of gestation (E16) in a thin subserosal zone about the urogenital sinus. At this time, the E16 ureter is composed of a simple cuboidal epithelium which is surrounded by 1 to 2 layers of condensed alpha-SM actin negative spindle cells. No immunostaining was detected along the ureter or its intrarenal branches until the 20th day of gestation (E20). alpha-SM actin expression in the E20 ureter exhibited regional differences. The number of alpha-SM actin positive smooth muscle cells was greatest in the distal ureter, intermediate in the mid ureter, and least in the proximal ureter near the kidney. While smooth muscle formation in the bladder was subserosal, in the ureter it was subepithelial. During postnatal life, alpha-SM actin expression increased in both organs as all periepithelial spindle cells stained positive and intensified their staining. Smooth muscle differentiation of the ureter and bladder occurs later in embryonic life than other visceral and vascular organs and occurs in an ascending fashion from the bladder to the intrarenal collecting system. It is likely that the activation of visceral smooth muscle myogenesis within the urinary tract is governed by positional information specific to the embryonic development of each organ.

Immunological liver diseases in children.

Autoimmune liver diseases comprise a number of disorders in which inflammatory damage to the liver is believed to derive from an autoimmune attack. These include autoimmune hepatitis (AIH), characterised by positive smooth muscle and/or nuclear (SMA/ANA) or liver kidney microsomal type 1 (LKM1) antibodies, autoimmune sclerosing cholangitis (ASC), usually SMA/ANA positive, and AIH after liver transplantation, which is positive for SMA, ANA, or atypical LKM. These disorders often present with symptoms indistinguishable from prolonged acute hepatitis. Less commonly the onset is insidious, with nonspecific symptoms, or with complications of portal hypertension. For AIH and ASC, experimental evidence suggests that usually in individuals genetically predisposed to autoimmunity, a liver self antigenic peptide is recognized by T lymphocytes which promote a cascade of autoaggressive processes. For AIH after liver transplantation, the pathogenic mechanisms remain to be elucidated. All types of autoimmune liver disorders appear to respond favourably to early treatment with prednisolone with or without azathioprine. For patients presenting with fulminant hepatic failure or with already advanced cirrhosis, immunosuppression is rarely effective and the only mode of treatment is liver transplantation. The role of other immunosuppressant or immunomodulatory drugs, like cyclosporin A, tacrolimus or ursodeoxycholic acid, in the treatment of autoimmune liver disorders remains to be defined.

Wound healing: A paradigm for lumen narrowing after arterial reconstruction

Purpose: The intimal hyperplasia hypothesis that equates lumen narrowing after arterial injury with intimal mass has recently been challenged. Evidence has emerged to suggest that lumen narrowing is caused in large part by changes in artery wall geometry rather than intimal mass per se. We have begun to explore this hypothesis in a unique nonhuman primate model of atherosclerosis. Methods: Monkeys who were fed an atherogenic diet for 3 to 5 years underwent experimental angioplasty of the left iliac artery. The contralateral iliac artery served as an intraanimal control. Arteries were removed 2, 4, 7, 14, 28, or 112 days later for analysis (6 or 13 per time point). Angioplasty dilated arteries by fracturing atheroma and stretching or tearing the media. Cross-sections of injured arteries were analyzed for expression of extracellular matrix components and cell surface integrins that are important in wound healing. Antibodies, riboprobes, or histochemical stains specific for fibrin, hyaluronan, versican (chondroitin sulfate–containing proteoglycan), procollagen-I, elastin, and the α 2β 1 and α Vβ 3 integrins were used. Results: A thin mural thrombus was seen at sites of denudation and plaque fracture (days 2 to 7). This provisional matrix was invaded by leukocytes (days 2 to 4) and α-actin–positive smooth muscle cells (SMCs; days 4 to 7). Thrombus was replaced by SMCs expressing hyaluronan and the associated versican proteoglycans (day 14). Versican was expressed throughout the neointima as it enlarged (day 28), but expression later subsided (day 112). Procollagen-I expression initially increased in the adventitia (day 4) and then in the forming neointima (day 14). Procollagen-I expression was found to persist within the adventitia and in the neointima in SMCs nearest the lumen (days 28 to 112). Elastin staining was prominent within the mature neointima (day 112) but not at earlier time points. Integrin expression also increased within the injured artery wall. α Vβ 3 staining (fibrin[ogen] receptor) increased in the injured media (days 2 to 7) and was then seen throughout the early neointima (day 7). Low level expression of α Vβ 3 subsequently persisted within the forming neointima (day 28). α 2β 1 (collagen receptor) expression increased in the neointima in SMCs nearest the lumen (day 28). Conclusions: Lumen narrowing after angioplasty in this model of atherosclerosis is caused largely by decreased artery wall diameter. The pattern of matrix and integrin expression within the injured artery wall is in many ways analogous to that of healing wounds. These observations suggest that tissue contraction may play a role in lumen narrowing at sites of arterial reconstruction. Strategies to inhibit wound contraction may prove effective in preventing restenosis. (J Vasc Surg 1998;27:96-108.)

'Revertant' DCIS in human axillary breast carcinoma metastases.

Recent experimental evidence obtained in Scid mice has suggested that the metastatic process is in large part epigenetically regulated and undergoes partial reversion once the metastatic process is completed: the metastatic colonies become more engaged in the process of growing in situ than actively metastasizing. Based on this experimental evidence, examples were sought of metastatic human cancers where similar reversion to an in situ growth state was occurring. Review of 200 cases of metastatic human breast cancer revealed a 21 per cent incidence of reversion to a ductal carcinoma in situ (DCIS) growth pattern within axillary nodal metastases. The revertant DCIS areas were characterized by an intact and circumferential basement membrane, as demonstrated by extracellular laminin and type IV collagen immunoreactivity. These revertant DCIS areas could be distinguished from primary DCIS, however, by the absence of surrounding myoepithelial cells in the former, identified in the latter by their positive maspin, S-100, and smooth muscle actin immunoreactivity. The pattern of revertant DCIS, poorly differentiated (comedo) (13 per cent), intermediate (non-comedo) (6 per cent), or well-differentiated (non-comedo) (2%), exhibited complete 100 per cent concordance with the primary DCIS pattern. The concordance of histological patterns held true for even the subtypes of DCIS determined by architectural pattern, such as the micropapillary or cribriform subtypes. Nuclear size by digital image analysis and Her-2/neu, p53, and Ki-67 status in the revertant DCIS also exhibited complete concordance with the primary DCIS counterparts. Cases exhibiting a revertant DCIS pattern tended to be ER-negative/EGFR-positive and exhibited significant nodal involvement (mean number, 9; mean area, 90 per cent) compared with cases lacking a revertant pattern (mean number, 4; mean area, 15 per cent) (P < 0.01) These findings suggest that reversion of the metastatic phenotype may also be occurring within autochthonous human metastasis.

Localization of Nonpancreatic Secretory Phospholipase A 2 in Normal and Atherosclerotic Arteries

Secretory nonpancreatic type II phospholipase A2 (snpPLA2) hydrolyzes fatty acids at the sn-2 position in phospholipids releasing free fatty acids (FFAs) and lysophospholipids. These products may act as intracellular second messengers or can be further metabolized into proinflammatory lipid mediators. The presence of snpPLA2 in extracellular fluids and serum during inflammation has suggested a role of the enzyme in this process. However, the presence of snpPLA2 in a variety of normal tissues suggests that snpPLA2 may also have physiological functions. Atherosclerosis appears to have an inflammatory component. Here we report on the snpPLA2 localization in normal and atherosclerotic lesions and on the properties of the isolated enzyme. A strong snpPLA2 immunoreactivity was observed in the arterial media that was colocalized with alpha-actin-positive vascular smooth muscle cells (SMCs) in both normal and atherosclerotic vessels. In aortic atherosclerotic lesions, snpPLA2 was observed colocalized with CD68-positive macrophages and HHF-35-positive SMCs and extracellularly in the lipid core. snpPLA2 was isolated from human normal arteries and from aorta with lesions. The enzyme was isolated by acid extraction of normal arterial tissues followed by immunoaffinity chromatography. The purified snpPLA2 had an expected molecular weight of 14 kD by polyacrylamide gel electrophoresis and appeared as a single band in immunoblotting. The enzymatic activity was followed by measuring release of fatty acids from phospholipid liposomes or LDL as substrates. The enzymatic activity was inhibited with two specific inhibitors for human snpPLA2: (1) monoclonal antibody 187 and (2) LY311727, a synthetic selective inhibitor. The mRNA for snpPLA2 was detected with reverse transcriptase polymerase chain reaction. These results indicate that snpPLA2 is present in human arteries and that it is able to hydrolyze phospholipids in LDL. The results support the hypothesis that snpPLA2 can release proinflammatory lipids at places of LDL deposition in the arterial wall.

Expression of platelet derived growth factor B chain and beta receptor in human coronary arteries after percutaneous transluminal coronary angioplasty: an immunohistochemical study.

To evaluate whether expression of platelet derived growth factor B (PDGF-B) protein is associated with expression of its receptor protein in human coronary arteries after angioplasty and to identify cells involved. PDGF is considered an important growth factor in the repair process of the vessel wall after angioplasty. In situ hybridisation has revealed expression of PDGF-A and -B chain messenger ribonucleic acid (mRNA) in human coronary arteries at sites of postangioplasty injury. Target and non-target sites of eight coronary arteries were studied immunohistochemically for PDGF-B and PDGF-beta receptor proteins in relation to macrophages, T lymphocytes, smooth muscle cells, and HLA-DR positive cells. The PDGF-B and PDGF-beta receptor proteins were expressed in areas with distinct repair, containing alpha actin negative spindle cells, macrophages and, at later stages, alpha actin positive smooth muscle cells as well. When the neointima was composed mainly of alpha actin smooth muscle cells, PDGF-B expression was rare and PDGF-beta receptor expression was negative. There is expression of PDGF-B and PDGF-beta receptor proteins at sites of postangioplasty repair in human coronary arteries. The associated cells are mainly macrophages and alpha actin negative spindle cells; the latter may be dedifferentiated smooth muscle cells. A link between PDGF expression and the postangioplasty time interval suggests a relation with cell differentiation as part of the maturation of the repair tissue. Mutual expression of both the growth factor and its receptor protein strongly suggests that in humans a PDGF mediated repair process occurs, with involvement of smooth muscle cells and macrophages.

Expression of the macrophage scavenger receptor in atheroma. Relationship to immune activation and the T-cell cytokine interferon-gamma.

Scavenger receptors mediate internalization of modified lipoproteins and foam cell transformation of monocyte-derived cytokines. We investigated macrophage scavenger receptor (MSR) expression in monocyte-macrophages from human peripheral blood and in atherosclerotic lesions and analyzed its relationship to T lymphocytes and immunoregulatory cytokines by immunohistochemistry and polymerase chain reaction (PCR). Antibodies specific for the two MSR isoforms were generated by immunizing rabbits with isoform-specific synthetic peptides conjugated to keyhole limpet hemocyanin. In human atherosclerotic plaques, these antibodies stained macrophages and foam cells in a pattern that corresponded to the distribution of the macrophage marker CD68. CD3-positive T cells and alpha-actin-positive smooth muscle cells exhibited no reactivity to the anti-MSR antibodies. The frequency of cells stained with antibodies to MSR type I was equal to that of cells stained for type II, suggesting that most macrophages coexpress both isoforms. Reverse transcription (RT)-PCR analysis confirmed that both MSR isoforms were expressed in all plaques examined. There was, however, a tendency toward a lower immunohistochemical staining intensity for MSR type I and a decreased number of lipid-rich foam cells in T cell-rich areas. The mRNAs for interleukin-2 and interferon-gamma, two major products of activated T cells, were detected by RT-PCR in all plaques tested. This indicates that activation of T lymphocytes occurs in atherosclerotic plaques. Since interferon-gamma downregulates MSR expression, these observations suggest a potential mechanism for local regulation of MSR expression in the atherosclerotic plaque.

963-19 Evidence for Complement Activation by Smooth Muscle Cells in Lesions of Advanced Pulmonary Hypertension (PH)

In PH and other vascular obstructive diseases, the mediators of intimal hyperplasia of arteries have been extensively studied. Little attention has been given to the pathogenesis of the more advanced pulmonary vascular lesions, such as fibrinoid necrosis and plexiform lesions. Recently, it was shown that the membrane attack complex of the complement (MAC) plays a role in pathologic processes chracterized by cell proliferation, including atherosclerosis. To contribute to the understanding of the development of the arterial obstructive lesions in PH, we studied the expression of MAC in lungs from 8 patients presenting advanced vascular disease: five with primary PH, two with PH secondary to Schistosomiasis and one secondary to a congenital heart defect (mean age 20; median 17.5 years), We characterized immunohistochemically the proliferative vascular lesions using antibodies that recognize the active form of MAC, α -actin and Factor VIII, in paraffin embedded tissue. The intimal lesions, including plexiform lesions, contained predominantly α -actin positive smooth muscle cells (SMC). Factor VIII strongly labelled the endothelial cells of arteries, including the vascular spaces within plexiform lesions. All 8 cases exhibited positive MAC reaction (mild to moderate) in the medial layer of arteries but not of veins, staining individual SMC and also lining the internal and/or external elastic membranes. MAC was constantly negative in the SMC of the plexiform lesions and in endothelial cells. In only 2 of 8 cases was MAC expressed (weakly) in intimal lesions. MAC was also positive focally in fibrinoid necrosis. We conclude that SMC are the main constituents of the intimal and plexiform lesions, and that MAC is always present in the medial SMC. Since MAC is known to induce cell proliferation, our findings may suggest that it participates in the pathogenesis of obstructive lesions in human PH, and that the fibrinoid necrosis of the arterial wall could be related to a complement attack which extends beyond the sublytic stage.

Medial thinning and atherosclerosis — evidence for involvement of a local inflammatory effect

Medial attenuation in relation to atherosclerotic plaques is poorly understood. We investigated the potential role of a local inflammatory response. Segments of carotid artery and descending aorta were studied. The samples were grossly normal ( n = 10), presented circumscribed atherosclerotic plaques ( n = 19) or confluent atherosclerotic lesions ( n = 8). Tissues were fixed in formalin or snap frozen in liquid nitrogen. Sections were stained with conventional staining methods and immunohistochemically (smooth muscle cells, macrophages, and T and B lymphocytes). Medial thickness was measured with an ocular micrometer; inflammatory infiltrates and medial vascularization were assessed semiquantitatively. Increasing severity of intimal lesions was accompanied by a significant increase in medial inflammation and vascularization and by a significant decrease in medial thickness. The inflammatory infiltrates in the media consisted of macrophages and T lymphocytes, localized predominantly around vasa vasorum. In advanced atherosclerosis they spread more diffusely. Inflammatory cells of the intimal atheroma also penetrated the media. At sites of inflammation the media contained HLA-DR positive smooth muscle cells with loss of collagen. The media in confluent atherosclerosis was almost devoid of smooth muscle cells, with loss of collagen and focal fibrosis. We postulate that the inflammatory reaction in the media relates to atherosclerosis, has a remodelling effect on medial tissues and may cause medial attenuation.

Interferon-induced chronic active hepatitis?

A 54-year-old man with chronic B hepatitis was treated with interferon alfa. Despite resolution of the hepatitis B viral infection, he experienced severe jaundice, ascites, and encephalopathy. Further work-up showed hyperglobulinemia, chiefly immunoglobulin G, and positive smooth muscle and antinuclear antibodies. Because of these “autoimmune” features, the patient was treated with prednisone. One month later, a significant clinical and biochemical improvement was observed. A possible autoimmune mechanism induced by interferon alfa is proposed as the cause for the perpetuation of the necroinflammatory activity.

The effects of Bay K 8644 on myocardial relaxation and cAMP levels in perfused rat heart: Role of sympathetic neurotransmitter release

Bay K 8644 typifies a number of drugs known to act directly on voltage-dependent calcium channels to increase calcium current. Such effects probably underly the drug's positive inotropic action and smooth muscle stimulation. Although the effects of this compound on myocardial contractility have been extensively described, its action upon myocardial relaxation is not well established. Either no changes or a prolongation in ventricular relaxation have been mentioned. On the other hand, during the course of other experiments performed in our laboratory with the perfused rat heart (unpublished results), we observed that Bay K 8644 elicits a moderate but consistent relaxant effect. The present work was undertaken in an attempt to clarify the effect of Bay K 8644 upon myocardial relaxation. Evidence will be presented showing that in the perfused rat heart, the positive inotropic action of Bay K 8644 occurs together with a prolongation of the contraction time (TTP) without changes in time to half relaxation (t 1/2). However, an enhancement of ventricular relaxation was detected by the proportional greater increase in maximal velocity of relaxation (-T) with respect to maximal velocity of contraction (+T) and the shortening of the time constant of relaxation (tau). These actions occur associated with a significant increase in cAMP levels and phospholamban phosphorylation. Either the relaxant effect as well as the increments in cAMP and phospholamban phosphorylation were abolished when the hearts were depleted of norepinephrine by previous treatment with reserpine. Depletion of norepinephrine stores also decreases the positive inotropic effect of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

The immunohistochemistry of gastrointestinal stromal tumors. Evidence supporting an origin from smooth muscle.

To study the histogenesis of gastrointestinal stromal tumors, 79 cases were evaluated for desmin (DES), vimentin (VIM), and S-100 protein immunoreactivity by the avidin-biotin immunoperoxidase procedure on paraffin-embedded, Bouin's-fixed tissue sections. All tumors showed weak vimentin positivity. Trapped non-neoplastic smooth muscle and nerve twigs were often noted, particularly at the tumor periphery. Significant tumor S-100 positivity was not identified in our series. Similarly, glial fibrillary acidic protein (GFAP) immunoreactivity (performed in 11 desmin-negative tumors) was not detected within either gastrointestinal stromal tumors or enteric glial cells. Fifty-three percent (53%) of all gastrointestinal stromal tumors (GIST) displayed positive tumor cell desmin immunoreactivity. All 10 esophageal and all four colorectal tumors were diffusely desmin positive and unequivocal smooth muscle lesions. In contrast, only 17 of 37 (46%) benign and six of nine (67%) malignant gastric tumors were desmin positive. Similarly, four of 10 (40%) benign and one of nine (11%) malignant small-bowel tumors expressed desmin. Several gastric neoplasms with prominent nuclear palisading resembling schwannian Antoni A regions were nonetheless desmin positive. Epithelioid gastric tumors were more frequently desmin positive than nonepithelioid tumors; however, this positivity did not attain statistical significance. Two gastrointestinal stromal tumors that were desmin negative in paraffin-embedded material had detectable antigen in frozen sections. Gastric and small-bowel tumors measuring less than 3 cm were significantly more often desmin positive than those 3 cm or greater. We conclude that the method of fixation, tissue preparation, and immunostaining may significantly affect the expression of desmin. Although the histogenesis of gastrointestinal stromal tumors remains controversial, most of these tumors show evidence of smooth muscle differentiation.

Primary Sclerosing Cholangitis in Childhood

Thirteen children (8 female) with primary sclerosing cholangitis are described, in whom the diagnosis was confirmed by the presence of characteristic changes on endoscopic retrograde cholangiopancreatography. Nine had clinical features of chronic inflammatory bowel disease 1 mo to 5 yr before the onset of primary sclerosing cholangitis (6 patients) or appearing simultaneously with primary sclerosing cholangitis (3 patients). In 4 patients clinical evidence of chronic inflammatory bowel disease was absent but 1 of the 4 was found to have microscopic colitis in colonoscopic biopsy specimens. Biopsies were not performed in the remaining 3 patients. High immunoglobulin G concentrations and positive antinuclear or smooth muscle antibodies were present in all patients except 1 who had been given immunosuppressants. In 7 patients treated with immunosuppressants and followed up for 9 mo to 10 yr there was modest symptomatic improvement. This improvement was accompanied by a fall in transaminase levels in 6 of the patients and histologic improvement in 3 of 4 patients who had undergone biopsy. Greater use of endoscopic retrograde cholangiopancreatography in the last 6 yr led to the identification of 10 of these 13 cases, suggesting a higher incidence of primary sclerosing cholangitis in childhood than would appear from the literature.

IgA Class Antibody Against Human Jejunum in Sera of Children With Dermatitis Herpetiformis

Sera of 44 children with dermatitis herpetiformis with granular IgA deposits in the papillary dermis were investigated on cryostat sections of normal jejunum of three children aged 2 months, 1 year, and 10 years by indirect immunofluorescence. Eighteen of 25 patients on a normal diet had an IgA class antibody showing the following staining patterns on substrate jejunums: tubular positivity in the lamina propria--around the crypts, beneath the villous epithelial basement membrane, and in some instances in the middle of the villous also, following the capillary system of villi; coalescence of tubular positivity at the muscularis mucosae; and positive blood vessels and smooth muscle endomysium. Eleven of 18 children with positive sera were put on a gluten-free diet (GFD) and their sera became negative. One of these 11 patients was challenged with gluten and the antibody reappeared. Nineteen patients examined only on a GFD and 30 healthy blood donors did not have this antibody. There was no strict correlation between the titer of antibody and the severity of jejunal mucosal damage.

The sympathomimetic activity of (±)-pindolol at β 1- and β 2-adrenoceptor sites

In isolated right atrial and stilboestrol-pretreated uterine preparations from both guinea-pigs and rats, pindolol elicited propranolol-sensitive positive chronotropic and smooth muscle relaxant actions. Although the pD 2 values for pindolol (8.4–9.2) and (−)-isoprenaline (ISO, 8.4–8.7) fell within the same range in these preparations, the maximum responses to pindolol were less than 15% of those to the catecholamine. Thus, pindolol did not display any selectivity for agonistic actions at β 1- or β 2-adrenoceptors. In uteri taken from progesterone-pretreated rats, the pD 2 value for (−)-isoprenaline was 9.5 and that of pindolol 8.5. In these preparations the maximal relaxant effect of pindolol (approximately 50% E max ISO) was greater than that found in oestrogen-pretreated uteri. Thus, it appears that the maximal response of pindolol in vitro can be related to the pD 2 value for (−)-isoprenaline. In anaesthetized cats, intravenous pindolol elicited non-β-adrenoceptor-mediated increases in heart rate and decreases in soleus muscle contractility. The mechanism(s) underlying the latter actions are unknown.

Liver disease in rheumatoid arthritis and Sjøgren's syndrome. Prospective study using biochemical and serological markers of hepatic dysfunction.

Inter-relationships of biochemical and immunological tests of liver function have been studied in a prospective study of 216 patients with rheumatoid arthritis (RA), 32 patients with Sjogren's syndrome, and 27 patients with the sicca syndrome, and these results have been compared with those obtained 289 patients with osteoarthrosis or with a form of seronegative polyarthropathy. In general the prevalence of abnormalities in serum alkaline phosphatase, bromsulphthalein excretion, smooth muscle antibody, and mitochondrial antibody in the former three groups was higher than in patients with osteoarthrosis. Patients with Sjogren's syndrome with RA had a higher prevalence of abnormalities of bromsulphthalein excretion, salivary duct antibody than patients with the sicca syndrome. Patients with RA had a higher pervalence of rheumatoid factor than those with the sicca syndrome. Patients with a positive smooth muscle or mitochondrial antibody were found to have a higher prevalence of hepatomegaly and splenomegaly, of abnormal liver function tests, of other autoantibodies, and of histological abnromalitis of liver than those in whom these tests were negative.

Chronic active hepatitis and Graves' disease.

Two young females who had chronic active hepatitis associated with Graves' disease are reported. Both patients had high circulating levels of immunoglobulin G and 1 had a monoclonal gammopathy which disappeared with steroid therapy. The other patient had exophthalmos and high circulating levels of long acting thyroid stimulator (LATS) which were paralleled by very high antibody titers to respiratory syncytial virus, herpes simplex, and echovirus 9. Both patients showed positive smooth muscle antibody and negative Australia antigen. In 1 case LATS and smooth muscle antibodies were found in the pleural fluid. Both patients had a wide variety of abnormal antibodies.